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DIADS-2

Depression in Alzheimer’s Disease Study-2

DIADS-2 Handbook

Version 1.1

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Document distribution

Version Version date Distribution Distribution date

1.0 30 Apr 04 Research Group, via PPM 8 30 Apr 04

1.1 10 Apr 06 Research Group, via PPM 33 11 Apr 06

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Document history

Version 1.0 (30 April 2004)

Version 1.1 (10 April 2006)

Numerous editorial and wording changes were made throughout the document to improveclarity. Substantive modifications were made to the following sections:

1.2 Design summary: The entry criterion regarding stability of AD treatment was changed tomatch the 16 July 05 protocol revision, version 1.5

2.4.1 Clinical site responsibilities: The following changes were made to the clinical siteresponsibilities:• The responsibility of submitting treatment assignment forms to CC was added• Data entry functions were replaced by data transmission responsibilities

2.4.2 Chairman’s Office responsibilities: The list of topics of papers and ancillary studies are tobe managed by the CO internally

2.4.3 Coordinating Center responsibilities: The following changes were made to the CCresponsibilities:• FDA post marketing AE reports are to be provided by the CC• Forms CD is to be created and maintained by the CC• Data entry functions regarding centralization of database were added

4.5 DIADS-2 forms completed by visit: Case Summary (CF), Clinical Site Dementia StudyList (DL), and Modified ADCS-Clinical Global Impression of Change Baseline Evaluation(MA) forms were added

4.6.6 Week 12: The mADCS-CGIC scores for discontinuation of study treatment were correctedto match the MO form; scores for discontinuation are 1, 2, 3, or 4

5.2.2 Eligibility: An explanation of therapeutic dose adjustments was added to the inclusioncriterion regarding stable treatment of AD; further explanation of this statement was addedin a footnote

6.3 Randomization procedures: A bullet was added about confirming eligibility and assuranceof review signature on Screening Summary (SS) and Baseline History (BH) forms

7.2.1 Modified ADCS-Clinical Global Impression of Change Follow-up Evaluation: Scoreswere corrected to match the MO form; The continuum of the mADCS-CGIC scale valueslay on a continuum of “much worse” (1) to “much improved” (7)

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7.6.2 Instructions for neuropsychological testing: Instructions for the neuropsychological testswere divided into separate subsections

7.6.3 Missing data codes for neuropsychological assessments: Additional data entry codeswere added to capture reasons for missing information on neuropsychological tests

10.1 Dosing schedule of sertaline: Dosing adjustments, in most cases, are to be limited to tworeductions (100 mg to 75 mg and then to 50 mg if needed) or one increase (100 mg to 125 mg)

10.5 Treatment termination: The mADCS-CGIC scores for study treatment termination werecorrected; scores for discontinuation are 1, 2, 3, or 4

10.8.3 Safety reporting: Procedures for completing the safety report form were revised asfollows:• Instructions regarding cascading events were removed• Updates to serious adverse events are to be captured on separate forms instead of

editing previous safety report forms

10.8.4 Death reporting and documentation: Updates are to be made by completing a new DeathReport (DR) form rather than editing a previously submitted DR form

11.1 Study drug packing and labeling: Only one extra bottle is included in the drug kit;additional bottles are ordered upon request

11.2 Study drug supply: Procedures for requesting extra bottles were added

11.6.1 Expiring study drugs: Expiring study drug is to be returned to pharmacy instead of beingdestroyed at the clinical site

12.2.1 Collection, labeling, and storage procedures: Procedures for the collection and storage ofthe genetic sample were modified:• The type of tube for the genetic sample was specified as a EDTA Vacutainer tube®

• Procedures for processing blood were added: Tubes are to be gently inverted to mixthe anticoagulant with the blood

• Genetic samples are to be stored for up to four days at 5 C; they should no longer beN

frozen for up to one month at -20 C or three months at -70 CN N

12.3 DNA sample shipping procedures: Procedures for the shipment of the genetic samplewere changed:• The maximum storage time for genetic samples was reduced to four days• Samples are shipped at room temperature; samples are not to be frozen• The address for DNA specimens shipments was changed

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14.1 Identification numbers and codes: Statement was added clarifying that all individuals,eligible or ineligible, receive a patient ID at the time of consent; patient IDs given toineligible patients are not reused

14.4 Missing data: Data code “don’t know” (d) was added; additional codes were added tocapture reasons for missing information on neuropsychological tests

14.7 List of DIADS-2 forms by form abbreviation: Case Summary (CF), Clinical SiteDementia Study List (DL), and Modified ADCS-Clinical Global Impression of ChangeBaseline Evaluation (MA) forms were added

14.8 List of DIADS-2 forms by function: Case Summary (CF), Clinical Site Dementia StudyList (DL), and Modified ADCS-Clinical Global Impression of Change Baseline Evaluation(MA) forms were included

15.1 Database overview: Section 15 was revised per changes in data entry and database editingprocedure: Instead of entering data at the site, forms and form edits are to be transmitted tothe CC

15.2 Data entry and form transmission procedures were added

15.3 Data editing and form edit transmission procedures were added to describe proceduresfor database editing

16.2 Personnel certification: Functions in which personnel certification is required wereexpanded. Description of additional requirements for these functions were specified

16.4 Data quality surveillance: Double data system was removed as a data entry check. Astatement was added regarding the procedures for first three-month audit afterrandomization

17.1 Appendices: Manuscript on Alzheimer’s Association guidelines for consenting cognitivelyimpaired adults was updated

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Contents

1. Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1. Overview of DIADS-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2. Design summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

2. Study organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62.1. Overview of organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.2. Clinical sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.3. Resource centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.4. Responsibilities of clinical sites and resource centers . . . . . . . . . . . . . . . . . . . . . . . 10

2.4.1. Clinical site responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112.4.2. Chairman’s Office responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.4.3. Coordinating Center responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132.4.4. Project office at NIMH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152.4.5. Other resource centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

2.5. Steering Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172.6. Study Officers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

3. Recruitment procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203.2. Ethnic and racial minority recruitment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

4. Visit management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234.1. Overview of visit schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244.2. Visit time windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254.3. Table of visit time windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264.4. Data collection schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274.5. DIADS-2 forms completed by visit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284.6. Visit by visit overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

4.6.1. Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314.6.2. Baseline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324.6.3. Week 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344.6.4. Week 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354.6.5. Weeks 8 and 16 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364.6.6. Week 12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384.6.7. Week 20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394.6.8. Week 24 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404.6.9. Weeks 36 and 48 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424.6.10. Weekly telephone contacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434.6.11. Unscheduled visits and contacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

4.7. Procedures for missed or incomplete visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454.8. Procedures for ascertaining losses to follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

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5. Screening: procedures, eligibility, and resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475.1. Consent overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485.2. Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

5.2.1. Overview of eligibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505.2.2. Eligibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515.2.3. Ineligible patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535.2.4. Operationalization of Depression of Alzheimer’s Disease . . . . . . . . . . . . 545.2.5. Definition of primary caregiver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605.2.6. Definition of assisted living . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615.2.7. Medical screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

5.3. Rules about co-enrollment into other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

6. Administrative procedures at screening and baseline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646.1. Assignment of study identifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656.2. Patient and caregiver location information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666.3. Randomization procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

7. Outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687.1. Overview and schedule of outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697.2. Synopsis of depression measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

7.2.1. Modified ADCS-Clinical Global Impression of Change Follow-upEvaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

7.2.2. Cornell Scale for Depression in Dementia . . . . . . . . . . . . . . . . . . . . . . . . . 737.2.3. Neuropsychiatric Inventory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747.2.4. Daily Affect Diary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757.2.5. Criteria ratings other than dAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

7.3. Synopsis of functional measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777.3.1. ADCS-Activities of Daily Living . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787.3.2. Dependence Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797.3.3. Alzheimer’s Disease Related Quality of Life Scale . . . . . . . . . . . . . . . . . 80

7.4. Synopsis of caregiver measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817.4.1. Beck Depression Inventory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827.4.2. Medical Outcomes Study Short Form Health Survey . . . . . . . . . . . . . . . . 837.4.3. Caregiver Activity Survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847.4.4. Burden Questionnaire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

7.5. Health measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867.5.1. General Medical Health Rating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877.5.2. Vital signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

7.6. Neuropsychological measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907.6.1. Synopsis of neuropsychological tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917.6.2. Instructions for neuropsychological testing . . . . . . . . . . . . . . . . . . . . . . . . 92

7.6.2.1. Mini-Mental State Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937.6.2.2. Wechsler Memory Scale-Third Edition Digits Backwards . . . . . . . . . 94

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7.6.2.3. Letter Fluency Task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957.6.2.4. Cognitive subscale of the Alzheimer’s Disease Assessment Scale

(ADAS-Cog) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967.6.2.5. Symbol Digit Modalities Test (SDMT) . . . . . . . . . . . . . . . . . . . . . . . . 977.6.2.6. Finger Tapping Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987.6.2.7. Etch-A-Sketch Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997.6.2.8. Hopkins Adult Reading Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

7.6.3. Missing data codes for neuropsychological assessments . . . . . . . . . . . . . 101

8. Clinical management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1028.1. Good clinical practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038.2. Ongoing monitoring of medical history and concomitant medications . . . . . . . . . 1048.3. Use of allowed study concomitant psychotropics . . . . . . . . . . . . . . . . . . . . . . . . . 105

8.3.1. Trazodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068.3.2. Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107

9. Caregiver psychosocial intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089.1. Overview of caregiver psychosocial intervention . . . . . . . . . . . . . . . . . . . . . . . . . 1099.2. Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109.3. Baseline counseling procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119.4. Follow-up counseling procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129.5. Educational materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1139.6. Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149.7. Quality assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

10. Sertraline treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11610.1. Dosing schedule of sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11710.2. Patient and caregiver instruction about study medication . . . . . . . . . . . . . . . . . . . 11810.3. Side effect monitoring and management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11910.4. Treatment adherence monitoring and documentation . . . . . . . . . . . . . . . . . . . . . . 12010.5. Treatment termination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12110.6. Unmasking of treatment assignment before week 24 . . . . . . . . . . . . . . . . . . . . . . 12210.7. Unmasking of treatment assignment at 24 weeks . . . . . . . . . . . . . . . . . . . . . . . . . 12310.8. Adverse event reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

10.8.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12510.8.2. Reporting on the Baseline and Follow-up Medical History forms . . . . . . 12610.8.3. Safety reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12710.8.4. Death reporting and documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

11. Study drug management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12911.1. Study drug packing and labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13011.2. Study drug supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13111.3. Study drug storage and accounting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13211.4. Study drug issue and accounting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

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11.5. Return of study drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13411.6. Procedures for expiring drug and drug returned for pill counts . . . . . . . . . . . . . . 135

11.6.1. Expiring study drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13611.6.2. Study drug returned for pill counts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

12. DNA banking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13812.1. DNA consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13912.2. Collection, labeling, and storage of DNA samples . . . . . . . . . . . . . . . . . . . . . . . . 140

12.2.1. Collection, labeling, and storage procedures . . . . . . . . . . . . . . . . . . . . . . 14112.2.2. Label for DNA specimen tube and BC form . . . . . . . . . . . . . . . . . . . . . . 142

12.3. DNA sample shipping procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14312.4. Access to samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14512.5. Destruction of DNA samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

13. Sertraline blood levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14713.1. Consent for blood sertraline levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14813.2. Collection, labeling, and storage of sertraline level samples . . . . . . . . . . . . . . . . 149

13.2.1. Collection, labeling, and storage procedures . . . . . . . . . . . . . . . . . . . . . . 15013.2.2. Labels for sertraline level specimens and BC form . . . . . . . . . . . . . . . . . 151

13.3. Shipping of sertraline level samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15213.4. Access to plasma samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

14. Forms management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15514.1. Identification numbers and codes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15614.2. Format of data collection forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15814.3. Completing forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16014.4. Missing data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16114.5. Handling forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16214.6. Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16314.7. List of DIADS-2 forms by form abbreviation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16414.8. List of DIADS-2 forms by function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

15. Data management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16815.1. Database overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16915.2. Data entry and form transmission procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17015.3. Data editing and form edit transmission procedures . . . . . . . . . . . . . . . . . . . . . . . 171

16. Quality assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17216.1. Clinic certification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17316.2. Personnel certification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17416.3. Performance monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17516.4. Data quality surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17616.5. Site visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

17. Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18117.1. Research Consent for Cognitively Impaired Adults . . . . . . . . . . . . . . . . . . . . . . . 18217.2. Minority recruitment training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18817.3. Patient information about study medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

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DIADS-2 Handbook

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1. Design

1.1. Overview of DIADS-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.2. Design summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

DIADS-2 Handbook 1. Design

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1.1. Overview of DIADS-2

Depression in the context of Alzheimer’s disease (AD) is a significant public health problemthat has a series of serious adverse consequences for patients and their caregivers. There has beenlittle research into the course of treatment of depression association with AD. This is in part due tothe absence of validated operational criteria for defining depression in AD. Recently, the NationalInstitute of Mental Health (NIMH) convened an expert consensus panel to develop draft criteria fordepression of Alzheimer’s disease (NIMH-dAD) and to establish research priorities in this area. These criteria are intended to facilitate further studies of the course and treatment of depression inAD.

The primary aim of this proposed multi-center study is to determine whether individuals withNIMH-dAD respond to antidepressant treatment using the medication sertraline. The secondary aimis to further validate the dAD syndrome by closely following the course of trial participants over 6months and also by obtaining longer-term outcomes through an entire year. One hundred and thirtypatients meeting criteria for NIMH-dAD and their caregivers will be recruited into the study at fiveclinical centers: Johns Hopkins, University of Southern California, University of Rochester,University of Pennsylvania, and Medical University of South Carolina. After detailed baselinecharacterization, they will be randomized to treatment with sertraline or placebo. They will befollowed with in-person visits for 24 weeks and with telephone calls at 36 and 48 weeks. All patientsand caregivers will receive psychosocial interventions for Alzheimer’s disease and depression. Patient outcomes will include: global improvement, depression, quality of life, cognitive functioning,activities of daily living, behavioral disturbance, health care service use, and adverse events. Caregiver outcomes will include: depression, quality of life, and caregiving burden.

For the first study aim, analyses will compare the two treatment groups on patient and caregiveroutcomes. For the second study aim, analyses will examine the longitudinal course of depressivesymptoms rated on the well validated Cornell scale and of depressive syndromes in the context ofAlzheimer’s disease using three different definitions: NIMH-dAD, DSM-IV for major or minordepression, and “Alzheimer’s Associated Affective Disorder”, which was derived empirically fromthe Cache County study of Memory in Aging. The predictive validity of defining depression in ADusing a symptoms scale for each of these three syndromes will be assessed longitudinally against thevarious study outcomes, and against efficacy of response to anti-depressant treatment.


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1.2. Design summary

Title• Depression in Alzheimer's Disease Study-2 (DIADS-2)

Objectives• Primary objective

– To evaluate the efficacy and safety of sertraline for the treatment of depression inpatients with Alzheimer's disease

• Secondary objectives– To determine whether treatment of depression affects critical non-mood outcomes in

patients with Alzheimer's disease and in their caregivers– To characterize the syndrome of depression of Alzheimer's disease over time and its

effect on patients and caregivers

Type of trial• Randomized, multicenter clinical trial • Two parallel treatment groups • Masked• 1:1 assignment ratio

Study population• 130 patients who meet the DIADS-2 handbook criteria for “Depression of Alzheimer's

Disease”

Sample size and power calculations• Two-sided alpha = 0.05• Power = 92%• Detectable difference, or change in distribution of seven categories of global rating scale

(mADCS-CGIC): – 8%, 18%, 22%, 25%, 20%, 5%, 2% in the group assigned to placebo – 3%, 8%, 17%, 17%, 36%, 13%, 6% in the group assigned to sertraline• Estimated 15% non-compliance

Treatments• Sertraline, target dose 100 mg per day (range 25-125 mg per day), given orally +

Standardized caregiver psychosocial intervention• Placebo + Standardized caregiver psychosocial intervention

Stratification• Stratified by clinical site

1.2. Design summary


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Masking• Treatment assignment masked to participants and all site personnel, including physicians,

nurses, and neuropsychologists

Inclusion criteria• Dementia due to Alzheimer's disease by DSM-IV (TR), with MMSE score of 10-26 inclusive• Depression of Alzheimer’s disease as operationalized in the DIADS-2 handbook • Sufficiently good health to be treated using the study protocol in usual care circumstances• Provision of informed consent for participation in the study by patient, caregiver, or

surrogate (if necessary)• Availability of patient’s primary caregiver to accompany the patient to study visits and to

participate in the study• Sufficient fluency, of the patient and caregiver, in written and spoken English to participate

in study visits, neuropsychological testing, and other outcome assessments• Stability of AD treatment (i.e., memantine or cholinesterase inhibitors): No changes are to be

made to AD medications (e.g., starting or stopping treatment) in the 3 months prior torandomization, with the exception that dose adjustments within the therapeutic range (i.e.,total daily dose of > 10mg of memantine, > 5mg of donepezil, > 16mg per day ofgalantamine, or > 6mg per day of rivastigmine) are allowed as long as 1) the patient hasreceived the minimum therapeutic range dose of higher for at least 3 months; 2) the last dosechange was at least 1 month prior to randomization; and 3) no further dose adjustments areplanned during the study’s 24-week treatment phase

Exclusion criteria • Presence of a brain disease that might otherwise fully explain the presence of dementia, such

as stroke, Parkinson's disease, traumatic brain injury, multiple sclerosis, and similar• Clinically significant hallucinations: a score of $4 on the NPI hallucinations domain, or the

need, in the opinion of the study psychiatrist, for antipsychotic medication• Clinically significant delusions that, in the opinion of the psychiatrist, require antipsychotic

medication• Treatment with antipsychotics in the 2 weeks prior to randomization• Contraindication for treatment with sertraline, in the opinion of the attending psychiatrist

(e.g., a history of dangerous or unacceptable side effects with sertraline treatment)• Failure of treatment with sertraline in the current episode of depression after convincing

evidence of a "good trial" (e.g., 8 weeks at the highest tolerated dose)• Treatment with a medication that would prohibit the safe concurrent use of sertraline, such as

selegeline • Need for hospitalization for depression, or suicidality• Residence in a nursing facility• Current participation in a clinical trial or in any study that may add a significant burden or

affect neuropsychological or other study outcomes• Current treatment with antipsychotics, anticonvulsants, other antidepressants,

benzodiazepines, and other psychotropic medications• Any condition that, in the opinion of the study physician, makes it medically inappropriate or

risky for the participant to enroll in the trial

1.2. Design summary


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Criterion for study treatment discontinuation• Patients who are not better, as determined by the mADCS-CGIC rating (scores of 1 to 4),

will be advanced to the "rescue" treatment at week 12

Duration of follow-up• 24 weeks in-person visits and 48 weeks phone follow-up

Data collection schedule• Scheduled in-person visits (weeks 2, 4, 8, 12, 16, 20, and 24 after randomization)• Telephone contacts (weekly for the first 8 weeks after randomization except for weeks with

in-person visits) • Telephone follow-up (36 and 48 weeks)

• Daily Affect Diaries (for 7 days) after in-person visits at baseline and weeks 4, 8, 12, 16,and 20

Outcomes• Patient

- Changes in mood - Differences of cognitive, function, and quality of life measures - Mortality - Adverse events

• Caregiver - Mood - Burden - Quality of life

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2. Study organization

2.1. Overview of organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.2. Clinical sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82.3. Resource centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92.4. Responsibilities of clinical sites and resource centers . . . . . . . . . . . . . . . . . . . . . . . . . . 102.5. Steering Committee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172.6. Study Officers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

DIADS-2 Handbook 2. Study organization

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2.1. Overview of organization

C Operating units of DIADS-2 are the clinical sites and resource centersC Main decision-making body is the Steering Committee• Study Officers address day-to-day issues in the conduct of the trial• Data and safety monitoring will be conducted by a National Institute of Mental Health boardC Additional committees are formed for special projects, as needed


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2.2. Clinical sites

Abbreviation Institution

JHU Johns Hopkins University

MUSC Medical University of South Carolina

PENN University of Pennsylvania

ROCH University of Rochester

USC University of Southern California


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2.3. Resource centers

Abbreviation Name Site

CO Chairman's Office Johns Hopkins HospitalBaltimore, MD

CC Coordinating Center Center for Clinical TrialsJohns Hopkins UniversityBloomberg School of Public HealthBaltimore, MD

PITT Laboratory for DNA banking Western Psychiatric Institute and Clinicand sertraline collections Geriatric Psychopharmacology

University of PittsburghPittsburgh, PA

PHAR Drug distribution center Investigational Drug ServiceJohns Hopkins PharmacyBaltimore, MD

PC Pharmaceutical company Pfizer Inc.New York, NY

NIMH Project office National Institute of Mental HealthBethesda, MD


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2.4. Responsibilities of clinical sites and resource centers

2.4.1. Clinical site responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112.4.2. Chairman’s Office responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122.4.3. Coordinating Center responsibilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132.4.4. Project office at NIMH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152.4.5. Other resource centers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16



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2.4.1. Clinical site responsibilities

• Recruit and certify staff as required to conduct DIADS-2• Submit protocol, consent, and other related documentation to local IRB• Ensure protocol is conducted in compliance with IRB regulations• Provide CC with documentation as necessary• Send Treatment Assignment (TA) form to CC and pharmacy upon randomizing a patient• Provide education and carry out the consent process for patients and caregivers• Treat and follow recruited participants according to the approved protocol• Collect trial data on DIADS-2 forms and send data to the CC on a regular basis• Respond to edit queries and submit form edits to the CC• Participate in Research Group (RG) meetings and other meetings as appropriate• Maintain drug kit accounting records• Collect data on treatment adherence via pill counts and patient caregiver report



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2.4.2. Chairman’s Office responsibilities

Administrative• Schedule conference calls• Schedule and make arrangements for meetings, including the annual meetings• Prepare minutes from conference calls and meetings• Interact with Pfizer regarding donation of study drug• Participate in site visiting as necessary• Manage IND related correspondence• Prepare and submit annual reports to the NIMH• Distribute materials for neuropsych battery administration• Develop and distribute recruitment materials• Provide support to DSMB

Outcomes component• Train and certify clinical site staff in assessment of patient and caregiver outcomes in

collaboration with CC• Act as liaison with clinical sites on questions and issues related to outcomes• Perform quality control audits in conjunction with CC• Create training video• Oversee the caregiver psychosocial intervention

Publications and presentations• Order and distribute manuscript reprints• Prepare and maintain list of topics for papers• Maintain progress report on initiated main trial and ancillary study papers



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2.4.3. Coordinating Center responsibilities

Administrative• Prepare agenda for conference call and meetings• Prepare and distribute meeting materials for Steering Committee, DSMB, Investigator, and

other study meetings• Develop study guidelines and policies in conjunction with CO• Act as liaison with central pharmacy regarding study drug ordering and distribution• Perform quality control checks for study medicines and placebo• Unmask treatment at the end of the study

Study documents• Develop and maintain study documents

- Protocol- Forms Notebook- Handbook- Policy and Procedures Memoranda

• Maintain official study chronology and study curriculum vitae• Serve as repository for all study materials• Create and maintain forms CD

Certification• Certify clinical sites• Train, test, and certify staff• Maintain ongoing re-certification

Data system and data management• Generate treatment assignment system envelopes and emergency unmasking envelopes• Create and maintain the study database• Receive and process data from sites• Institute and maintain data quality assurance procedures

- Computerized data edits- Data audits

2.4. Responsibilities of clinical sites and resource centers2.4.3. Coordinating Center responsibilities


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Interaction with field sites• Communicate with clinical sites regarding changes to protocol and other study documents,

safety reports, DSMB recommendations, and status of the trial• Answer questions and interact with clinical site staff on an as-needed basis• Plan and conduct site visits

Reports• Prepare interim data monitoring reports for the DSMB• Organize and manage submissions (e.g. safety reports, changes in protocol, annual reports,

or new investigator) to the drug company• Manage distribution of adverse event reports for submission to IRBs• Prepare and distribute monthly status reports• Prepare and distribute site visit reports• Provide post-marketing reports to the FDA

Data analysis• Conduct interim and final analyses

Ancillary studies• Coordinate the review and implementation of ancillary studies

Publications and presentations• Prepare slides for presentations• Coordinate submissions to national repository



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2.4.4. Project office at NIMH

• Serve as member of the Study Officer, Steering Committee, DSMB, and Research Group• Act as liaison between the sponsor and Research Group• Provide administrative and fiscal advice• Participate in site visits if desired• Participate in the design, conduct, and analysis of DIADS-2



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2.4.5. Other resource centers

Pharmaceutical company: Pfizer• Provide study drug and matching placebo

Drug distribution center: Johns Hopkins Pharmacy• In conjunction with CO, order drug and matching placebo from the pharmaceutical

company• Prepare drug kits according to the randomization scheme• Ship drug kits to sites as needed


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2.5. Steering Committee

Overview• The Steering Committee is the primary decision-making body of DIADS-2• The Steering Committee is a representative body of the investigators

Responsibilities• Make decisions regarding:

– Design issues– Study procedures– Allocation of study resources– Priorities for meeting competing demands of the study

• Review study progress and act to correct deficiencies in the data collection or analysisprocedures

• Review and approve the publication and study findings• Review and approve ancillary studies• Receive and act upon recommendations from the DSMB

Composition

Co-chairs Constantine Lyketsos, MD, MHS (CO)Barbara Martin, PhD (CC)

Other voting members Ira Katz, MD (PENN)Jacob Mintzer, MD (MUSC)Anton Porsteinsson, MD (ROCH)Paul Rosenberg, MD (JHU)Lon Schneider, MD (USC)George Niederehe, PhD (NIMH)

Non-voting members Crystal Evans, MS (CO)Anne Shanklin, MA, CCRP (CC)Clinical coordinator representative, TBAElizabeth Zachariah (NIMH)Peter Rabins, MD (CO)Cynthia Munro, PhD (CO)Curtis Meinert, PhD (CC)


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2.6. Study Officers

Overview• The Study Officers serve as the agents of the Steering Committee in carrying out the day-to-

day administrative responsibilities of the trial and in reviewing and preparing issues forconsideration by the Steering Committee

Responsibilities• Be the branch of the Steering Committee charged with overseeing and addressing the day-to-

day issues in the conduct of the trial• Review and prepare issues, policies, and proposals for consideration by Steering Committee• Be responsible for implementation of Steering Committee decisions• Address other managerial and administrative issues as needed• Be accountable to the Steering Committee and report to the Steering Committee

Composition

Study chair Constantine Lyketsos, MD, MHS (CO)

Study vice chair Lon Schneider, MD (USC)

CC director Barbara Martin, PhD (CC)

NIMH collaborator George Niederehe, PhD (NIMH)

Rotating members (Rotation to occur annually in the order listed) Paul Rosenberg, MD (JHU)

Ira Katz, MD, PhD (PENN)Anton Porsteinsson, MD (ROCH)Jacobo Mintzer, MD (MUSC)

DIADS-2 Handbook

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3. Recruitment procedures

3.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203.2. Ethnic and racial minority recruitment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

DIADS-2 Handbook 3. Recruitment procedures

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3.1. Overview

DIADS-2 study participants will be typically outpatients with AD, recruited from outpatientclinics at study sites at Johns Hopkins Hospital, Medical University of South Carolina, University ofPennsylvania, University of Rochester, and University of Southern California. All sites operateoutpatient memory or geriatric psychiatry clinics where patients who might be eligible for DIADS-2.Each site has at least one outpatient location from in which recruitment will be based, and some sitesmay have satellites.

All DIADS-2 sites are experienced with the recruitment of participants with Alzheimer's diseaseand psychiatric symptoms into clinical trials. Therefore, recruitment procedures may vary slightlyfrom site to site. Sites will develop their own recruitment plans and be responsible for monitoringrecruitment success on a regular basis. The clinical site directors, CC, and CO will monitorrecruitment success on a monthly basis.

In general, each site will recruit from several sources:

• Patients from the established outpatient clinic patients • Patients seen in the clinical sites for the first time • Residents of assisted living facilities affiliated with the site • Participants referred by local physicians• Participants recruited from targeted advertisements in local media

For participants recruited from patients seeking clinical care at a given site, recruitment activitieswill include chart review, recruitment over the phone, discussion with physicians, and recruitment inthe clinic waiting areas. Recruitment from assisted living facilities will be in collaboration with theoperators of such facilities. It is up to the sites to decide where they will see participants recruitedfrom assisted living facilities. Evaluation and follow-up at the facilities will be permitted. In allcases, the specific recruitment procedures used will be in accordance with HIPAA regulations andwill be approved by local IRBs.

The Chairman's Office has created a set of recruitment materials (i.e., brochure, sampleadvertisements, recruitment letter to physicians) that the sites may use as part of their recruitmentactivities. These have been developed in collaboration with the DIADS-2 study consultantsregarding ethnic and racial minority recruitment and are appropriate for the diverse ethnic and racialgroups that DIADS-2 is attempting to recruit. Sites will supplement these with additional materials asneeded. In all cases, recruitment materials must be IRB approved prior to being used as part of studyactivities. These materials will primarily be used to recruit from doctors’ offices.

3.1. Overview


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Some of the recruitment materials were created to be advertised through the media; however, it isexpected that media-based recruitment will not be needed and that most of the recruitment can beaccomplished from clinical sources locally. Therefore, each site will consider the need to recruitusing the media and will develop its own plans if the site's experience suggests that this type ofrecruitment will be helpful. The DIADS-2 study leadership will reconsider the need for a largermedia effort if currently planned recruitment activities are not successful.


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3.2. Ethnic and racial minority recruitment

The DIADS-2 leadership and individual site staff are committed to enrolling participantsrepresentative of the population aged 65 and older in their respective communities. The study-widegoal is to recruit 23 African-American and 14 Hispanic patients of the total 130 study recruits. Thesespecific targets for recruitment will be reviewed quarterly by the Study Chair and annually during theresearch group's meetings (see the "Ethnic and Racial Minority Recruitment Plan" submitted toNIMH as part of the "Just in Time" portions of the grant application). The activities involved inensuring that DIADS-2 participants reflect the population of individuals 65 and older includeconsultation by experts, specific training in recruitment of minorities, development of culturallyspecific educational and recruitment materials, and development of site specific detailed recruitmentplans and targets. Site specific recruitment plans in this area will be developed during the first studyinvestigators’ meeting and will be reviewed and updated on an annual basis.

DIADS-2 Handbook

23

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4. Visit management

4.1. Overview of visit schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244.2. Visit time windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254.3. Table of visit time windows . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264.4. Data collection schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274.5. DIADS-2 forms completed by visit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284.6. Visit by visit overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304.7. Procedures for missed or incomplete visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454.8. Procedures for ascertaining losses to follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

DIADS-2 Handbook 4. Visit management

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4.1. Overview of visit schedule

The enrollment process for DIADS-2 will involve two in-person visits. The first visit is thescreening visit. The second visit is the baseline visit.

Follow-up will include both scheduled and unscheduled visits and contacts. The three types ofscheduled visits and contacts are:

C Scheduled in-person follow-up visits (weeks 2, 4, 8, 12, 16, 20, and 24) C Telephone contacts (weeks 1, 3, 5, 6, and 7)C Telephone follow-up (weeks 36 and 48)

Target dates for in-person follow-up visits and telephone contacts are calculated from the date ofbaseline. The time intervals around visit target dates are referred to as visit windows. Visit windowsare outlined in section 4.3.

The two types of unscheduled follow-up visits and contacts are:

C Patient or caregiver-initiated in-person visitsC Patient or caregiver-initiated phone calls


25

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4.2. Visit time windows

Screening and baseline visitsScreening and baseline visits can occur on the same day. However, no more than 2 weeks can

elapse between screening and baseline. Target dates and allowable time windows for in-personfollow-up visits and telephone contacts are then calculated from the date of randomization (baselinevisit).

Scheduled in-person follow-up visitsScheduled in-person follow-up visits are to occur at 2 weeks and 4 weeks after randomization,

and then every 4 weeks thereafter, up to 24 weeks. Clinic personnel should make every effort toschedule patients in as close as possible to the target dates. However, the target dates have allowabletime windows around them for each visit. The target dates and allowable time windows for visits areillustrated in the table of visit time windows (section 4.3). The allowable time windows arecontiguous; that is, one in-person follow-up visit window is always open at any given time. Theclosing of the allowable time window for one visit and the opening of the allowable time window forthe next occurs at the midpoint between the target dates for the two consecutive visits. The purposeof contiguous allowable time windows is to permit as many in-person visits as possible to becompleted and to thereby minimize the amount of missing safety and efficacy data. The onlyrestriction on the allowable time windows are minimum separations between scheduled, in-personfollow-up visits (also given in the table in section 4.3).

Scheduled telephone follow-up contactsScheduled telephone follow-up contacts are to occur at 36 and 48 weeks after baseline. The

minimum time separation between the 36-week call and the last in-person visit, and between the twotelephone contacts, is 6 weeks. Visit time windows for the scheduled telephone follow-up contactsare shown in section 4.3.

Unscheduled visits or telephone contactsUnscheduled visits or telephone contacts may occur as needed. No time windows or minimum

time separations are imposed for such visits or contacts.


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4.3. Table of visit time windows

Visit ID Type of visit Target time Allowed window

SCR Screening -1 week 0 to 2 weeks before baseline

BL Baseline 0 week

F02 In-person follow-up 2 weeks 2 weeks ± 1 week

F04 In-person follow-up 4 weeks 4 weeks - 1 week4 weeks + 2 weeks

F08 In-person follow-up 8 weeks 8 weeks ± 2 weeks





T36 Telephone follow-up 36 weeks 36 weeks ± 6 weeks

T48 Telephone follow-up 48 weeks 48 weeks ± 6 weeks

Minimum time separation required between in-person visits:

Visit ID Timeseparation

SCR - BL None

BL - F02 1 week

F02 - F04 1 week

F04 - F08 2 weeks

All other intervalsbetween in-person follow-ups

2 weeks

F24 - T36 6 weeks

T36 - T48 6 weeks


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4.4. Data collection schedule

SCR BLvisit visit Follow-up contacts (weeks from BL)-1 0 2 4 8 12 16 20 24 36 48

Procedures

Consent T T T T T T T T T T T

History, or interim history T T T T T T T T T T T

Vital signs, ongoing medical

monitoring T T T T T T T T T T T

Physical, neurological,

mental state exams T . . . . . . . . . .

Blood banking for DNA . T . . . . . . . . .

Blood collection for sertraline . . . T . T . . . . .

levels

Review of compliance . . T T T T T T T . .

Review of medication use T T T T T T T T T . .

Review inclusion/exclusion T T . . . . . . . . .

Review of adverse events . . T T T T T T T . .

Dispensing of study drug . T T T T T T T . . .

Caregiver psychosocial

intervention . T . T T T T T T . .

Criteria for dAD,

DSM-IV major or minor

depression, “AAAD” . T T T T T T T T . .

Mood Outcome Measures

mADCS-CGI . T T T T T T T T . .

Cornell Scale for Depression . T T T T T T T T . .

NPI . T T T T T T T T T T

Daily Affect Diary (7 days) . T . T T T T T . . .

Non-Mood Patient Measures

ADCS-ADL scale . T . . T . T . T T T

Dependence Scale . T . . T . T . T . .

ADRQL . T . . T . T . T . .

Neurocognitive Battery

NART-R . T . . . . . . . . .

Mini-Mental State Exam . T . . T . T . T . .

ADAS-Cog . T . . T . T . T . .

Digit Span Subtest . T . . T . T . T . .

Symbol Digit Modalities Test . T . . T . T . T . .

Finger Tapping Test . T . . T . T . T . .

Letter Fluency . T . . T . T . T . .

Etch-a-Sketch Test . T . . T . T . T . .

Caregiver Measures

Beck Depression Questionnaire . T . . T . T . T . .

SF-12 . T . . T . T . T . .

Burden Questionnaire . T . . T . T . T . .

Caregiver Activity Survey . T . . T . T . T . .

General Medical Health

Rating . T T T T T T T T . .

Medication Adherence . . T T T T T T T . .


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4.5. DIADS-2 forms completed by visit

SCRvisit-1

BLvisit

0

Follow-up contacts (weeks from BL)

2 4 8 12 16 20 24 36 48

Alzheimer-Associated AffectiveDisorder Criteria Rating (AC) . AC AC AC AC AC AC AC AC

. .

Activities of Daily Living Inventory (AD) . AD . . AD . AD . AD AD AD

Drug Kit Accounting Log (AL)* . . . . . . . . . . .

Blood Collection (BC) . BC . BC . BC . . . . .

Beck Depression Inventory (BD) . BD . . BD . BD . BD . .

Baseline Medical History (BH) . BH . . . . . . . . .

Blood Specimen Shipment Notification (BN)* . . . . . . . . . . .

Burden Questionnaire (BQ) . BQ . . BQ . BQ . BQ . .

Caregiver Activity Survey (CA) . CA . . CA . CA . CA . .

Clinic Certification (CC)* . . . . . . . . . . .

Case Summary (CF)2 . . . . . . . . . . .

Conflict of Interest Disclosure (CI)* . . . . . . . . . . .

Cornell Scale for Depression in Dementia (CS) . CS CS CS CS CS CS CS CS . .

Daily Affect Diary (DA)§ . DA . DA DA DA DA DA . . .

Depression of Alzheimer’s Disease Criteria Rating (DC)

. DC DC DC DC DC DC DC DC . .

Death Documentation (DD)* . . . . . . . . . . .

Clinical Site Dementia Study List (DL)* . . . . . . . . . . .

Dependence Scale (DP) . DP . . DP . DP . DP . .

Death Report (DR)† . DR DR DR DR DR DR DR DR DR DR

Request to Destroy DNA Sample (DS)† . DS DS DS DS DS DS DS DS DS DS

Form Edit List (FE)* . . . . . . . . . . .

Follow-up Medical History (FH) . . FH FH FH FH FH FH FH . .

General Medical Health Rating (GM) . GM GM GM GM GM GM GM GM . .

Ineligibility Summary (IS)† IS IS . . . . . . . . .

Abridged Knowledge Assessment (KA)* . . . . . . . . . . .

4.5. DIADS-2 forms completed by visit


29

SCRvisit-1

BLvisit

0

Follow-up contacts (weeks from BL)

2 4 8 12 16 20 24 36 48

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Modified ADCS-Clinical Global Impression of Change Baseline Evaluation (MA)

. MA . . . . . . . . .

Major Depression Criteria Rating (MD) . MD MD MD MD MD MD MD MD . .

Minor Depression Criteria Rating (MI) . MI MI MI MI MI MI MI MI . .

Modified ADCS-Clinical Global Impression of Change Follow-up Evaluation (MO)

. .

MO MO MO MO MO MO MO . .

Medical Outcomes Study Short FormHealth Survey (MS) . MS . . MS . MS . MS . .

Missed or Incomplete Visit/TelephoneContact (MV)*

. . . . . . . . . . .

Neuropsychiatric Inventory (NP) . NP NP NP NP NP NP NP NP NP NP

Neuropsychological Test Summary (NS) . NS . . NS . NS . NS . .

Personnel Certification (PC)* . . . . . . . . . . .

Patient and Caregiver Location (PL)‡ PL . . . . . . . . . .

Alzheimer’s Disease Related Quality Of Life Scale (QL) . QL . . QL . QL . QL . .

Study Drug Issue and Return (SD) . SD SD SD SD SD SD SD SD . .

Safety Report (SR)† . . SR SR SR SR SR SR SR . .

Screening Summary (SS) SS . . . . . . . . . .

Treatment Assignment (TA) . TA . . . . . . . . .

Telephone Follow-up (TF) . . . . . . . . . TF TF

Transmittal Form (TM)* . . . . . . . . . . .

Treatment Termination (TT)† . . TT TT TT TT TT TT . . .

Treatment Unmasking (TU)‡ . . . . . . . . TU . .

*Use as needed

†Use as needed at the indicated visits

‡Use at the indicated visit in addition to using as needed

§Distribute at indicated visits

2Completed for the first two patients at each site


30

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4.6. Visit by visit overview

4.6.1. Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314.6.2. Baseline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324.6.3. Week 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344.6.4. Week 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354.6.5. Weeks 8 and 16 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364.6.6. Week 12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384.6.7. Week 20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394.6.8. Week 24 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404.6.9. Weeks 36 and 48 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424.6.10. Weekly telephone contacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434.6.11. Unscheduled visits and contacts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44



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4.6.1. Screening

At the screening visit, study staff will:C Discuss study with prospective patient and caregiver and obtain consent from bothC Obtain patient’s medical history• Obtain patient’s social security number for death registry monitoringC Perform physical, neurological, and mental state exams on the patientC Collect patient’s vital signsC Assess and record eligibility• Obtain name and address of personal physician, if any• Administer Mini-Mental State Exam (MMSE)

Required formsC Screening Summary (SS) formC Patient and Caregiver Location (PL) form



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4.6.2. Baseline

At the baseline visit, study staff will:C Verify ongoing consentC Obtain DNA consent, if separate from main consentC Review eligibilityC Record interim medical historyC Collect vital signs• Collect blood sample for DNA banking, if DNA consent is signedC Collect General Medical Health RatingC Ascertain mood outcome measures:

- Modified ADCS-Clinical Global Impression Baseline Evaluation- Cornell Scale for Depression in Dementia- Neuropsychiatric Inventory

C Rate criteria for depressionC Ascertain non-mood patient measures:

- ADCS-Activities of Daily Living Scale- Dependence Scale- Alzheimer’s Disease Related Quality of Life

C Administer the neurocognitive battery:- Mini-Mental State Exam- Cognitive subscale of the Alzheimer’s Disease Assessment Scale- Digit Span Subtest - Symbol Digit Modalities Test- Finger Tapping Test- Letter Fluency - Etch-a-Sketch Test

- National Adult Reading Test-RevisedC Ascertain caregiver measures:

- Caregiver Activities Survey- Beck Depression Inventory- Medical Outcomes Study Short Form Health Survey- Burden Questionnaire

• Hand out Daily Affect DiaryC Obtain the randomized treatment assignmentC Dispense study medications and review instructions for medication useC Provide caregiver psychosocial interventionC Review visit schedule, compliance monitoring, and adverse event reporting



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Required formsC Baseline Medical History (BH)C Neuropsychological Test Summary (NS)C Depression criteria rating forms:

- Alzheimer-Associated Affective Disorder Criteria Rating (AC)- Depression of Alzheimer’s Disease Criteria Rating (DC)- Major Depression Criteria Rating (MD)- Minor Depression Criteria Rating (MI)

C Mood outcome measures forms:- Cornell Scale for Depression in Dementia (CS)- Neuropsychiatric Inventory (NP)

C Modified ADCS-Clinical Global Impression Baseline Evaluation (MA)C Non-mood patient measures forms:

- ADCS Activities of Daily Living Inventory (AD)- Dependence Scale (DP)- Alzheimer’s Disease Related Quality of Life Scale (QL)

C Caregiver measure forms:- Beck Depression Inventory (BD)- Medical Outcomes Study Short Form Health Survey (MS)- Burden Questionnaire (BQ)- Caregiver Activity Survey (CA)

C General Medical Health Rating (GM)C Blood Collection (BC)C Treatment Assignment (TA)C Study Drug Issue and Return (SD)C Daily Affect Diary (DA)

MaterialsC Neuropsychological test booklet for baseline visit and testing materials



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4.6.3. Week 2

At week 2, study staff will:C Verify ongoing consentC Review interval medical historyC Review and record current medicationsC Collect vital signsC Collect General Medical Health RatingC Review compliance and adverse eventsC Receive and record the amount of unused study drugC Dispense new supply of study drugC Refer patient to a study physician if participant exhibits a notable change in condition or is

medically unstable• Collect previously distributed Daily Affect DiaryC Rate depression criteria• Ascertain mood outcomes:

- Modified ADCS-Clinical Global Impression of Change- Cornell Scale for Depression in Dementia- Neuropsychiatric Inventory

Required forms• Follow-up Medical History (FH)C Depression criteria rating forms:


C Mood outcome measures:- Modified ADCS-Clinical Global Impression of Change Follow-up Evaluation (MO)- Cornell Scale for Depression in Dementia (CS)- Neuropsychiatric Inventory (NP)

• General Medical Health Rating (GM)C Study Drug Issue and Return (SD)



35


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4.6.4. Week 4


medically unstable• Distribute new Daily Affect Diary booklet• Collect blood for sertraline levels• Provide caregiver psychosocial interventionC Rate depression criteria• Ascertain mood outcomes:

- Modified ADCS-Clinical Global Impression of Change - Cornell Scale for Depression in Dementia- Neuropsychiatric Inventory

Required forms• Follow-up Medical History (FH)C Depression criteria rating forms:



• General Medical Health Rating (GM)• Blood Collection form (BC)C Study Drug Issue and Return (SD)• Daily Affect Diary (DA)



36


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4.6.5. Weeks 8 and 16

At weeks 8 and 16, study staff will:C Verify ongoing consentC Review interval medical historyC Review and record current medicationsC Collect vital signsC Collect General Medical Health RatingC Review compliance and adverse eventsC Receive and record the amount of unused study drugC Dispense new supply of study drugC Refer patient to a study physician if participant exhibits a notable change in condition or is

medically unstable• Collect previously distributed Daily Affect Diary• Distribute new Daily Affect Diary • Provide caregiver psychosocial interventionC Rate depression criteria• Ascertain mood outcomes:


• Ascertain non-mood outcomes:- ADCS-Activities of Daily Living Scale- Dependence Scale- Alzheimer’s Disease Related Quality of Life

• Administer the neurocognitive battery:- Mini Mental State Exam- Cognitive subscale of the Alzheimer’s Disease Assessment Scale- Digit Span Subtest - Symbol Digit Modalities Test- Finger Tapping Test- Letter Fluency - Etch-a-Sketch Test

• Assess caregiver measures:- Caregiver Activities Survey- Beck Depression Inventory- Medical Outcomes Study Short Form Health Survey- Burden Questionnaire

4.6. Visit by visit overview4.6.5. Weeks 8 and 16


37


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Required formsC Follow-up Medical History (FH)C Neuropsychological Test Summary (NS)C Depression criteria rating forms:



C Non-mood patient measure forms:- ADCS-Activities of Daily Living Inventory (AD)- Dependence Scale (DP)- Alzheimer’s Disease Related Quality of Life Scale (QL)


C General Medical Health Rating (GM)C Study Drug Issue and Return (SD)C Daily Affect Diary (DA)

MaterialsC Neuropsychological test booklet for week 8 or 16 and testing materials



38


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4.6.6. Week 12


medically unstableC Collect previously distributed Daily Affect DiaryC Distribute new Daily Affect DiaryC Assess patient’s response of the depressive disturbance on mADCS-CGICC Discontinue study treatment for patients who do not show improvement on mADCS-CGIC

(scores 1, 2, 3, or 4) and advance patients to “rescue” treatmentC Collect blood for sertraline levelsC Provide caregiver psychosocial interventionC Rate depression criteriaC Ascertain mood outcomes:


Required formsC Follow-up Medical History (FH)C Depression criteria rating forms:


C Mood outcome measure forms:- Modified ADCS-Clinical Global Impression of Change Follow-up Evaluation (MO)- Cornell Scale for Depression in Dementia (CS)- Neuropsychiatric Inventory (NP)

C General Medical Health Rating (GM)C Blood Collection (BC)C Study Drug Issue and Return (SD)C Daily Affect Diary (DA)



39


(2:55 pm) Wed, 8 Nov 2006 /hll



40


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4.6.7. Week 20


medically unstableC Collect previously distributed Daily Affect DiaryC Distribute new Daily Affect Diary C Provide caregiver psychosocial interventionC Rate depression criteriaC Ascertain mood outcomes:


Required formsC Follow-up Medical History (FH)C Depression criteria rating forms:



C General Medical Health Rating (GM)C Study Drug Issue and Return (SD)C Daily Affect Diary (DA)



41


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4.6.8. Week 24

At week 24, study staff will:C Verify ongoing consentC Review interval medical historyC Review and record current medicationsC Collect vital signsC Collect General Medical Health RatingC Review compliance and adverse eventsC Receive and record the amount of unused study drugC Refer patient to a study physician if participant exhibits a notable change in condition or is

medically unstableC Collect previously distributed Daily Affect DiaryC Unmask treatment assignment and assign patient to standard careC Provide caregiver psychosocial interventionC Rate depression criteriaC Ascertain mood outcomes:


C Ascertain non-mood outcomes:- ADCS-Activities of Daily Living Scale- Dependence Scale- Alzheimer’s Disease Related Quality of Life

C Administer the neurocognitive battery:- Mini-Mental State Exam- Cognitive subscale of the Alzheimer’s Disease Assessment Scale- Digit Span Subtest - Symbol Digit Modalities Test- Finger Tapping Test- Letter Fluency - Etch-a-Sketch Test

C Assess caregiver measures:- Caregiver Activities Survey- Beck Depression Inventory- Medical Outcomes Study Short Form Health Survey- Burden Questionnaire

4.6. Visit by visit overview4.6.8. Week 24


42


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Required formsC Follow-up Medical History (FH)C Neuropsychological Test Summary (NS)C Depression criteria rating forms:



C Non-mood patient measure forms:- ADCS-Activities of Daily Living Inventory (AD)- Dependence Scale (DP)- Alzheimer’s Disease Related Quality of Life Scale (QL)


C General Medical Health Rating (GM)C Study Drug Issue and Return (SD)C Treatment Unmasking (TU) (received from CC)

MaterialsC Neuropsychological test booklet for week 24 and testing materials



43


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4.6.9. Weeks 36 and 48

At weeks 36 and 48, study staff will gather the following information from phone contacts:C Vital statusC Medical statusC Current residenceC Reasons for transition of residence, if appropriateC Neuropsychiatric InventoryC Activities of Daily LivingC Death registry monitoring for those participants who cannot be located or contacted

Required formsC Telephone Follow-up (TF)C Neuropsychiatric Inventory (NP)C ADCS-Activities of Daily Living Inventory (AD)



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4.6.10. Weekly telephone contacts

The purpose of the weekly telephone contacts is to enhance compliance and retention and toprovide medical monitoring. No data collection forms are designated for these contacts. However,the following information should be recorded in the patient’s file and included on the data collectionforms completed at the next scheduled follow-up visit if there is a change since the last follow-up:

• Medical status• Residence of the patient and caregiver



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4.6.11. Unscheduled visits and contacts

Patients may contact the clinical site personnel in between scheduled follow-up visits regardingmedical or cognitive problems that they are experiencing. Information on the nature of thecomplaints should be recorded in the clinical notes of the patient’s study file and included on datacollection forms completed at the next scheduled follow-up visit. The only exception are seriousadverse events which are to be recorded upon hearing of such an event (section 10.8.3). Clinical sitepersonnel are to use medical judgment regarding recommendations or referrals.


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4.7. Procedures for missed or incomplete visits

PurposeC Record data about missed or incomplete visits, telephone contacts, or procedures

FormC Missed or Incomplete Visit/Telephone Contact (MV) form

WhenC At close of a visit window for any missed follow-up visit or for any follow-up visit with

specific forms not completedC For any missed telephone contact or for any telephone contact with specific forms not

completed

By whomC Study coordinator

Procedures for missed or incomplete in-person visitsC For a missed visit:

- Date of missed visit is the last date of the visit window- Indicate reason for missed visit

C For an incomplete visit:- Date of incomplete visit is the date on which a partial set of procedures was performed- Document missed procedures and forms- Indicate reason for missed procedures and forms

C Study drug may be issued or returned by mail; in this circumstance, also complete StudyDrug Issue and Return (SD) form

Procedures for missed or incomplete telephone contacts at weeks 36 and 48C For a missed telephone contact:

- Date of missed telephone contact in the last date of the telephone contact window- Indicate reason for missed telephone contact

C For an incomplete telephone contact:- Date of incomplete telephone contact is date on which a partial set of telephone

procedures was performed- Indicate reason for incomplete telephone contact


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4.8. Procedures for ascertaining losses to follow-up

PurposeC Ascertain patient’s vital statusC Ascertain patient’s study treatment status since the date of most recent contactC Document reason(s) patient did not attend visitC Ascertain if patient is lost to follow-up

WhenC Whenever patient misses a study visit and is difficult to contact

By whomC Study coordinator or other certified study personnel

Search strategiesC Contact all persons identified on the Patient and Caregiver Location (PL) form

- Telephone different times during the day/evening- Send letter via regular or certified registered mail to determine if patient is still at

listed addressC Check current telephone directory for listings both for the patient and the caregiver

specified on the PL form C Check post office for forwarding address; ask patient’s contacts for forwarding addressC Trace patient via social security numberC Check obituariesC Check state vital records

DIADS-2 Handbook

48

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5. Screening: procedures, eligibility, and resources

5.1. Consent overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485.2. Eligibility criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495.3. Rules about co-enrollment into other studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

DIADS-2 Handbook 5. Screening: procedures, eligibility, and resources

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5.1. Consent overview

In all cases, consent issues will be ultimately guided by the IRBs who oversee the study sites.Informed consent for participation in DIADS-2 will be obtained both from the patient withAlzheimer's disease who will be treated as part of the trial and from his or her primary caregiver,both of whom are considered to be study participants. Consent will be obtained prior to conductingthe screening visit for the study. Individuals who obtain consent will be trained in the process ofobtaining informed consent using standards and methods established by the local sites and theiroverseeing IRBs. All patients with Alzheimer's disease will provide informed consent forparticipation if they are capable. If this is not possible, consent will be obtained from an appropriatesurrogate using procedures acceptable to the local IRBs. A document entitled "Research Consent forCognitively Impaired Adults: Recommendations for Institutional Review Boards and Investigators" isprovided as a resource in the Appendix 17.1 of this Handbook.

The caregiver will in all cases provide consent for his or her own participation in the trial. If acaregiver is not able to provide consent due to cognitive impairment, this individual is notappropriate for this study because he or she is not able to provide the information necessary for therating of several of the outcome measures.


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5.2. Eligibility criteria

5.2.1. Overview of eligibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 505.2.2. Eligibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515.2.3. Ineligible patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535.2.4. Operationalization of Depression of Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . 545.2.5. Definition of primary caregiver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605.2.6. Definition of assisted living . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615.2.7. Medical screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62



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5.2.1. Overview of eligibility

Eligibility to participate in the study will be based on whether prospective participants meet thecriteria for enrollment articulated in section 5.2.2 (also specified in the protocol). Study clinicianswill determine whether or not prospective participants meet these criteria for enrollment in aface-to-face visit with the prospective patient and caregiver. This visit will be conducted at alocation that is at the discretion of the site director and may include the site's outpatient clinic, theprospective patient’s home, or an assisted living facility. Eligibility determination will consist ofhistory taking, record review, and examination to establish eligibility which will be documented inthe Screening Summary (SS) form. Reason for ineligibility will be documented in the IneligibilitySummary (IS) form. In some cases, eligibility will be established mostly by record review in the caseof established clinic patients. In other cases, eligibility will be established by a full evaluationconducted by site study staff as part of the screening visit. Study staff should use their discretion inchoosing the logistics of each screening visit for prospective patient as long as eligibility ornon-eligibility can be determined at the conclusion of the visit.

In addition, the specifics of the screening visit will be documented by study staff in a "sourcedocument." This will contain all the necessary information so that a site monitor can be persuadedupon record review that the patient and caregiver met study entry criteria. This will be the samesource document in which all subsequent clinical notes regarding the care of this patient in the trial,if randomized, will be maintained.



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5.2.2. Eligibility

Inclusion criteria• Dementia due to Alzheimer's disease by DSM-IV (TR), with MMSE score of 10-26

inclusive• Depression of Alzheimer’s disease as operationalized in the DIADS-2 handbook • Sufficiently good health to be treated using the study protocol in usual care circumstances• Provision of informed consent for participation in the study by patient, caregiver, or

surrogate (if necessary)• Availability of patient’s primary caregiver to accompany the patient to study visits and to

participate in the study• Sufficient fluency, of the patient and caregiver, in written and spoken English to participate

in study visits, neuropsychological testing, and other outcome assessments• Stability of AD treatment (i.e., memantine or cholinesterase inhibitors): No changes are to

be made to AD medications (e.g., starting or stopping treatment) in the 3 months prior torandomization, with the exception that dose adjustments within the therapeutic range (i.e.,total daily dose of $10mg of memantine, $5mg of donepezil, $16mg per day ofgalantamine, or $6mg per day of rivastigmine) are allowed as long as 1) the patient hasreceived the minimum therapeutic range dose or higher for at least 3 months; 2) the lastdose change was at least 1 month prior to randomization; and 3) no further doseadjustments are planned during the study's 24-week treatment phase*

Exclusion criteria • Presence of a brain disease that might otherwise fully explain the presence of dementia,

such as stroke, Parkinson's disease, traumatic brain injury, multiple sclerosis, and similar• Clinically significant hallucinations : a score of $4 on the NPI hallucinations domain, or†

the need, in the opinion of the study psychiatrist, for antipsychotic medication• Clinically significant delusions that, in the opinion of the psychiatrist, require antipsychotic

medication• Treatment with antipsychotics in the 2 weeks prior to randomization• Contraindication for treatment with sertraline, in the opinion of the attending psychiatrist

(e.g., a history of dangerous or unacceptable side effects with sertraline treatment)• Failure of treatment with sertraline in the current episode of depression after convincing

evidence of a "good trial" (e.g., 8 weeks at the highest tolerated dose)• Treatment with a medication that would prohibit the safe concurrent use of sertraline, such

as selegeline • Need for hospitalization for depression, or suicidality• Residence in a nursing facility

5.2. Eligibility criteria5.2.2. Eligibility


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• Current participation in a clinical trial or in any study that may add a significant burden oraffect neuropsychological or other study outcomes

• Current treatment with antipsychotics, anticonvulsants, other antidepressants,benzodiazepines, and other psychotropic medications

• Any condition that, in the opinion of the study physician, makes it medically inappropriateor risky for the participant to enroll in the trial

* The following apply to this criterion: 1) Once a therapeutic dose has been reached for at least 3 months, if dose adjustments

are to be made within the therapeutic range only 1 month of stable dose is required prior to randomization; 2) after

randomization further adjustments of dose of these AD treatments are not permitted; 3) a therapeutic total daily dose is

defined as 400 IU or higher of vitamin E, 20mg of memantine, 5mg or higher of donepezil, 16mg per day or higher of

Galantamine, 6mg per day or higher of rivastigmine; and 4) examples of dose adjustments with the therapeutic range are the

following: increase from 16 mg per day to 24 mg per day of Galantamine, or from 6 to 9mg per day of rivastigmine, or

decrease from 10mg to 5mg of donepezil

Hypnagogic hallucinations ALONE are not exclusionary†



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5.2.3. Ineligible patients

Patients who reach a stop sign on the Screening Summary (SS) or Baseline Medical History(BH) forms are considered ineligible for DIADS-2. A caution sign indicates cautionary instructions;conditions regarding eligibility must be met before the date of randomization for the patient to beeligible for the trial. The Ineligibility Summary (IS) form must be completed and transmitted to theCC for the purpose of recording demographics and reasons for ineligibility. Patients are to bereferred back to the patient’s primary care physician, if necessary.



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5.2.4. Operationalization of Depression of Alzheimer’s Disease

Depression of Alzheimer’s Disease (dAD) criteria rating will occur at baseline for eligibility andat all scheduled follow-up visits for DSM-IV (TR) criteria comparisons. Training for dAD will occuryearly at the DIADS-2 training meeting in which site inter-rater reliability will be assessed. In addition,the first two cases to be enrolled in DIADS-2 at each site will also be discussed by the SteeringCommittee to ensure inter-rater conformity. Operationalization of dAD criteria is discussed in thedocument below, obtained from Olin et. al, American Journal of Geriatric Psychiatry, 10:125-128, 2002.

Process of interviewAll information to rate the dAD criteria is to be obtained from patient report, caregiver report,

review of medical records, and examiner/rater observations. The process must include an interviewwith the patient and separately with the caregiver; during each interview the rater should inquire as tothe presence or absence of each of the ten items below. After completing both interviews, theinterviewer must make a judgment reconciling the results.

The rater must make a judgment as to whether patient's self-report of symptoms is valid or appearsinfluenced by impaired cognition. The rater should make this judgment based on the severity ofcognitive impairment, corroboratory information from caregiver(s) and the medical record, andobservations made during clinical interview.

Similarly, the rater must make a judgment as to whether the caregiver's report of symptoms isvalid or appears influenced by mood factors (i.e., caregiver depression), cultural factors (i.e., caregiver'sbelief in how the patient should act or how elderly people should behave in general), denial (i.e.,caregiver's desire to minimize symptoms), and caregiver education (i.e., caregiver's degree of knowledgeand sophistication regarding dementia and its complications).

Elements of dAD1. Three (or more) of the following symptoms have been present during the same 2-week period and

represent a change from previous functioning:• At least one of the symptoms is either 1) depressed mood or 2) decreased interest and pleasure• To be rated as present, each pertinent symptom must be present most days, four hours per day,

during the past two weeks

5.2. Eligibility criteria 5.2.4. Operationalization of Depression of Alzheimer’s Disease


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Criterion Operationalization

1. Clinically significantdepressed mood(e.g., depressed, sad, hopeless,discouraged, tearful)

Patient appears depressed or reports a decline in mood that, in thejudgment of the rater, affects social or psychological functioning.This judgment will usually need to combine observation andpatient/caregiver reports. Since caregivers frequently over-ratedepressed mood, the interviewer will need to take special care todistinguish between "not caring" (apathy) and more acute/distressedsad mood (depression). The interviewer may choose not to rate theaffective liability of "emotional incontinence" if it does not seem tobe associated with changes in mood.

2. Decreased positive affect orpleasure in response to socialcontacts and usual activities

Patient exhibits or reports decreased pleasure/positive affect inresponse to social contacts and activities that were pleasurable inthe past (no time limits). The rater should elicit examples from thepatient and caregiver of activities that the patient has usually foundpleasurable in the past; in addition, it is helpful to inquire aboutactivities that most people find pleasurable (e.g., a good meal,visiting with grandchildren, attending a family event, etc.). If theinterviewer is still uncertain on this item it might be helpful to askthe patient or caregiver whether the patient is still "having as muchfun as he/she used to," "still enjoying life", "has a zest for life". The interviewer may rate this item as positive if the patient has apoor "vital sense", for example.

3. Social isolation orwithdrawal

Patient exhibits or reports decreased desire to be around people orincreased desire to be alone. Other symptoms on this item mightinclude being quieter and more withdrawn when with other people. Signs of social isolation or withdrawal include emotionalwithdrawal during the interview or a caregiver report of consistentemotional withdrawal in social situations (i.e., feeling that theparticipant is physically present but not emotionally engaged). Donot rate if these are lifelong traits; there must be a change that isreported or observed. Do not rate if patient's withdrawal andisolation appear to be motivated by an effort to avoid tasks thatchallenge cognition, rather than due to an affective loss of interestin activities.



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4. Disruption in appetite Patient demonstrates reduced interest in food, reduced appetite fromusual habits, complains that food doesn't taste right, or > 5% weightloss in past 6 months (in absence of intent to diet or lose weight). In the absence of change in food intake or weight, a report ofnotably diminished interest in food might be scored positive on thisitem.

5. Disruption in sleep Change in sleep patterns is evident. The change may involve initial(more than one hour to fall asleep) or terminal (awakening morethan one hour early) insomnia or increased number of nighttimeawakenings (more than 2 for at least half hour each). The importantaspect of this criterion is the change from usual sleep habits and/orsense of poor quality of sleep. It is often difficult to obtain accurateinformation on this item, particularly if the caregiver and patient donot share a room or bed. In the absence of other information, areport of sleep not being as refreshing as it used might suffice toscore this item positive. Do not count awakenings for purposes oftoileting or hygiene if the patient is able to fall back to sleep rapidly(within 30 minutes).

6. Psychomotor changes (e.g.,agitation or retardation)

Agitation: Patient exhibits excessive motor activity due to innertension and may include inability to sit still, pacing, and/orhand-wringing. This does not imply disruptive or oppositionalbehavior or combativeness/violent behavior. While there may be aspectrum of affective tone in agitation (i.e., tense/worried vs.violent/oppositional), agitation in depression may be diagnosedthroughout the spectrum. Do not include repetitive, stereotypedmovements if they do not appear to have an affective "tone".Retardation: Patient exhibits slowed speech, thinking, and bodymovements; increased pauses before answering; speech that isdecreased in volume, inflection and amount, or variety of content,or muteness. The rater will need to assess the contribution ofmedical conditions to this item as outlined above, sincepsychomotor retardation is often mimicked by medical conditions.



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7. Irritability Patient is easily annoyed, irritated, or angered, and the severity ofirritability is noted as a change from participant's usual personalitytraits. ( i.e., the patient may be described as having a short temper,"flying off the handle," "going off over little things", sudden flashesof anger, being abnormally impatient, being argumentative ordifficult to get along with, or having rapidly changing moods). Therater should exclude simple frustration over cognitive deficits ordifficulties performing daily tasks, and try to include symptoms thatappear to have an irritable affective component that is not a reactionto understandable stressors. The rater should be careful to rule outdelirium which can mimic this symptom.

8. Fatigue or loss of energy Patient appears fatigued or complains of loss of energy. In theabsence of complaints of loss of energy, the rater may make ajudgment to include under the item complaints of easy fatigabilityor complaints of multiple unexplained somatic symptoms (so-called"positive review of systems”). The rater must take special careunder this item to consider medical confounds as described above.

9. Feelings of worthlessness,hopelessness, or excessive orinappropriate guilt

Patient expresses feeling worthlessness, hopelessness, or guilt. Theguilt should seem excessive and disproportionate to the participant'sknown stressors or situation. Include feelings of pessimism,negativity, lowered self-esteem, or negative sense of the future;include a sense of foreshortened future (i.e., "no future"). Includedelusional guilt.

10. Recurrent thoughts ofdeath, suicidal intention, plan,or attempt

Patient expresses recurrent thoughts of death, wanting to die, tohasten death, or to commit suicide. Include suicidal intent, plan, orattempt. The rater must make a judgment as to whether patient'sdesire to die is a desire to hasten death in order to end currentdistress, or a decision to forego aggressive medical care inaccordance with participant's spiritual, moral, and ethical beliefs.

Medical confoundsThe rater should not rate items that in his/her judgment are clearly due to a medical condition other

than Alzheimer’s disease. For example, there are many medical conditions that can cause fatigue and/orpsychomotor retardation including malignancy, congestive heart failure, chronic obstructive pulmonarydisease, neuromuscular conditions, overuse of sedative medications, metabolic abnormalities (hypoglycemia, hyperglycemia, and hypernatremia), and conditions associated with neurologicaldeficits (particularly sensorimotor deficits, apraxia, or agnosia). The "mask facies" and diminishedfacial affective responses seen in Parkinson's disease may mimic depressed mood or anhedonia.



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Anorexia or weight loss may be due to malignancy or gastrointestinal pathology. Frequent awakeningsmay be caused by pain, by respiratory distress due to sleep apnea, or need to toilet or to be cleaned(listed under item 5). Endocrine abnormalities such hypothyroidism, apathetic hyperthyroidism,Cushing's disease, Addison's disease, and paracrine disturbances of malignancy may mimic many of thedepressive symptoms listed.

A. All criteria are met for diagnosis of Dementia of the Alzheimer Type (DSM-IV TR).

B. The symptoms cause clinically significant distress or disruption in functioning. It is important forthis item to take note of changes and not lifelong predispositions. The rater should consider typicalareas of functioning such as social, occupational, and psychological, but must consider the socialcontext of the patient to determine what areas of functioning are appropriate. For example, if thepatient is a nursing home resident with advanced dementia the rater might consider the patient'sability to assist with activities of daily living, participation in recreational activities, whetherpatient acknowledges and participates in visits by family and friends, etc. For a patient with earlyor questionable dementia residing alone in the community, the rater might consider patient's abilityto participate in paid or volunteer work, travel independently, socialize with friends or familyoutside the home, pay bills and maintain independence in other instrumental activities of dailyliving, etc. The appropriateness of areas of functioning will also depend on cultural norms (i.e., anelderly man may never have cooked regularly for himself, and so lack of ability to cook is not asignificant finding), personal history (i.e., occupational and educational history may affect therange of current interests, activities, and hobbies), etc. The rater is encouraged to make this item asspecific to the individual as possible.

C. The symptoms do not occur exclusively during the course of a delirium. Delirium can mimicvirtually all the symptoms of Depression of Alzheimer's Disease and is probably the mostimportant condition to rule out. The attentional disturbance of delirium is particularly likely tomimic the aforementioned symptoms of anhedonia, social withdrawal, appetite disturbance,psychomotor agitation or retardation, and fatigue. Delirious patients are notoriously impulsive andare thus prone to emotional over-reaction to minor stressors and irritability, feelings ofworthlessness and suicidal thoughts/acts. In addition, sleep disturbances are very common indelirium.

D. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse ora medication). When considering the effects of abused substances (such as alcohol, stimulants,opioids, benzodiazepines, barbiturates, etc.), the rater should keep in mind that patients can appeardepressed both while intoxicated and while withdrawing from these substances, and that the mooddisorder of withdrawal can be protracted (i.e., lasting weeks or months) particularly in fragileelderly patients. When considering prescription medications, note that the commonest medicationsto mimic depression are sedating (i.e., opioid analgesics, benzodiazepines, anesthetics, barbiturates,anticonvulsants, antidepressants, and antipsychotics) but the rater must keep in mind the possibilityof idiosyncratic reactions to any medication. Do not assume that "therapeutic" levels rule outmedication toxicity, because many medications with an established range of therapeutic serumlevels can mimic depression when at supratherapeutic levels or in the high-therapeutic part of therange (e.g., digoxin, lithium, phenytoin, carbamazepine, valproic acid, amitriptyline, andnortriptyline).



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E. The symptoms are not better accounted for by other conditions such as major depressive disorder,bipolar disorder, bereavement, schizophrenia, schizoaffective disorder, psychosis of Alzheimer’sdisease, anxiety disorder, or substance-related disorder.

Specify if:

Co-occurring onset: if onset antedates or co-occurs with the AD symptomsPost-AD onset: if onset occurs after AD symptoms

Specify:

With Psychosis of Alzheimer’s DiseaseWith Other Significant Behavioral Signs and SymptomsWith Past History of Mood Disorder



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5.2.5. Definition of primary caregiver

Caregivers are critical to the care of persons with dementia and are an integral part of theDIADS-2 study design. Study patients will by definition have at least one caregiver who willparticipate in the study. The study staff will enumerate all caregivers involved in the care of eachpatient with Alzheimer's disease as part of the screening process. They will then identify the patient'sprimary caregiver as defined below. The primary caregiver will then be asked to be part of the studyand will receive the caregiver intervention articulated in the protocol and this Handbook (section 9).The caregiver will also provide information used to rate many of the study outcome measures. Inrare instances when a patient may have two primary caregivers, which only one will be called uponto take part in the study.

Definition of primary caregiver: The individual primarily responsible for meeting the day-to-daycare needs of a person with dementia. The primary caregiver may be a family member, friend, orhired professional (e.g., nursing aide). In cases where both a family member and a hired professionalare involved, the primary caregiver is the person who provides most of the ADL support in-person orinteracts with the patient for the longest time period during the patient’s waking hours.



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5.2.6. Definition of assisted living

The definition of assisted living is as follows: A residence providing a combination of housing,personalized supportive services, and health care to support the needs, both scheduled andunscheduled, of those who need help with activities of daily living. This includes group homes,board and care homes, and national chains and excludes licensed nursing facilities.



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5.2.7. Medical screening

Medical screening is to be conducted on all patients. A physician is to review the screeninginformation and interview the potential patient and caregiver. Physicians are to oversee the mentalstatus and physical examinations at the screening visit. The purpose of the medical screening is toestablish that the patient is medically appropriate to enroll in the trial and to receive study medicationthat is to be prescribed by the study physician at each site. Each clinical site director is responsiblefor ensuring that local medical screenings are conducted by appropriately licensed physicians and aredone in accordance with good clinical practices, principles of medical ethics, and local rules andregulations.


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5.3. Rules about co-enrollment into other studies

After the informed consent is signed and until the end of the 24-week interval of treatment afterrandomization, DIADS-2 investigators are not to enroll patients in any additional studies that mayadd significant burden or affect treatment outcomes, such as neuropsychological testing as part of anAlzheimer's disease center annual monitoring. If investigators wish to enroll DIADS-2 patients instudies that do not fit the above rule, they must first obtain approval of the DIADS-2 Study Chairwho may in turn decide whether Steering Committee approval is necessary. Alternatively,investigators may seek Steering Committee approval to enroll DIADS-2 patients in an ancillary studyaccording to the DIADS-2 ancillary study policy.

DIADS-2 Handbook

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6. Administrative procedures at screening and baseline

6.1. Assignment of study identifiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656.2. Patient and caregiver location information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666.3. Randomization procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

DIADS-2 Handbook 6. Administrative procedures at screening and baseline

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6.1. Assignment of study identifiers

PurposeC Assign identifiers to all prospective patients that will allow protection of confidentiality

FormC Screening Summary (SS) form

WhenC Screening visit


ProceduresC Assign a patient ID

- Patient ID will be a letter followed by 3 numbers- The ID numbers available for each clinical site will be distributed on sheets of labels

from the CC. The IDs should be assigned after the patient signs the consent form. Remove the next available ID label and place on Screening Summary (SS) form. Thepatient ID for each patient will remain the same for the duration of the trial

- All potential patients, eligible or ineligible, receive a patient ID upon signing theconsent form

C Assign a patient 4-letter code consisting of four characters (also see section 14.1):Example: Brian John Franklin

B - first letter of first nameJ - first letter of middle nameFR - first two letters of last name

Don HoD - first letter of first nameX - "X" to be used if patient does not have middle nameHO - if last name consists of only 2 letters, use “X” for a character to

conceal the patient’s identify- If the patient or clinical site personnel are concerned about confidentiality, a 4-letter

code independent of the person’s name may be chosen- The 4-letter code remains the same for the duration of the trial- The 4-letter code should be unique within a clinical center; a number can be used for

the 4 character to make a code uniqueth

• Assign a caregiver a unique 4-letter code in the same manner as above- If a patient’s caregiver changes, the new caregiver must be assigned a new unique 4-

letter code


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6.2. Patient and caregiver location information

PurposeC Record contact information for patient, caregiver, and patient’s personal physician

WhenC Screening visitC Update as necessary

FormC Patient and Caregiver Location (PL) form


ProcedureC Obtain contact information from patient and caregiverC Keep form in patient's study file; contact information is not submitted to the CCC Ask the patient and caregiver at each visit if there have been any changes• Update new contact information directly on the PL form

Search strategies for patients not returning for follow-upC See section 4.8


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6.3. Randomization procedures

PurposeC Obtain treatment assignmentC Mask patients and clinical site personnel to treatment assignment

Forms• Baseline Medical History (BH) formC Screening Summary (SS) formC Treatment Assignment (TA) form

WhenC At the baseline visit, after all data collection procedures are completed

By whomC Certified study personnel

Procedures prior to randomizationC Verify that consent form was signedC Verify that all eligibility data were collected and criteria met

Procedures at baseline visitC Complete Baseline Medical History (BH) form• Check SS and BH forms to confirm patient’s eligibility; sign assurance of review before

randomizationC Open next sequential randomization envelope to obtain medication identifier

- Medication identifier is a 3-digit number printed on the Treatment Assignment (TA)form inside the envelope

- This number corresponds to the "Drug Kit ID" printed on the study medication C Record the patient’s ID and 4-letter code on the TA form; sign and date the formC Fax a copy of the form to the CC (443-287-5797) and to the pharmacy (410-614-8074)C File a copy of the form in a notebook of all TA formsC File the original TA form in the patient’s fileC Also record treatment assignment on the Drug Kit Accounting Log (AL) formC Issue study drug according to procedures outlined in section 11.4C Instruct patient and caregiver on medication dose and scheduleC Instruct patient and caregiver to bring back study drug bottle (even if empty) when they

come back for the next visitC Give patient and caregiver a list of potential side effects that should be watched for and

instructions for contacting study personnel

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7. Outcome measures

7.1. Overview and schedule of outcome measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 697.2. Synopsis of depression measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707.3. Synopsis of functional measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777.4. Synopsis of caregiver measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817.5. Health measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867.6. Neuropsychological measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

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7.1. Overview and schedule of outcome measures

This section contains synopses of the DIADS-2 outcome measures. Each synopsis provides thereference for the measure and basic rules involved in its administration. All DIADS-2 personnel areto be trained in the administration of each measure as part of study training procedures articulated bythe Study Chair and Steering Committee. These synopses also specify who is rated on each measure(i.e., patient with Alzheimer's disease or caregiver) and what information is to be used in the rating.Most of the measures used to rate the patient incorporate information from the primary caregiver. This information should be obtained from the primary caregiver who signs consent to be in the study,as specified in the eligibility criteria and defined in this handbook, and participates in the baselineratings.

It is expected that this caregiver will accompany the patient to study follow-up visits wherefollow-up ratings will be made. However, it is recognized that occasionally a primary caregiver maynot be able to be present at a specific visit. Less often, the primary caregiver may withdraw from thestudy and no longer participate in it; or rarely, this caregiver may die. In such instances, every effortshould be made to rate the scale with information from the same primary caregiver. This informationmight, in rare instances, have to be obtained over the phone around the time of the patient's clinicvisit (within 48 hours). If this information cannot be obtained in this time frame from the primarycaregiver, then it should be obtained from the next best source of information available to the studyteam based on best clinical judgment. In rare instances, such ratings will not be made if reliableinformation cannot be obtained, and the data will be recorded as missing.

In addition to providing information to rate the patient with AD, the primary caregiver is alsoconsidered a study participant and is to be rated on specific caregiver measures as specified in theprotocol. These include the Beck Depression Inventory (measuring caregiver depression), MedicalOutcomes Study Short Form Health Survey (measuring caregiver quality of life), BurdenQuestionnaire (measuring caregiver burden), and Caregiver Activity Survey (measuring time taken tocare for the patient with AD). In cases where the primary caregiver who signed consent is notavailable at a given visit to rate these measures, the following protocol should be followed: First,attempts should be made to rate these measures, which are all self-report, via mail, or over the phonewithin a few days. If this is not possible and/or the primary caregiver is truly not available to makethe ratings at that visit, then the Beck Depression Inventory and Medical Outcomes Study Short FormHealth Survey should be recorded as missing data since such personalized follow-up providing dataon a different individual would not be interpretable. In contrast, the Burden Questionnaire andCaregiver Activity Survey might still provide valuable information and should be rated by a differentcaregiver who knows the patient well, selected based on the study team's best judgment. In rareinstances these ratings will not be made if reliable information cannot be obtained, and the data willbe recorded as missing.


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7.2. Synopsis of depression measures

7.2.1. Modified ADCS-Clinical Global Impression of Change Follow-up Evaluation . . . 717.2.2. Cornell Scale for Depression in Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737.2.3. Neuropsychiatric Inventory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747.2.4. Daily Affect Diary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757.2.5. Criteria ratings other than dAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76



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7.2.1. Modified ADCS-Clinical Global Impression ofChange Follow-up Evaluation

Summary• The mADCS-CGIC is a systematic method that assesses clinically significant change in a

patient’s depressive disturbance. The mADCS-CGIC requires the administrator to considera number of aspects of the depressive disturbance prior to providing a “global” assessmentof change. These include: mood, enjoyment of activities, interest and initiative,neurovegetative function (sleep, appetite, sexuality), and depressive cognitions (such assense of the future, self confidence, self esteem)

Purpose• Assessment of clinically significant change in overall clinical status and depressive

disturbance

Forms• Modified ADCS-Clinical Global Impression of Change Baseline Evaluation (MA) form• Modified ADCS-Clinical Global Impression of Change Follow-up Evaluation (MO) form

When• The mADCS-CGI Baseline Evaluation is completed at the baseline visit by recording notes

on the MA form • The follow-up evaluation (mADCS-CGIC or MO form), occurs at all scheduled follow-up

visits, using the baseline notes as a reference By whom

• DIADS-2 certified clinician

Who is rated• Patient with dementia

Procedures for obtaining information• Rating is based on caregiver interview and patient examination, along with a comparison of

notes from the mADCS-CGI Baseline Evaluation


7.2. Synopsis of depression measures7.2.1. Modified ADCS-Clinical Global Impression of Change Follow-up Evaluation

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• The study clinician will use a 7-point-Likert scale to rate each patient along a continuumfrom "much worse" (1) to "much improved" (7) with a rating of 4 being "no change." Thisrating is conducted twice: 1) to rate a global assessment of change in the overall clinicalstatus (comparison of all items on mADCS-CGI Baseline Evaluation) and 2) to focus onmood disturbance, considering the patient's mood, enjoyment of activities, interest andinitiative, neurovegetative function, and depressive cognitions (comparison of select itemsindicated on the Modified-ADCS Clinical Global Impression of Change Follow-upEvaluation form)

• If the patient does not show improvement at week 12 (scores 1-4 on the MO form), thepatient’s treatment is to be discontinued per protocol

Reference• Schneider, L.S., Olin, J.T., Doody, R.S., Clark, C.M., Morris, J.C., Reisberg, B., Schmitt,

F.A., Grundman, M., Thomas, R.G., Ferris, S.H. (1997). Validity and reliability of theAlzheimer's Disease Cooperative Study- Clinical Global Impression of Change. TheAlzheimer's Disease Cooperative Study. Alzheimer's Disease & Associated Disorders,11(Suppl 2), S22-32



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7.2.2. Cornell Scale for Depression in Dementia

SummaryC This widely used measure of depression in the context of dementia has been shown to be

sensitive to change in assessing treatment response in AD-associated depression. Itinvolves a comprehensive approach to rate specific symptoms with input from patients andcaregivers and exhibits a high concordance with the clinical diagnosis of major, minor, andabsent depression

PurposeC Measure of depression in patients with dementia

FormC Cornell Scale for Depression in Dementia (CS) form

WhenC Complete at baseline and at all scheduled follow-up visits

By whomC DIADS-2 certified clinician

Who is ratedC Patient with dementia

Procedure for obtaining informationC Ratings are based on semi-structured patient and caregiver interviews C Separate ratings are made during the patient and caregiver interviews. The patient should

be interviewed and rated first, and then the caregiver. If these ratings are discrepant, theclinician is to make a consensus rating based on clinical judgment

C Ratings are as follows: 0= absent; 1= mild or intermittent; 2= severeC Ratings are based on symptoms and signs occurring during the week prior to interview. If

severe and intermittent, score as severe. No score should be given if symptoms result fromphysical disability or illness

ReferenceC Alexopoulos, G.S., Abrams, R.C., Young, R.C., Shamoian, C.S. (1988). Cornell Scale for

Depression in Dementia. Biological Psychiatry, 23, 271-284



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7.2.3. Neuropsychiatric Inventory

SummaryC The NPI five mood domains (depression, anxiety, irritability, sleep disorder, and eating

disorder) are used to assess type and severity of depressive disturbances in this measure

PurposeC Assessment of neuropsychiatric and other behavioral symptoms of dementia

FormC Neuropsychiatric Inventory (NP) form

WhenC Complete at baseline and at all scheduled follow-up visits



Procedure for obtaining informationC Ratings are based on the caregiver interview; questions are read verbatim C The type and severity of neuropsychiatric disturbances in functional domains, including

seven non-mood domains and five mood domains, are assessed. The non-mood domainsinclude delusions, hallucinations, agitation/aggression, aberrant motor behavior, euphoria,and disinihibition. The mood domains include depression, anxiety, irritability, sleepdisorder, and eating disorder

C Frequency (1=occasionally, less than once/week; 4 = very frequently, once or more/day orcontinuously) and severity (1=mild, 2=moderate, 3=severe) scales in each domain arescored based on responses from an informed caregiver involved in the patient's life

ReferenceC Cummings, J.L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D.A., Gornbein, J.

(1994). The Neuropsychiatric Inventory: Comprehensive Assessment of Psychopathologyin Dementia. Neurology, 44, 2308-2314



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7.2.4. Daily Affect Diary

SummaryC This tool assesses the patient's affect through daily ratings recorded by the caregiver. The

diary is designed to capture a greater variability in symptoms, helping to differentiatebetween depression in Alzheimer's disease and major depression. Methods for directratings of affect have been validated for patients with Alzheimer's disease, and they havebeen applied to the assessment of treatment outcomes

PurposeC Assessment of patient's affect between in-person visits

FormC Daily Affect Diary (DA) form

When

C Distribute at baseline and all scheduled follow-up visits except weeks 2 and 24

By whomC Caregiver (see section 7.1)


Procedure for obtaining informationC Staff are to explain instructions for the DA form at time of distributionC The caregiver, completing one entry per day, rates the patient's mood for a 7-day period

starting the day after the visit C The diary is returned at the next scheduled follow-up visit, and typically, another diary is

distributed for completion during the next interim period



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7.2.5. Criteria ratings other than dAD

PurposeC Record whether a patient meets elements of diagnostic criteria for Depression of Alzheimer's

Disease according to: - Alzheimer's Associated Affective Disorder (AAAD)- Major Depressive Episode (MDD)- DSM-IV (TR)- Minor Depressive Episode (MDE)- DSM-IV (TR)

FormsC Depression of Alzheimer’s Disease Criteria Rating (DC) formC Alzheimer-Associated Affective Disorder Criteria Rating (AC) formC Major Depression Criteria Rating (MD) formC Minor Depression Criteria Rating (MI) form

WhenC Complete at baseline and all scheduled follow-up visits



Procedure for obtaining informationC Ratings are based on the patient and caregiver interview, review of medical records, and

examiner/rater observations C dAD ratings require specific training from the CO prior to administration

ReferencesC Lyketsos, C.G., Breitner, J., Rabins, P.V. 2001b. An evidence- based proposal for the

classification of neuropsychiatric disturbance in Alzheimer's disease. The InternationalJournal of Geriatric Psychiatry16, 1037-1042

C Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000


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7.3. Synopsis of functional measures

7.3.1. ADCS-Activities of Daily Living . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787.3.2. Dependence Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797.3.3. Alzheimer’s Disease Related Quality of Life Scale . . . . . . . . . . . . . . . . . . . . . . . . 80



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7.3.1. ADCS-Activities of Daily Living

SummaryC This measure is an Activities of Daily Living (ADL) inventory developed by the

Alzheimer’s Disease Cooperative Study to assess functional performance in patients withAD. The scale discriminates the stages of severity of AD, from very mild to severelyimpaired

PurposeC Assessment of patient’s daily living functioning

FormC Activities of Daily Living Inventory (AD) form

WhenC Complete at baseline and follow-up visits at 8, 16, and 24 weeks. Conduct over the phone

at 36 and 48 weeks By whom

C DIADS-2 certified clinician


Procedures for obtaining information

C The clinician obtains ratings by administering a structured interview to the caregiver. Thecaregiver is queried as to whether patient attempted each of the 24 items during the prior 4weeks and at which level the patient performed these activities

ReferenceC Galasko, D., Bennett, D., Sano, M., Ernesto, C., Thomas, R., Grundman, M., & Ferris, S.

(1997). An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study Alzheimer's Disease & AssociatedDisorders, 11(Suppl 2), S33-39



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7.3.2. Dependence Scale

SummaryC This is a structured scale developed for longitudinal studies of AD and has been used as a

predictor of nursing home placement. The scale rates degree of dependence or assistanceneeded by a patient. The interview is conducted with the caregiver and yields a total scoreand a level of dependence

PurposeC Assessment of dependence of the patient’s day-to-day living

FormC Dependence Scale (DP) form

When

C Complete at baseline and scheduled follow-up visits at weeks 8, 16, and 24



Procedure for obtaining informationC The clinician obtains ratings by administering a structured interview to the caregiver. The

caregiver is queried about patient's level of dependence during the last month Reference

C Stern, Y., Tang, M.X., Albert, M.S., Brandt, J. Jacobs, D.M., Bell, K., Marder, K., Sano,M., Devand, D., Albert, S.M., Bylsma, F., Tsai, W.Y. (1997) Predicting time to nursinghome care and death in individuals with Alzheimer's Disease JAMA, Mar 12, 277(10):806-12



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7.3.3. Alzheimer’s Disease Related Quality of Life Scale

SummaryC The Alzheimer’s Disease Related Quality of Life Scale (ADRQL) is used to assess health-

related quality of life of persons with Alzheimer’s disease. As a proxy based measure, it isadministered to caregivers, who are asked to identify recently observed behaviors of theindividual that are reflective of various aspects of that person’s quality of life. TheADRQL consists of 47 structured items that describe behaviors associated with 5 areas ordomains of importance to persons with AD

PurposeC Assessment of the patient’s health-related quality of life

FormC Alzheimer’s Disease Related Quality of Life Scale (QL) form

When

C Complete at baseline and scheduled follow-up visits at weeks 8, 16, and 24



Procedure for obtaining informationC The clinician obtains ratings by administering a structured interview to the caregiver. The

caregiver is queried to identify observed behaviors which have been observed recently inthe patient and are correlated to the patient's quality of life

ReferenceC Gonzales-Salvador, T., Lyketsos, C.G., Baker, A.S., Rogues, C., Hovanek, L., Steele, C.D.,

Brandt, J. (2000). Quality of life of patients with dementia in long-term care. InternationalGeriatric Psychiatry, 15, 181-189


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7.4. Synopsis of caregiver measures

7.4.1. Beck Depression Inventory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 827.4.2. Medical Outcomes Study Short Form Health Survey . . . . . . . . . . . . . . . . . . . . . . . 837.4.3. Caregiver Activity Survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847.4.4. Burden Questionnaire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85



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7.4.1. Beck Depression Inventory

Summary• This is a 21-item, 63-point self-report questionnaire of depressive symptoms presented in

multiple-choice format. It can be scored on 2 subscales of particular value: psychologicaland somatic symptoms

Purpose• Assessment of caregiver depression

Forms• Beck Depression Inventory (BD) form

When• Complete at baseline and scheduled follow-up visits at weeks 8, 16, and 24

By whom• Caregiver by self-report questionnaire

Who is rated• Caregiver (original caregiver only); if the original caregiver is not available, see section 7.1

Procedure for obtaining information• Study clinician gives the caregiver the questionnaire to complete during the visit.

Caregiver provides self-report of depressive symptoms including psychological and somaticsymptoms

Reference• Beck, A.T., Ward, C.H., Mendelson, M., Mock, J., Erbaugh, J. (1961). An inventory

measuring depression. Archives of General Psychiatry, 4, 561-571



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7.4.2. Medical Outcomes Study Short Form Health Survey

Summary• The 12-item questionnaire, otherwise called the Short Form-12 from the Medical Outcomes

Study, will be used to measure caregiver quality of life, general health status, andfunctioning. This brief self-report instrument includes four scales: the effects of health onphysical functioning, freedom from bodily pain, mental health, and overall perception ofgeneral health

Purpose• Measure of caregiver quality of life, general heath status, and functioning

Form• Medical Outcomes Study Short Form Health Survey (MS) form

When• Complete at baseline and follow-up visits at weeks 8, 16, and 24

By whom• Caregiver by self-report questionnaire


Procedure for obtaining information• Study clinician gives the caregiver the questionnaire to complete during the visit• Ratings are based on caregiver self-report from this questionnaire, which measures the

caregiver's physical health problems, energy/vitality, social functioning, role limitationsdue to emotional problems, general mental health, and quality of life

Reference• Ware, J, Kosinski, M, Keller, SD (1996). A 12-item Short Form Health Survey:

Construction of scales and preliminary tests of reliability and validity. Medical Care,34 (3)



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7.4.3. Caregiver Activity Survey

Summary• The Caregiver Activity Survey measures the time spent caring for Alzheimer's patients with

their day-to-day activities. The assessment consists of six items related to usingtransportation, eating, dressing, looking after one's appearance, assisting one in leisureactivities, and supervising the person

Purpose• Measurement of caregiver time spent caring for or aiding an Alzheimer patient with

day-to-day activities

Forms• Caregiver Activity Survey (CA) form


By whom• DIADS-2 certified clinician


Procedure for obtaining information• The clinician obtains ratings by administering a structured interview to the caregiver • The caregiver is asked to report time spent caregiving on a "typical day," which does not

include time spent giving care for acute medical illnesses, hospital appointments, andunusual behavior changes

Reference• Davis, K.L., Martin, D.B., Kane, R., Patrick, D., Pesking, E.R., Raskind, M.A., Puder, K.L.

(1997). The Caregiver Activity Survey (CAS): development and validation of a newmeasure for caregivers of persons with Alzheimer's disease. International Journal ofGeriatric Psychiatry, 12 (10) 978- 988



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7.4.4. Burden Questionnaire

Summary• Caregiver burden includes 22 items and is administered through questionnaire

Purpose• Assessment of caregiver burden

Form• Burden Questionnaire (BQ) form


By whom• Caregiver by questionnaire


Procedure for obtaining information• The study clinician gives the caregiver the questionnaire to complete during the visit• For each item, the caregiver is asked to indicate how often he or she has experienced a

certain emotion• Each item is rated on a 5-point scale, ranging from 0 (never) to 4 (nearly always)

Reference• Zarit, S.H., Reever, K.E., Bach-Peterson, J. (1980). Relatives of impaired elderly:

Correlates of feelings of burden. Gerontologist, 20 649-655. Copyright. TheGerontological Society of America


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7.5. Health measures

7.5.1. General Medical Health Rating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877.5.2. Vital signs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89



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7.5.1. General Medical Health Rating

Summary• The General Medical Health Rating (GMHR) is a global clinical rating designed to

quantify the severity of general co-morbidity in a patient with dementia

Purpose• Assessment of the severity of general medical co-morbidity in a patient with dementia

Form• General Medical Health Rating (GM) form

When• Complete at baseline and all in-person follow-up visits

By whom• DIADS-2 certified clinician


Procedure for obtaining information• Using a 4-point scale, the study clinician will rate the patient’s general medical health

based on the patient’s medical history and caregiver’s and patient’s observations

InstructionsRaters are asked to review a patient's current and past medical history unrelated to the dementia. History is taken from the patient in the form of a review of systems, and from an informant,typically a family member or a clinician that knows the patient well. The history also involvesinformation about the patient's current, routine medications for their medical co-morbidities. Medicines taken for dementia, for co-morbid mental (or behavioral) disorders, are excluded, asare over-the-counter preparations. Raters are also asked to meet briefly and interact with thepatient. This process of information collection requires 10-15 minutes and overlaps withbaseline or follow-up clinical assessments. It is recommended that a clinician practice rating 10patients in collaboration with another clinician that has experience rating the scale prior toroutine clinical use of the GMHR.



7.5.1. General Medical Health Rating

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The rater should use their best clinical judgment to make the rating on the four-point scale. Therating should be made after taking into account: 1) number and severity of co-morbid generaldiagnoses/conditions; 2) number of routine medications for these conditions; and 3) thepatient’s overall appearance.

When making the rating, consider only clinically active general medical diagnoses that areeither symptomatic or require continued treatment. For example, controlled hypertension orarthritis or angina would be considered, but a remote healed fracture would not. Also, consideronly medications used routinely (not "as needed") for the treatment of a co-morbid generalmedical condition. Do not consider over-the-counter medications used occasionally, without aclear indication, or not under a physician's direction. It is not necessary to follow the number ofmedical diagnoses/conditions or medications exactly when making the rating. Instead ratersshould use their best clinical judgment. In terms of appearance, assess whether the patient lookshealthy, unhealthy, unwell, or ill. Morbidity associated with dementia should not be consideredin making this rating.

Reference• Lyketsos, C.G., Galik, E., Steele, C. (1999). The General Medical Health Rating: A

bedside global rating of medical co morbidity in patients with dementia. Journal of theAmerican Geriatrics Society, 47 (4) 487-491



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7.5.2. Vital signs

Using standard clinical methods, blood pressure, pulse, and respirations are measured after thepatient sits at rest for 5 minutes. Weight is measured with minimally appropriate clothing necessaryto preserve dignity. All of these measures are recorded in the Screening Summary (SS), BaselineMedical History (BH), and Follow-up Medical History (FH) forms at the respective visits.


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7.6. Neuropsychological measures

7.6.1. Synopsis of neuropsychological tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917.6.2. Instructions for neuropsychological testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927.6.3. Missing data codes for neuropsychological assessments . . . . . . . . . . . . . . . . . . . 101



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7.6.1. Synopsis of neuropsychological tests

DIADS-2 neuropsychological tests are administered per instruction of the neuropsychologicaltesting advisor in the Chairman’s Office. All new neuropsych test administors are required to becertified prior to testing. Raw data are recorded in booklets assigned for each visit. TheNeuropsychological Test Summary (NS) form contains key values from the neuropsychologicalbattery and is filled out as part of the case record form. Data from this form are to be transmitted tothe CC and entered in the DIADS-2 database. The raw data booklets are maintained as part of thepatient’s study source documents and may be audited by the CO.

Neuropsych testing occurs at weeks 8, 16, and 24. All tests are administered to the patient bythe DIADS-2 certified psychometrician.



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7.6.2. Instructions for neuropsychological testing

7.6.2.1. Mini-Mental State Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937.6.2.2. Wechsler Memory Scale-Third Edition Digits Backwards . . . . . . . . . . . . . . . . . . . 947.6.2.3. Letter Fluency Task . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957.6.2.4. Cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog)

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967.6.2.5. Symbol Digit Modalities Test (SDMT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977.6.2.6. Finger Tapping Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 987.6.2.7. Etch-A-Sketch Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 997.6.2.8. Hopkins Adult Reading Scale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100


7.6. Neuropsychological measures7.6.2. Instructions for neuropsychological testing

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7.6.2.1. Mini-Mental State Exam

Summary• The Mini-Mental State Exam (MMSE) is a well-known cognitive screen for the detection

of dementia and estimation of its severity. The particular domains most often affected inAD (i.e., orientation and memory) are included in this instrument

Purpose• Measure of dementia and estimate global cognitive impairment

When• Complete at baseline and at follow-up visits at weeks 8, 16, and 24

By whom• DIADS-2 certified psychometrician


Procedure for obtaining information• The psychometrician uses the standardized interview to assessed global cognitive

functioning in the areas of orientation, memory, attention/concentration, language, andpraxis. Tasks include naming, following verbal and written commands, writing a sentenceand coping two overlapping shapes

Reference• Folstein, M.F., Folstein, S.E., McHugh, P.R. (2001). Mini-Mental State Examination

Professional Manual. Psychological Assessment Resources, Odessa, FL



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7.6.2.2. Wechsler Memory Scale-Third Edition DigitsBackwards

Purpose• Measure of attention and working memory




Procedure for obtaining information• The patient is asked to repeat sequences of single digit numbers that are read aloud by the

examiner. Digits must be repeated in reverse order. The length of the sequences increasesprogressively. Responses are recorded verbatim

Reference• Wechsler, D. (1997). Wechsler Memory Scale-Third Edition Administration and Scoring

Manual. New York: The Psychological Corporation



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7.6.2.3. Letter Fluency Task

Purpose• Measure of word-list generation and executive functioning




Procedure for obtaining information• The patient is asked to generate orally as many words as possible that begin with the letters

"S" and "P," excluding proper names, foreign words, and different forms of the same word(ie., start, starting, and started). The patient is allowed one minute to generate words foreach letter

Reference• Borkowski, J.G., Benton, A.L., Spreen, O. (1967). Word fluency and brain damage.

Neuropsychologia, 5, 135-140



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7.6.2.4. Cognitive subscale of the Alzheimer’s DiseaseAssessment Scale (ADAS-Cog)

Purpose• Measure of various cognitive skills and language abilities in patients with Alzheimer's

disease




Procedure for obtaining information• Scores are obtained for orientation, word-list recall and recognition, object naming, ability

to follow simple requests, ideational and constructional praxis, and expressive language.Higher scores indicate worse performance

Reference• Rosen, W.G., Mohs, R.C., Davis, K.L., (1984). A new rating scale for Alzheimer's disease.

American Journal of Psychiatry 141(11): 1356-1364



98

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7.6.2.5. Symbol Digit Modalities Test (SDMT)

Purpose• Measure of psychomotor speed and visual perceptual decoding




Procedure for obtaining information• The patient is asked to associate single-digit numbers with unfamiliar symbols. A stimulus

set of nine printed digit-symbol pairs is presented above rows of numbers without theappropriate symbols. The patient is instructed to draw the correct symbol below each ofthe numbers using the digit-symbol code presented above. The score is based on thenumber of substitutions completed within a 90-second time limit

Reference• Smith, A. (1973). Symbol Digit Modalities Test- Administration and Scoring Manual.

Western Psychological Services




99

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7.6.2.6. Finger Tapping Test

Purpose• Measure of fine motor speed


By whom

• DIADS-2 certified psychometrician


Procedure for obtaining information• The patient is asked to tap a lever with the index finger of each hand in 10-second intervals

Reference• Reitan, R.M, Wolfson, D (1993). The Halstead-Reitan Neuropsychological Test Battery:

Theory and clinical interpretation. Tucson, AZ: Neuropsychology Press




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7.6.2.7. Etch-A-Sketch Test

Purpose• Measure of perceptual motor learning and implicit memory




Procedure for obtaining information• The patient is asked to complete mazes using templates placed over an Etch-a-Sketch panel.

The test is administered multiple times in a learning phase and, again, after a delay• Subjects whose depression remits are expected to improve over trials, and to retain what

they have learned, whereas those who remain depressed are not expected to benefit frompractice

Reference• Etch-A-Sketch Test. Lafayette Instrument Company




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7.6.2.8. Hopkins Adult Reading Scale

Purpose• Measure of ability to pronounce irregularly spelled words to obtain an estimate of

premorbid IQ


By whom

• DIADS-2 certified psychometrician


Procedure for obtaining information• The patient is asked to read aloud a list of irregularly spelled words of increasing difficulty,

a skill thought to remain intact even if other cognitive skills have deteriorated• Scores on this test provide estimates of premorbid IQ and enable estimation of the extent of

cognitive decline

Reference• Nelson, H.E. (1982). The National Adult Reading Test (NART): Test manual. Windsor,

Berkshire, UK: NFER-Nelson



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7.6.3. Missing data codes for neuropsychologicalassessments

The following codes on the Neuropsychological Test Summary (NS) form are used to explainmissing information. These codes are to be written directly on the form and sent to the CC for dataentry.

c = Task not administered because patient was unable to comprehend an entire task. Forindividual items, scores of 0 (or worst score) can be assigned

s = Sensory impairment or physical limitation (example: patient is completely blind orcompletely deaf or hemiplegic). Do not use this code if patient complains of being unableto see or hear only certain stimuli when he or she can see or hear other items in the battery. In those cases, a score of 0 (or worst score) should be assigned

r = Patient refused test. Do not use if patient refuses only one or two items in a test, but thencontinues with other items. In those cases, a score of 0 (or worst score, as in the case of theADAS-Cog) should be assigned

e = Reasons other than above. This includes examiner error (forgot to administer oradministered incorrectly), or test not attempted due to time constraints

DIADS-2 Handbook

103

ClinicmgrDIADS-2Notebooks3\Handbookv1.1\manall_22wpd

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8. Clinical management

8.1. Good clinical practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038.2. Ongoing monitoring of medical history and concomitant medications . . . . . . . . . . . . 1048.3. Use of allowed study concomitant psychotropics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

DIADS-2 Handbook 8. Clinical management

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8.1. Good clinical practices

Good Clinical Practice (GCP) is an international ethical and scientific quality standard fordesigning, conducting, recording, and reporting trials that involve the participation of humansubjects. Investigators have a commitment to adhere to regulatory guidelines such as the Code ofFederal Regulations and ICH guidelines.


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8.2. Ongoing monitoring of medical history and concomitantmedications

Ongoing monitoring of medical history and concomitant medications is to occur at scheduledin-person visits (weeks 2, 4, 8, 12, 16, 20, and 24 after randomization); at telephone contacts (weeklyfor the first 8 weeks after randomization except the weeks with an in-person visit); and atunscheduled follow-up visits and contacts if needed. Concomitant medications and changes tomedical history are to be documented in the patient’s medical chart and on the Follow-up MedicalHistory (FH) form.


106

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8.3. Use of allowed study concomitant psychotropics

8.3.1. Trazodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068.3.2. Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107



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8.3.1. Trazodone

If a patient requires medication for a sleep disorder, study clinicians will be allowed to prescribetrazodone 25 mg to 100 mg at bedtime to help sleep, if necessary. This should be documented in thepatient’s medical chart and on the Follow-up Medical History (FH) form.



108

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8.3.2. Risperidone

If a patient requires medication for the treatment of emergent hallucinations or clinicallysignificant delusions, study clinicians will be allowed to prescribe risperidone 0.5 mg to 2.0 mg perday, if necessary. This should be documented in the patient’s medical chart and on the Follow-upMedical History (FH) form.

DIADS-2 Handbook

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9. Caregiver psychosocial intervention

9.1. Overview of caregiver psychosocial intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099.2. Schedule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109.3. Baseline counseling procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1119.4. Follow-up counseling procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129.5. Educational materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1139.6. Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1149.7. Quality assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

DIADS-2 Handbook 9. Caregiver psychosocial intervention

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9.1. Overview of caregiver psychosocial intervention

The DIADS-2 caregiver psychosocial intervention is targeted at the primary caregiver of thepatient with Alzheimer's disease and will consist of caregiver counseling, caregiver education, and24-hour availability for crisis intervention. It will be anchored around scheduled follow-up visitsand will occur between the primary caregiver and a designated clinician who will be trained in theadministration of the intervention by the CO. The intervention will be delivered by a DIADS-2certified and licensed clinician (i.e., physician, nurse, psychologist, social worker, and counselor)identified by the clinical site director as a site designee to deliver the intervention. DIADS-2 clinicalsite directors will designate clinicians with at least 3 years of experience in the care of persons withdementia to provide the intervention after they are trained. In general, one person at each site willdeliver the intervention, but each site will have several individuals trained in providing theintervention as backups. Every effort will be made to have the same person deliver the interventionat all visits with the same caregiver. If this is not possible then a different designee will administerthe intervention at follow-up visits. Individuals designated to administer the intervention will betrained in its administration by the developers, Peter Rabins and Constantine Lyketsos, at theDIADS-2 initial and follow-up annual training meetings.


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9.2. Schedule

The caregiver psychosocial intervention will be provided to the primary caregiver at the baselinevisit and at each subsequent scheduled follow-up visits during the 24-week treatment period exceptweek 2. Sections 9.3 and 9.4 outlines the procedures for the baseline and follow-up visits.


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9.3. Baseline counseling procedures

First visit (up to 30 minutes)*• Explain the purpose of the intervention:

- To improve the day-to-day quality of life of the person with dementia- To improve the caregiver’s ability to care for them, and- To help sustain the caregiver in her/his difficult task

• Overview of the intervention: A brief counseling session lasting up to 30 minutes atbaseline, and then at all follow-up visits up to 20 minutes. At each session the clinicianwill review and update the care plan using the patient and caregiver checklists, provideeducational materials, discuss specific issues in depth, work on caregiving skills, and makeany necessary referrals (e.g., PT, support groups, home health, etc.)

• Provide information in writing as to how to reach the care team on a 24/7 basis to deal withcrises (see example “Availability Form” provided)

• Provide and discuss caregiver educational materials: a) 36-Hour Day and the b) JHUFamily Guidelines

• Review systematically the “JHU Supportive Care Checklists” first for patient and then forcaregiver. Record the elements of the plan on the checklist

• Provide illness teaching about depression in AD, its recognition, causes, and treatment. Hand out the article from the Johns Hopkins Memory Bulletin on Depression in AD

• Special topic of the day: Choose a care problem (or issue) to focus on during this visit. Begin by asking: “What is the biggest care problem you are having right now?” Might alsofocus the discussion around one of the JHU Family Guidelines, parts of the SupportiveCare checklists, or from the recent history that the caregiver provided. Discuss this topic indepth with the caregiver with an eye to teaching caregiving skills and problem solvingstrategies. Tailor to the caregiver’s level of sophistication

• Document duration of the intervention, the topics covered, and place the completedchecklists in the source document. Document duration of intervention also in the BaselineMedical History (BH) form

*It is recognized that not all caregivers need detailed counseling at every visit and that many refuse to be counseled at specific

time points. Such refusals should be honored. All caregivers should be offered the educational materials and information

about the study team’s 24-hour availability. As well, occasional visits will be short, lasting much less than the suggested time

frame. This, too, is appropriate. It is left to clinical judgment to determine the exact length of each counseling session. If a

caregiver requires more support or counseling than can be provided during these sessions, they should be referred to the

appropriate resources in the area, as usual care would dictate.


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9.4. Follow-up counseling procedures

Follow-up visits (about 20-30 minutes)

• Remind of the purpose and overview of the ongoing intervention

• Remind of team’s 24/7 availability and how to access it

• Prompt for and answer questions about any of the written materials provided in the past(e.g., 36-Hour Day, JHU Guidelines, and Memory Bulletin article on depression in AD) orany other issues the caregiver has questions about

• Review and update the “JHU Supportive Care Checklists” first for patient and then forcaregiver. Update as necessary the elements of the plan on the checklist

• Update, as needed, illness teaching about depression in AD, its recognition, causes, andtreatment

• Special topic of the day: Choose a care problem (or issue) to focus on during this visit. Begin by asking: “What is the biggest care problem you are having right now?” Might alsofocus the discussion around one of the JHU Family Guidelines, parts of the SupportiveCare checklists, or from the recent history that the caregiver provided. Discuss this topic indepth with the caregiver with an eye to teaching caregiving skills and problem solvingstrategies. Tailor to the caregiver’s level of sophistication

• Document duration of the intervention, the topics covered, and place the completedchecklists in the source document. Document duration of intervention also in the Follow-up Medical History (FH) form


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9.5. Educational materials

DIADS-2 caregivers will be provided with the following educational materials to be used as partof the caregiver psychosocial intervention:

C The book The 36 Hour Day by Mace and Rabins (Johns Hopkins Press)C The Johns Hopkins Division of Geriatric Psychiatry and Neuropsychiatry Guidelines for

Caregivers of persons with dementia (Steele et. al.)C Copies of “Depression in Alzheimer’s Disease” (Lyketsos) in the October 10, 2003 issue of

The Johns Hopkins Memory Bulletin

These materials are available from the Chairman’s Office.


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9.6. Documentation

Information regarding the administration of the caregiver psychosocial intervention (i.e.,duration of the session) will be documented in either the Baseline Medical History (BH) form or theFollow-up Medical History (FH) form. However, the specifics of the intervention will bedocumented in the source document for every patient at each visit which will not be entered into thedatabase. Minimal documentation will include the date and time of the counseling visit, whoadministered the intervention, which caregiver received the intervention, and what topics werecovered. Completed copies of the "Supportive Care Checklists" updated at each visit will also beincluded in the source record documentation. This is found in the caregiver psychosocialintervention materials provided by the Chairman’s Office.


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9.7. Quality assurance

To ensure proper administration of the caregiver psychosocial intervention, in addition to annualtraining, and the 2-hour teleconference call regarding in its administration and the source documentsof a 10% random sample of visits, stratified by site, will be audited by Dr. Peter Rabins. Dr. Rabinswill provide feedback to each clinical site director regarding the findings of the audit.

DIADS-2 Handbook

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10. Sertraline treatment

10.1. Dosing schedule of sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11710.2. Patient and caregiver instruction about study medication . . . . . . . . . . . . . . . . . . . . . . 11810.3. Side effect monitoring and management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11910.4. Treatment adherence monitoring and documentation . . . . . . . . . . . . . . . . . . . . . . . . . 12010.5. Treatment termination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12110.6. Unmasking of treatment assignment before week 24 . . . . . . . . . . . . . . . . . . . . . . . . . . 12210.7. Unmasking of treatment assignment at 24 weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12310.8. Adverse event reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

DIADS-2 Handbook 10. Sertaline treatment

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10.1. Dosing schedule of sertraline

The target study dose will be 100 mg per day, provided as a single dose in the morning. Patientswill start on 50 mg of sertraline daily for one week. The dose will be increased to 100 mg after aweek. Every effort should be made to achieve this target dose for the vast majority of randomizedpatients.

Clinicians will have the option of increasing or decreasing the daily dose by 25 mg in the first 4 weeks of study depending on response and tolerability. However, such dose adjustments should becarried out judiciously and only after careful consideration and discussion within the site team. Forexample, some patients will have unacceptable side effects on 100 mg and will have to be reduced toa lower dose so as to continue on study treatment. Others will tolerate the medication well and theirpsychiatrist might feel that they would tolerate and might benefit from the higher dose of 125 mg perday. Reductions of dose will only be allowed for unacceptable side effects. It is anticipated thatdose adjustments in most cases will be limited to two reductions (e.g., from 100 mg to 75 mg, then to50 mg if needed) or to one increase (from 100 mg to 125 mg).


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10.2. Patient and caregiver instruction about study medication

A patient and caregiver instruction leaflet is to be provided as a resource to explain toparticipants about the study medication, information how to take the medicine, and possible sideeffects. Study staff are to also review this information with the patient and caregiver and to answerany questions before dispensing study drug or placebo. An example of such a document appears inAppendix 17.3. This resource explains study medication handling procedures in simple English andalso provides useful information about sertraline.


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10.3. Side effect monitoring and management

Caregivers and patients will be instructed about the known side effects of sertraline and willalso be asked to monitor for unknown side effects and to report them to the study team. Theinstruction leaflet in section 17.3 will be the basis for education about side effects. Treatment sideeffect monitoring will take place at every scheduled follow-up visits and in-person follow-up visit. For every follow-up visit, the patient and caregiver are interviewed systematically using a checklistof known common sertraline side effects. Severity or absence of each symptom since the last studyvisit is recorded in the Follow-up Medical History (FH) form. If there is a change in the patient’smedical status in the interim between follow-up visits, the information should be recorded in thepatient’s file and included on the data collection form completed at the next scheduled follow-upvisit. All reported side effects that meet the study definitions of an adverse event will be recordedaccording to study procedures articulated in section 10.8.


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10.4. Treatment adherence monitoring and documentation

Caregivers and patients will be instructed on proper use of the study medication to ensureadherence. They will also be asked to keep track of their study drug supply and to return any unusedportions of the study drug supply to provide information on compliance. The instruction leaflet insection 17.3 will be the basis for education about study drug supply and adherence. At eachscheduled follow-up visit study clinical staff will record a caregiver estimate of the amount of pillstaken since the last visit as prescribed in the Study Drug Issue and Return form. Clinical staff willalso review the returned unused medication supply, conduct pill counts, and reconcile this with thesupply provided. This reconciliation will be used to estimate number of missed doses.


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TtermDIADS-2Notebooks3\Handbookv1.1\manall_22wpd

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10.5. Treatment termination

In general, treatment termination during the first 12 weeks of the double-blind treatment periodwill occur under limited circumstances. The most common reason for treatment termination will bepatient’s or caregiver’s refusal of further treatment of the patient. Refusal of treatment does notnecessarily imply refusal to continue to be followed in the study; every effort is to be made tocontinue to follow patients who refuse further study treatment at follow-up visits. If this shouldoccur, the treatment termination form is to be completed and faxed to the CC.

The allowed dosage reduction to 75 mg for unacceptable side effects is expected to greatlyreduce the need for investigator-initiated treatment termination. However, in rare occasions (e.g.,allergic reaction), treatment termination may be initiated by the investigator for safety reasons. Insuch cases, if the patient continues to be in need of different treatment for “Depression ofAlzheimer's Disease”, the patient should be treated according study physician’s discretion and withinthe standard of care. As with participant-initiated treatment termination, the participant should befollowed and rated on study outcomes as specified in the protocol if possible.

At the conclusion of 12 weeks of double-blind therapy, if the patient’s mood has not improvedfollowing the parameters specified in the protocol (mADCS-CGIC=1-4), study double-blindtreatment will be terminated and patients will be treated for depression according to the studyphysician's discretion within the standard of care. The treatment prescribed will be recorded.

Study physicians are reminded that withdrawal symptoms have been reported after abruptdiscontinuation of sertraline. Consequently, if DIADS-2 patients are to stop study drug for whateverreason (e.g., patients/caregivers decide to stop drug, or study physician’s stops at study treatment atweek 12), they should be tapered off the study drug using the usual clinical practices employedlocally for sertraline discontinuation. Patients and caregivers should be advised about this issue atthe start of the study. They should be advised to contact the local study team to plan a taper if theydecide to discontinue study treatment.


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10.6. Unmasking of treatment assignment before week 24

Reasons for unmasking before 24 weeks• The need to unmask a patient’s treatment assignment before 24 weeks should happen

rarely, if ever• Unmasking of treatment assignment before 24 weeks should be limited to emergency

situations, such as accidental overdose, in which withholding knowledge of the identity ofthe drug will lead to unreasonable danger or suffering

• Unmasking before 24 weeks should not be necessary for the medical management ofpotential side effects; if a patient experiences an adverse event that the study physicianthinks could be related to a study drug and considers significant enough to require action,the drug should be stopped and the patient treated according to best medical judgment

Procedures for unmasking before 24 weeks• For each medication identifier, the clinical sites will have an opaque, sealed envelope

containing the identity of the drug labeled with that identifier• In an emergency situation, the study physician may elect to unmask a patient’s treatment

assignment• To the extent possible without compromising medical care, knowledge of the treatment

assignment should be limited to one person, preferably not the treating physician• The designated person unmasks the study treatment by opening the appropriate envelope

and reading the information contained on the Treatment Unmasking (TU) form

Reporting and review of unmaking• Any unmasking of treatment assignment before 24 weeks must be reported using the TU

form- A copy of the TU form should be faxed to the Coordinating Center immediately- The original TU form should be filed in the patient’s study file

• The unmasking envelopes will be inspected at site visits to verify documentation of allopened envelopes

• To encourage accountability, any instance of unmasking before 24 weeks and the reasonfor it will be discussed and evaluated by the Steering Committee


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10.7. Unmasking of treatment assignment at 24 weeks

Reason for unmasking• Once patients have completed the data collection required for the 24-week visit, treatment

assignment is to be unmasked, so that patients and physicians have knowledge of studytreatment when deciding about future, “off-study” treatment

Procedures for unmasking• If possible, clinic staff should notify the Coordinating Center 1 day before they anticipate

unmasking treatment assignment at 24 weeks• On the day of the 24-week visit, clinic staff should complete all data collection before

contacting the CC to request the unmasking• CC staff will complete the Treatment Unmasking (TU) form and fax it to the clinic• The patient and caregiver should be told of the treatment assignment• The TU form should be included in the patient’s study file


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10.8. Adverse event reporting

10.8.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12510.8.2. Reporting on the Baseline and Follow-up Medical History forms . . . . . . . . . . . . 12610.8.3. Safety reporting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12710.8.4. Death reporting and documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128



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10.8.1. Overview

Definitions from FDA regulations for post-marketing studies• Adverse drug experience: Any adverse event associated with the use of a drug in humans,

whether or not considered drug related, including: An adverse event occurring in the courseof the use of a drug product in professional practice; an adverse event occurring from drugoverdose whether accidental or intentional; an adverse event occurring from drug abuse; anadverse event occurring from drug withdrawal; and any failure of expectedpharmacological action

• Serious adverse drug experience: Any adverse drug experience occurring at any dosethat results in any of the following outcomes: Death, a life-threatening adverse drugexperience, inpatient hospitalization or prolongation of existing hospitalization, a persistentor significant disability/incapacity, or a congenital anomaly/birth defect. Important medicalevents that may not result in death, be life-threatening, or require hospitalization may beconsidered a serious adverse drug experience when, based upon appropriate medicaljudgment, they may jeopardize the patient or subject and may require medical or surgicalintervention to prevent one of the outcomes listed in this definition. Examples of suchmedical events include allergic bronchospasm requiring intensive treatment in anemergency room or at home, blood dyscrasias or convulsions that do not result in inpatienthospitalization, or the development of drug dependency or drug abuse

Data collection• The primary mode of data collection on adverse drug experiences will be via systematically

asked, close-ended questions regarding known or expected side effects or complications ofthe study treatment that occurred since the last in-person visit

• Patients and caregivers also will be asked, in an open-ended manner, about the occurrenceof adverse events other than those already recorded

• All serious adverse events that occur during the 24-week treatment period are to bereported on a Safety Report (SR) form, regardless of adherence to treatment or presumedassociation with study treatment

• All deaths that occur during the 48-week follow-up period are to be reported on a DeathReport (DR) form



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10.8.2. Reporting on the Baseline and Follow-up MedicalHistory forms

Purpose• Systematically record information regarding known side effects of sertraline and

complications of AD and depression• Solicit open-ended information about any other adverse events experienced by patients

Forms• Baseline Medical History (BH) form• Follow-up Medical History (FH) form

When• At baseline and every scheduled in-person follow-up visit

By whom• Study physician and coordinator

Procedures• Ask patients and caregivers all questions (section J on the BH form and section G in the

FH form about known side effects of sertraline and complications of AD and depressionand record; for side effects, answer as “none”, “mild”, “moderate”, or “severe”

• Ask patients and caregivers an open-ended question about whether the patient has hadadverse experiences other than those already addressed- Specify other adverse experiences in section J in BH form and section G in FH form- Indicate whether event was “mild”, “moderate”, or “severe”



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10.8.3. Safety reporting

Purpose• Report all serious adverse events that occur during the 24-week treatment period, regardless

of adherence to treatment or presumed association with study drug

Form• Safety Report (SR) form

Other potentially related forms• Treatment Termination (TT) form• Death Report (DR) form

When• Reporting procedures should be started immediately upon learning of a serious adverse

event• Within 1 working day of learning of a serious adverse event, complete and fax SR form to

the CC at (443) 287-5797• Updates should be faxed to the CC as new information becomes available

By whom• Study physician and coordinator

Procedures• Complete one SR form for each serious adverse event• Complete SR form with as much information as available, include a narrative description of

events, clinical significance, presumed association with study drug, any extenuatingcircumstances, and if applicable, date of treatment termination

• If more space is needed on the form, continue the information on an additional form, andmark the appropriate form sequence number in Section A

• If study treatment is terminated, complete a Treatment Termination (TT) form and fax tothe CC

• If additional information becomes available, use a new SR to capture updates and labelform as a follow-up safety report in Section B. Fax the form to the CC

• All Safety Reports and substantive updates received at the CC will be forwarded to the COand the clinical sites for submission to IRBs (if required by local IRB policy), and also willbe sent to Pfizer and NIMH



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10.8.4. Death reporting and documentation

Purpose• Report all deaths that occur during the 48-week follow-up period

Forms• Death Report (DR) form• Death Documentation (DD) form

Potentially related form• Safety Report (for deaths that occur during the 24-week treatment period)

When• Reporting procedures should be started immediately upon learning of a death• Within 1 working day of learning of a death, complete and fax the Death Report form to

the DIADS-2 CC at (443) 287-5797• If death occurred during 24-week treatment period, also complete and fax a Safety Report

to the DIADS-2 CC• Essential information required on the DR form is the clinic, patient ID, date of death,

source of death notification, and, if available, a physician’s opinion regarding the cause ofdeath

• If a physician’s opinion regarding the cause of death is not immediately available, thisshould be provided as an update on a few form as soon as it becomes available

• To update information on a DR form, capture updates on a new DR form and indicate thatform is a follow-up in Section B. Fax the form to the CC

• Request a death certificate and complete the Death Documentation form as soon asdocumentation is obtained; a copy of the documentation of death (with the identifyinginformation concealed and the patient’s ID and 4-letter code written in) should be stapledto the form and mailed to the CC

DIADS-2 Handbook

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11. Study drug management

11.1. Study drug packing and labeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13011.2. Study drug supply . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13111.3. Study drug storage and accounting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13211.4. Study drug issue and accounting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13311.5. Return of study drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13411.6. Procedures for expiring drug and drug returned for pill counts . . . . . . . . . . . . . . . . . . 135

DIADS-2 Handbook 11. Study drug management

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11.1. Study drug packing and labeling

Overview• Each patient will be randomized to a unique study drug kit ID, linked to a medication kit• Each drug kit will be labeled with a unique study drug kit ID• Each drug kit will contain 8 bottles as shown in the table below, to cover all possible doses of

study drug• Each bottle will be labeled with a bottle number to correspond to the visit• Each kit will contain an extra bottle, to accommodate reasonable variability in scheduling, as

shown in the table below• Additional extra bottles (X2-X5) are available from the pharmacy upon request

Table of dose and bottle contents by visit

VisitWeeksfrom rz Target dose

Tabletsrequired Bottle contents

PRN bottle contents(for other doses)*

BL 0 50 mg (2 x 25 mg) x 7 days100 mg (4 x 25 mg) x 7 days

42 x 25 mg 60 x 25 mg in excessof (18.5 days)

--

F02 2 100 mg (4 x 25 mg) x 14 days 56 x 25 mg 80 x 25 mg (20 days) --

F04 4 100 mg (2 x 50 mg) x 28 days 56 x 50 mg 80 x 50 mg (40 days) X1: 40 x 25 mg (40 days)





F24 24 No drug dispensed; returns only

*Bottle X1 is included in the main kit. Bottles X2 through X5 are available upon request.


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11.2. Study drug supply

Ordering and distribution• Each clinical site will receive 4 kits at the start of the study• Sites are to notify the CC and Pharmacy each time a kit is assigned to a patient at

randomization; to do this the Treatment Assignment (TA) form is to be faxed to both places• The pharmacy will send a replacement kit to the site, so the number of kits in stock should

remain at four

Loss of study drug or other unusual circumstances• If a patient loses study drug or for some other reason requires additional drug to be issued,

the “extra” or PRN bottles of 25 mg tablets may be used• In the rare instance that more drug is required beyond that provided in the kit, the clinical

site personnel should contact the CC, and the CC will communicate with the pharmacyregarding distribution of more drug for the appropriate medication kit identifier

Requesting extra bottles (X2 through X5)• If the X1 bottle is issued for whatever reason (dose reduction, visit extension, etc.) the site

will contact the pharmacy via fax. The pharmacy will then send to the site the remaining“extra” bottles (X2 through X5) for the kit requested.


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11.3. Study drug storage and accounting

Study drug storage• Study drug should be kept in a secure location; it must be locked, and access must be

restricted to certified study personnel• Study drug should be stored at room temperature and protected from moisture, freezing,

and excessive heat

Study drug accounting• The clinical sites are to use the Drug Kit Accounting Log (AL) form to record the status of

all study drug kits received from the study pharmacy- When study drug kits are received, the drug kit identifier, date received, and the

expiration date are to be recorded on the log (columns a-c), along with the initials ofthe study staff person making the log entry (column d)

- Whenever a study drug kit is assigned to a patient at randomization, the patient’s studyID and 4-letter code are to be recorded in columns e and f, and the date and initials ofthe study staff person making the log entry are to be entered in columns g and h;documentation of the randomization also is to be made on the Treatment Assignmentform obtained from the randomization envelope (see section 6.3)

- Whenever a study drug kit is returned to the study pharmacy for drug expirationreasons, this should be recorded in columns i and j

• The issue and return of individual bottles from a study drug kit at each patient visit are notrecorded on the Drug Kit Accounting Log, but rather on the Study Drug Issue and Returnform (see section 11.5)

• The clinical site’s inventory of study drug will be audited against the study pharmacy’srecords, the Drug Kit Accounting Log, and the Study Drug Issue and Return forms at sitevisits


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11.4. Study drug issue and accounting

Instructions for issuing study drug• Patients are to be issued drug from the medication kit to which they were assigned at

randomization• Study drug is to be issued to patients at every in-person study visit except for the last one

(week 24)• At each of these visits, patients are to be issued the bottle labeled for that visit (see

section 11.1)- At baseline and week 2, patients are to be given a bottle containing 25 mg sertraline

tablets or matching placebo- At weeks 4, 8, 12, 16, and 20, patients typically are to be given a bottle containing 50

mg sertraline tablets or matching placebo; for patients who are on a dose other than thetarget dose of 100 mg, an “extra” bottle containing 25 mg sertraline tablets ormatching placebo also may be issued (extra bottles are labeled X1 - X5)

- The issue of a bottle or bottles of study drug is to be recorded on the Study Drug Issueand Return (SD) form; the expiration date, dosage, and bottle number are to berecorded, and the small label attached to the bottle with a rubber band is to be affixedto the form in the designated place

• Effort should be made to bring patients in according to the target visit schedule given insection 4.2; however, study drug bottles contain extra tablets (see table in section 11.1) toallow some leeway for the scheduling of the next follow-up visit

• At each in-person study visit, study personnel should complete the SD form, whether or notstudy drug is actually issued or returned; information about the issue of study drug,including the date issued or the reason drug was not issued, is recorded in section B

• When issuing bottles of study drug, the patient’s name, patient ID, and the date should bewritten onto the bottle label

• Patients should be given a list of symptoms to watch for when taking study drug, along withinstructions for contacting study personnel

• If necessary, clinics may issue an “extra” bottle to replace lost or wasted (e.g., a bottle isspilled on the ground) study drug (section 11.2); the issue of drug at other than a scheduledin-person visit should be recorded on a separate SD form as an “N” (unscheduled visit)

• Study drug may be mailed to a patient who misses a scheduled in-person visit if the studyphysician thinks it’s medically appropriate to continue the study drug in the absence of an in-person visit; both the Missed or Incomplete Visit (MV) form and the SD form should becompleted


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11.5. Return of study drug

Instructions for the return of unused study drug issued to patients• Study personnel should ask and remind patients and their caregivers to bring back all

bottles of study drug that are empty, partially used, or unused to their next in-person visit• If patients fail to bring back their study bottles at an in-person visit, they should be told not

to use any more pills out of the old bottles but to bring them back at the next visit• When completing the Study Drug Issue and Return (SD) form at each in-person follow-up

visit, study personnel should record information about the return of study drug in section C,including whether the patient returned bottles, and if so, the number of tablets that remainin each returned bottle

• If patients return empty, partially used, or unused bottles of study drug at some time otherthan an in-person visit (e.g., by mail), an SD form should be completed and the visit IDrecorded as an “N” (unscheduled) visit

• After completion of the SD form, empty, partially used, or unused bottles of study drugbrought back by a patient should be destroyed according to local institutional procedures

DIADS-2 Handbook

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11.6. Procedures for expiring drug and drug returned for pillcounts

11.6.1. Expiring study drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13611.6.2. Study drug returned for pill counts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137

DIADS-2 Handbook 11.6. Destruction of study drug

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11.6.1. Expiring study drug

Management of expiring drug• When study drug is bottled and packaged by the Johns Hopkins Investigational Drug

Service, an expiration date of one year or less from the time of bottling and packaging isput on the labels

• Clinical site personnel should monitor the expiration dates of the unused study drug kitsthey have in stock; 6 months before unused kits are to expire, personnel should requestreplacements from the Johns Hopkins Investigational Drug Service

Replacement of expiring study drug• After a replacement kit has been received, the corresponding unused study drug kit that is

expiring is to be returned to the pharmacy as instructed• Return of unassigned expiring study drug kits is to be recorded on the Drug Kit Accounting

Log (AL) form (see section 11.3)• Receipt of the replacement kit is to be recorded on the AL form

DIADS-2 Handbook 11.6. Destruction of study drug

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11.6.2. Study drug returned for pill counts

Instructions for destruction of study drug returned for pill counts• Document study drug returned for pill counts on the Study Drug Issue and Return (SD) form• Keep study drug in the bottles administered to the patients; store bottles in a secure location• Study drug will be audited by the CC at site visits• After auditing is complete, destroy drug following local institutional procedures• Destruction of study drug is to be recorded on the AL form

DIADS-2 Handbook

139

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12. DNA banking

12.1. DNA consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13912.2. Collection, labeling, and storage of DNA samples . . . . . . . . . . . . . . . . . . . . . . . . . . . 14012.3. DNA sample shipping procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14312.4. Access to samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14512.5. Destruction of DNA samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146

DIADS-2 Handbook 12. DNA banking

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12.1. DNA consent

C All DIADS-2 patients will be asked to provide a blood sample for DNA banking andgenetic testing; however, refusal to provide samples will not exclude the patient fromparticipating in the main study

C Consent for DNA banking and genetic testing will be obtained at baseline using local IRB-approved consent forms and following DIADS-2 consent procedures

C Consent may be obtained in a separate form or by separate endorsement (i.e., initial orsignature specific to DNA banking and genetic testing) on the DIADS-2 patient consentform; the prototype consent follows the former format


141

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12.2. Collection, labeling, and storage of DNA samples

12.2.1. Collection, labeling, and storage procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14112.2.2. Label for DNA specimen tube and BC form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142



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12.2.1. Collection, labeling, and storage procedures

• Blood samples are to be drawn from patients at the baseline visit for DNA banking• Labels, from a sheet of freezer-safe labels marked as “DIADS-2 labels for DNA

specimens”, should be prepared; one label from each of the two columns marked as “Bloodtube labels” and “BC form labels” should be completed with the patient’s ID and four-lettercode, the visit ID, and the date, using freezer-safe ink

• At the time of blood collection, study personnel obtaining the blood sample for DNAbanking will record the date and time of the blood draw on the Blood Collection (BC) form

• The blood tube label should be placed on a large (10 ml) “purple top” EDTA Vacutainer®

tube• The BC form label should be placed on the BC form in section B• Tubes are to be inverted gently to mix the anticoagulant with blood; avoid excess agitation

of the sample to reduce the likelihood of hemolysis• Store the genetic sample upright and refrigerate at 5 C for up to four daysN

• For shipping procedures, see section 12.3



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1 2DIADS-2 DNA ( T ) Srt lev ( )

— — — — Pt ID: Pt 4-ltr: __ __ __ __

Vst ID: __ __ __ Date: ____/____/_____

12.2.2. Label for DNA specimen tube and BC form

The contents of the DNA BC form label are to be affixed to the BC form which is later sent tothe CC to be entered in the DIADS-2 database.


144

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12.3. DNA sample shipping procedures

Shipping will be in accordance with all applicable laws and regulations for the shipping ofbiological samples. Cost associated with shipping of samples to Pittsburgh will be borne by DIADS-2.

Procedure• Sites may ship samples only on Mondays, Tuesdays, or Wednesdays, NOT on Thursdays or

Fridays; the lab is not open to receive samples on weekends or holidays. Samples are to besent by FedEx for arrival on the next working day

• Blood samples are to be stored at upright 5 C for up to 4 daysN

• Study staff will attach the completed labels on the tube and Blood Collection (BC) form.Samples are placed in a zip-lock polyethylene bag. Bags with samples will be placed in theshipping container at room temperature; samples are not to be frozen. BC form is to beincluded with each shipment

• Fax Blood Specimen Shipment Notification (BN) form to the University of Pittsburgh and tothe DIADS-2 Chairman’s Office

• Call or e-mail Maggie Kirshner (412-246-6273; [email protected]) or Denise Sorisio (412-246-6272; [email protected]) in advance with the tracking number of the shipment

• Samples will be sent to: Geriatric Psychopharmacology Labc/o Maggie KirshnerWPIC/UPMC, Room 14453811 O’Hara StreetPittsburgh, PA 15213

• The University of Pittsburgh will store the blood samples for the duration of the DIADS-2and up to 5 years after the end of the study (March 1, 2013). After this time, the remainderof the samples will either sent to DIADS-2 investigators or destroyed

• Laboratory Manager, Maggie Kirshner, will provide EDTA Vacutainer tubes, plastic bags,®

and a shipping container to each site. She can be reached at (412) 246-6273

12.3. DNA sample shipping procedures


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Shipment records• The "carrier's receipt" of the overnight mail shipment and Blood Specimen Shipment

Notification (BN) form will be maintained at each DIADS-2 site in a special file

• Upon arrival at the University of Pittsburgh, samples will be registered in a computerdatabase as "inventory of samples"

• An inventory of samples received by Geriatric Psychopharmacology will be kept at theUniversity of Pittsburgh. This file will be sent to the DIADS-2 CO as necessary to reconcilesample lists


146

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12.4. Access to samples

C Access to and use of the genetic samples stored at the University of Pittsburgh's GeriatricPsychopharmacology are to be governed by a "Memorandum of Understanding" (MoU)between the DIADS-2 Study Chair and Dr. Bruce Pollock, as well as the legalrepresentative of the University of Pittsburgh, Michael Crouch

C The MoU will specify that the samples are the property of the DIADS-2 SteeringCommittee (SC), that they will be stored at the University of Pittsburgh at its expense, andthat all use of the samples will require final approval of the DIADS-2 SC; in all cases IRBapproval will be required to analyze these samples

C Samples will be stored but not extracted or analyzed until funding has been obtained tocover the costs associated with genetic testing; if funding is obtained, any report that makesuse of data derived from the samples in abstracts, presentations, publications, etc. willacknowledge the origin of the samples and DIADS-2


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12.5. Destruction of DNA samples

PurposeC Ensure that DNA samples are destroyed when requested

WhenC Patient or legal representative withdraws consent for DNA banking

FormC Request to Destroy DNA Sample (DS) form

By whomC Coordinator or other study personnel• Specimen repository at University of Pittsburgh

ProceduresC Complete the Request to Destroy DNA Sample (DS) form for each patient or legal

representative who withdraws his/her consent for DNA bankingC Fax a copy of the DS form to University of Pittsburgh, attention Bruce Pollock

at (412) 246-6260C Fax a copy of the DS form to the CCC Specimen repository will destroy DNA samples, as requestedC Specimen repository personnel will verify the patient ID and name codes, record the

number of aliquots destroyed, sign item off on DS form, fax a copy to the CC, and send theoriginal back to the appropriate clinical site

DIADS-2 Handbook

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13. Sertraline blood levels

13.1. Consent for blood sertraline levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14813.2. Collection, labeling, and storage of sertraline level samples . . . . . . . . . . . . . . . . . . . . 14913.3. Shipping of sertraline level samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15213.4. Access to plasma samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

DIADS-2 Handbook 13. Sertraline blood levels

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13.1. Consent for blood sertraline levels

C Consent will be obtained at the screening visit using local IRB-approved consent forms andfollowing DIADS-2 consent procedures

C Participation in sertraline plasma level determination will be offered to all DIADS-2participants; however, refusal of participation in sertraline plasma level determination willNOT be a reason for exclusion from the main study

C Patients may elect to opt out at any time from this aspect of the studyC Consent may be obtained on a separate form from the DIADS-2 patient consent form

(e.g., combined with the consent for DNA and genetic testing), or by separate endorsement(i.e., initial or signature specific to blood sertraline levels) on the patient consent form; theprototype consent follows the latter format


150

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13.2. Collection, labeling, and storage of sertraline levelsamples

13.2.1. Collection, labeling, and storage procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15013.2.2. Labels for sertraline level specimens and BC form . . . . . . . . . . . . . . . . . . . . . . . . 151

13.2. Collection, labeling, and storage of sertraline level samples


151

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13.2.1. Collection, labeling, and storage procedures

• Blood samples are to be drawn from patients at the week 4 and 12 visits for laboratorydeterminations of sertraline plasma concentrations

• Labels, from a sheet of freezer-safe labels marked as “DIADS-2 labels for sertraline levelspecimens”, should be prepared; one label from each of the three columns marked as “Bloodtube labels”, “Plasma specimen labels”, and “BC form labels” should be completed with thepatient’s ID and four-letter code, the visit ID, and the date, using freezer-safe ink

• At the time of blood collection, study personnel obtaining the blood sample for sertralinelevels will record the dose of study medication, date and time study medication last taken,and date and time of the blood draw on the Blood Collection (BC) form

• The blood tube label should be placed on a large (10 ml) “purple top” EDTA tube and usedfor blood collection

• The BC form label should be placed on the BC form in section B• As soon as possible after blood collection, ideally within 2 hours, blood samples are to be

processed to obtain plasma; samples are best kept on ice or refrigerated until processing- The tubes will be spun down in a centrifuge for 10 minutes- The supernatant plasma will be transferred with a pipette to a storage tube- The storage tube should be labeled with the plasma specimen label

• The tubes with the remaining red blood cells will be discarded• Plasma samples are to be placed upright in a -20 c or -70 c freezerN N

- Those stored at -20 c may be stored for up to a month before shippingN

- Those stored at -70 c may be stored for up to 3 months before shippingN

• For shipping procedures, see section 13.3

13.2. Collection, labeling, and storage of sertraline level samples


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1 2DIADS-2 DNA ( ) Srt lev ( T )

— — — — Pt ID: Pt 4-ltr: __ __ __ __

Vst ID: __ __ __ Date: ____/____/_____

13.2.2. Labels for sertraline level specimens and BC form

Information regarding the blood collection is to be completed on the sertraline BC form label.This label is then affixed to the BC form which is later transmitted to and entered by the CC.


153

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13.3. Shipping of sertraline level samples

Shipping will be in accordance with all applicable laws and regulations for the shipping ofbiological samples. Costs associated with shipping of samples to Pittsburgh will be covered byDIADS-2.

Procedure• Sites may ship samples only on only Mondays, Tuesdays, or Wednesdays, but not on

Thursdays or Fridays; the lab is not open to receive samples on weekends or holidays. Samples are to be sent by FedEx for arrival on the next working day

• Samples stored at -20 c are to be shipped to the Geriatric Psychopharmacology monthly; N

alternatively, samples stored at -70 c may be shipped every 3 monthsN

• Samples are placed in a zip-lock polyethylene bag, than placed in the shipping containerwith enough dry ice to keep samples frozen for 48 hours. A copy of the Blood SpecimanShipment Notification (BN) form detailing the contents of the shipment, is to be includedwith each shipment

C The BN form also is to be faxed to University of Pittsburgh and to the DIADS-2Chairman’s Office

• Plasma samples are be sent to: Bruce G. Pollock, M.D., Ph.D.Geriatric PsychopharmacologyRoom 1438, WPIC3811 O'Hara StreetPittsburgh, PA 15213(412) 246-6273 (phone)(412) 246-6260 (fax)

• Plasma tubes will be frozen at -70 c at Geriatric Psychopharmacology at the University ofN

Pittsburgh

• Geriatric Psychopharmacology will batch sertraline samples and analyze them periodicallyduring the study; plasma drug concentration data linked to study identifiers will be sent tothe DIADS-2 Chairman's Office periodically in Excel format

• After the determination of plasma sertraline levels, any unused plasma will be destroyed

• Laboratory Manager Maggie Kirshner will provide Vacutainer tubes, plastic bags, and ashipping container to each site; she can be reached at (412) 246-6273

13.3. Shipping of sertraline level samples


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Shipment records• The "carrier's receipt" of the overnight mail shipment and BN form will be maintained at

each DIADS-2 site in a special file

• Upon arrival at the University of Pittsburgh, samples will be registered in a computerdatabase as "inventory of samples"

• An inventory of samples received by the Geriatric Psychopharmacology Lab will be kept atthe University of Pittsburgh; this file will be sent to the DIADS-2 CO as necessary toreconcile sample lists


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13.4. Access to plasma samples

• Access to and use of the samples stored at the Geriatric Psychopharmacology Laboratoryare to be governed by a "Memorandum of Understanding" (MoU) between the DIADS-2Study Chair and Bruce G. Pollock, M.D., Ph.D., as well as the legal representative of theUniversity of Pittsburgh, Michael Crouch

• The MoU specifies that the samples are the property of the DIADS-2 Steering Committee(SC), and will be analyzed at the University of Pittsburgh to determine sertraline levels,and use of the samples shall require approval of the DIADS-2 SC. In all cases, IRBapproval will be required to analyze these samples

• Any report that makes use of data derived from the samples in abstracts, presentations, andpublications require approval of the DIADS-2 SC and shall acknowledge the origin of thesamples and DIADS-2 in a way that is acceptable to the SC

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14. Forms management

14.1. Identification numbers and codes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15614.2. Format of data collection forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15814.3. Completing forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16014.4. Missing data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16114.5. Handling forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16214.6. Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16314.7. List of DIADS-2 forms by form abbreviation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16414.8. List of DIADS-2 forms by function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

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14.1. Identification numbers and codes

Clinic ID• 3- or 4-character alpha code• Assigned by the CC• Uniquely identifies the clinic

Patient ID • 4-character alpha-numeric code, one letter followed by 3-digit number, used to uniquely

identify a patient in the database• Link between patient ID and personal identifiers is maintained at the local clinical site only• A sequence of patient ID is allotted to each clinical site by the CC• Individual IDs are assigned to all patients, eligible or ineligible, by the clinic coordinator at

the time of consent and start of data collection (see section 6.1)• Patient ID remains the same for the duration of the trial• Patient IDs given to ineligible patients are not to be reused

Patient 4-letter code• 4-character alpha code that will be part of the database and used as a secondary patient

identifier for quality assurance purposes• Assigned by the coordinator along with Patient ID at the time of consent and start of data

collection• Suggested convention for the 4-letter code is first letter of first name + first letter of middle

name + first two letters of last name• If a person has no middle name, the appropriate field may be filled with an X• If a person has only one name, all characters for the 4-letter code may be taken from that

name• If patient or clinic personnel are concerned about confidentiality, a 4-letter code independent

of the person's name may be chosen• The 4-letter code should be unique within a clinical center; a number can be used for the 4th

character to make a code unique• Remains the same for the duration of the trial, regardless of "error" in creating it or change in

name

Caregiver 4-letter code• Assign a caregiver a unique 4-letter code in the same manner as above; if a patient’s

caregiver changes, the new caregiver must be assigned a new, unique 4-letter code

14.1. Identification numbers and codes


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Visit ID • 1- to 3-character alpha-numeric code• Determined by purpose of visit and timing with respect to visit windows• Visit ID:

SCR screeningBL baseline assessment and randomizationF# scheduled followup visits, number corresponds to the week of visit target date (e.g.,

F02 is followup visit intended to occur 2 weeks following randomization)T# scheduled telephone follow-up, number cooresponds to the week of target dateN unscheduled visit

Staff ID• 3-character alpha-numeric code• Uniquely identifies each clinic staff member• Assigned by the CC upon completion and approval of personnel certification


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14.2. Format of data collection forms

Headers and footers• Each DIADS-2 form includes an instruction box at the top of the first page that gives:

- Purpose of the form - When it should be completed - Who administers the form - Specific instructions for the form

• The header at the top left of the page identifies the study• The top right of the first page of each form to be entered into the DIADS-2 database has a

space marked by "Keyed: ( )"• The top right of subsequent pages is reserved for the patient ID, which should be written on

each page of the form• The footer includes:

- 2-letter form abbreviation - Form revision number and date - Form name - Page number

• When a form is revised: - If the revision affects the data that are collected, the form revision number and date

will change - If the form is revised without affecting the data collection (eg, an instruction is added,

or the wording of an item is revised for clarity but the intent of the item is unchanged),only the revision date of the form will be changed

Key fields• The first 8 items of each form are the key fields, which identify the clinic, patient, visit,

form, and caregiver:

Clinic, patient, and visit identification

1. Clinic ID: __ __ __ __2. Patient ID: __ __ __ __3. Patient 4-letter code: __ __ __ __4. Date of visit: __ __ - __ __ - __ __ __ __

month day year5. Visit ID: __ __ __6. Form & revision: __ __ __7. Sequence number of this form: __8. Caregiver 4-letter code: __ __ __ __

14.2. Format of data collection forms


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• The form and revision number will be printed on the form in item 6 as well as in the footer• If a form is used only for one specific visit, the visit ID will also be printed on the form in

item 5• In general, date of visit (item 4) should be the date the procedure being reported was

carried out; instructions may be provided on the form if there is some uncertainty as towhat date to use in this item

• Each regularly scheduled follow-up visit or telephone contact will have an associated timewindow - This time window is an interval during which the visit may be completed and not be

considered missed - Visit time windows are discussed in section 4.2

• If an item requires additional space on a certain form, a sequence number can be entered initem 7 and additional forms can be completed to capture overflow information

Assurance of review• Each form contains a section for assurance of review• The designated personnel, often the study physician and coordinator, should review the

form carefully before signing• The items in this section include:

- Designated personnel ID - Designated personnel signature - Date the form was reviewed


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14.3. Completing forms

General guidelines for completing data collection formsC Use ink that is dark enough to photocopy legiblyC Enter the patient ID at the top right of every page of formC Print all written responsesC Right justify all numbers, enter leading "0" where applicableC Left justify all letter codes, leave remaining spaces blankC Enter data in the units and number of digits prescribed on form

- Do not record fractions- Use a decimal only if hard coded (printed on the form)- Record a value behind a hard-coded decimal point, including "0" if applicable

C Perform all computations using a calculatorC Review all responses for completeness and accuracy before signing off on formC To correct a response:

- Draw 1 or 2 lines through incorrect response- Write correct response next to or above it- Put initials and date in the margin by the correction- Do not obliterate, erase, or white-out incorrect responses

C Explanatory comments may be written in the margins or on the last page of the formC Whenever possible, forms should be completed in real time, not retroactivelyC Data should not be written onto forms in advance of a patient visit (for example, with

data from a previous visit that one thinks is unlikely to have changed, to be verified at thevisit)

C Only the most recent version of a form should be used for data collection

Instructions on specific data collection formsC Skip patterns may be designated in one of two ways:

- By an arrow from the response to a box with the number of the next item to be completed- By an italicized instruction at the end of an item

C Other special instruction are indicated on the form in italics; examples include:- check only one: only one of the listed responses should be checked- check all that apply: one or more of the listed responses can be checked- specify: a response should be printed on the line(s) provided

C For information related to eligibility:- An arrow drawn from a response item to a STOP sign indicates a condition that makes a

person ineligible- A caution sign indicates cautionary instructions; a patient may continue being screened if

the condition regarding eligibility is met before randomization- The remainder of the form does not need to be completed or entered into the database- The Ineligibility Summary (IS) form must be completed for screen failures. The person

should not be randomized- A caution sign is used when a person is currently ineligible but may become eligible

after specification is taken, such as stopping a medication or waiting for a required timeinterval; information about the action required is provided in italics


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14.4. Missing data

C If some data are missing and cannot be obtained when the form is reviewed, write theappropriate code in the first left hand space of the empty data field:

n = Not applicable in this situationm = Data missing; will not be obtainedd = Don’t know? = Data temporarily missing; to be collected or resolved in the near future

C If “?” is used, update form or page with complete data when availableC For the Neuropsychological Test Summary (NS) form, use the following codes for missing

information:c = Task not administered because patient was unable to comprehend an entire tasks = Sensory impairment or physical limitationr = Patient refused teste = Examiner error


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14.5. Handling forms

C DIADS-2 forms are organized by visit and function on the Forms CD; packets of forms fora given patient visit can be printed from these electronic files

C One complete set of DIADS-2 master forms should be kept in the DIADS-2 FormsNotebook

C If copying forms from the Forms Notebook or Forms CD, make a limited number of copiesat a time because forms typically need to be revised, especially at the beginning of the trial

C Forms necessary for each visit are outlined in section 4.5 of this handbook


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14.6. Storage

• A separate file folder or notebook should be created for each patient randomized- The patient folder or notebook is to contain all completed data collection forms for a

patient- The Visit Time Windows Schedule should be kept at the front of each patient's folder or

notebook, outlining the individualized visit time windows for that patient- Sets of forms from each visit may be separated into sections by colored paper dividers,

folders, or other means- Forms should be arranged chronologically by visit, with the most recent visit

immediately behind the Visit Time Windows Schedule• Patient files should be stored in a locked room or locked filing cabinet• Consent statements should be filed separately from the participant folders in a secure place• It is preferable for documents with individual patient identifiers (e.g., the Patient and

Caregiver Location (PL) form) to be filed separately from the patient notebooks


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14.7. List of DIADS-2 forms by form abbreviation

Form abbreviation Form name Data entry requiredY/N

AC Alzheimer-Associated Affective Disorder Criteria Rating Y

AD Activities of Daily Living Inventory Y

AL Drug Kit Accounting Log N

BC Blood Collection Y

BD Beck Depression Inventory Y

BH Baseline Medical History Y

BN Blood Specimen Shipment Notification Y

BQ Burden Questionnaire Y

CA Caregiver Activity Survey Y

CC Clinic Certification N

CF Case Summary N

CI Conflict of Interest Disclosure N

CS Cornell Scale for Depression in Dementia Y

DA Daily Affect Diary Y

DC Depression of Alzheimer’s Disease Criteria Rating Y

DD Death Documentation Y

DL Clinical Site Dementia Study List N

DP Dependence Scale Y

DR Death Report Y

DS Request to Destroy DNA Sample Y

FE Form Edit List N

FH Follow-up Medical History Y

GM General Medical Health Rating Y

14.7. List of DIADS-2 forms by form abbreviation


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Form abbreviation Form name Data entry requiredY/N

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IS Ineligibility Summary Y

KA Abridged Knowledge Assessment N

MA Modified ADCS-Clinical Global Impression of Change

Baseline Evaluation

N

MD Major Depression Criteria Rating Y

MI Minor Depression Criteria Rating Y

MO Modified ADCS- Clinical Global Impression of Change

Follow-up Evaluation

Y

MS Medical Outcomes Study Short Form Health Survey Y

MV Missed or Incomplete Visit/Telephone Contact Y

NP Neuropsychiatric Inventory Y

NS Neuropsychological Test Summary Y

PC Personnel Certification N

PL Patient and Caregiver Location N

QL Alzheimer’s Disease Related Quality of Life Scale Y

SD Study Drug Issue and Return Y

SR Safety Report Y

SS Screening Summary Y

TA Treatment Assignment Y

TF Telephone Follow-up Y

TM Transmittal Form N

TT Treatment Termination Y

TU Treatment Unmasking Y


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14.8. List of DIADS-2 forms by function

Patient and caregiver data forms (Pt & cg data)Eligibility and baseline forms (Eligibility and baseline)

Patient and Caregiver Location (PL)Screening Summary (SS)Baseline Medical History (BH)

General follow-up forms (General follow-up)Follow-up Medical History (FH)General Medical Health Rating (GM)Telephone Follow-up (TF)

Depression criteria rating forms (Depression criteria)Depression of Alzheimer’s Disease Criteria Rating (DC)Alzheimer-Associated Affective Disorder Criteria Rating (AC)Major Depression Criteria Rating (MD)Minor Depression Criteria Rating (MI)

Mood outcome forms (Mood outcome)Modified ADCS-Clinical Global Impression Baseline Evaluation (MA)Modified ADCS-Clinical Global Impression of Change Follow-up Evaluation (MO)Cornell Scale for Depression in Dementia (CS)Neuropsychiatric Inventory (NP)Daily Affect Diary (DA)

Functional measure forms (Functional measures)Activities of Daily Living Inventory (AD)Dependence Scale (DP)Alzheimer’s Disease Related Quality of Life Scale (QL)

Caregiver burden, depression, quality of life measure forms (Caregiver measures)Burden Questionnaire (BQ)Beck Depression Inventory (BD)Caregiver Activity Survey (CA)Medical Outcomes Study Short Form Health Survey (MS)

Neuropsychology measures forms (Neuropsych measures)Neuropsychological Test Summary (NS)

Study drug forms (Study drug)Study Drug Issue and Return (SD)Drug Kit Accounting Log (AL)

Blood specimen forms (Blood specimen)Blood Collection (BC)Blood Specimen Shipment Notification (BN)

14.8. List of DIADS-2 forms by function


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Treatment assignment and unmasking forms - illustration only (Tx assignment)Treatment Assignment (TA)Treatment Unmasking (TU)

“As needed” patient data forms (“As needed” Pt data)Ineligibility Summary (IS)Missed or Incomplete Visit/Telephone Contact (MV)Treatment Termination (TT)Safety Report (SR)Death Report (DR)Death Documentation (DD)Request to Destroy DNA Sample (DS)

Administrative forms (Administrative)Clinic Certification (CC)Personnel Certification (PC)Abridged Knowledge Assessment (KA)Conflict of Interest Disclosure (CI)Case Summary (CF)Clinical Site Dementia Study List (DL)Database Edit (DE)Transmittal Form (TM)Form Edit (FE)

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15. Data management

15.1. Database overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16915.2. Data entry and form transmission procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17015.3. Data editing and form edit transmission procedures . . . . . . . . . . . . . . . . . . . . . . . . . . 171

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15.1. Database overview

• DIADS-2 data system is a centralized database located at the CC• Sites are to transmit forms and form edits to the CC on a regular basis• Forms and form edits are received and processed by the CC. Errors on key identifiers are

queried upon receipt; other errors are to appear on the monthly edit reports• Sites are to resolve all queries in a timely manner; monthly edit reports are to be returned by

the date indicated on the report • Form edits are to be sent to the CC for correction in the database• Outstanding queries are reported to the DSMB on an annual basis


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15.2. Data entry and form transmission procedures

Purpose• Transmit forms to be entered into the database at the CC

Form• Transmittal (TM) form

When • Whenever forms to be data entered are completed at the site

By whom• Study coordinator or nurse

Procedures• Send copies of completed forms to the CC on a weekly or biweekly basis, depending on

volume. Large shipments are to be sent via Fed Ex; smaller shipments may be faxed to theCC at 443-287-5797

• For all form transmittals, complete sections A and B on the TM form and include this in eachform shipment; store a copy of the TM form at the site

• Check forms for completeness prior to shipment; do not include original forms or forms thatdo not require keying in these shipments

• See section 15.3 for procedures on database editing


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15.3. Data editing and form edit transmission procedures

Purpose• Transmit form edits requiring a database edit

Forms• Form Edit List (FE) form

When • Whenever edits are made to a form already sent to the CC

By whom• Study coordinator or nurse

Procedures• Document edit by striking out original value and initialing and dating the edit; record

information about the edit on the FE form• Fax copies of the forms with changes and a completed FE form to the CC (multiple edits

can be documented on one FE form)• For edits resulting from a monthly edit report, follow the above procedures and also

document action on the monthly edit report as before and include the report with theshipment to the CC

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16. Quality assurance

16.1. Clinic certification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17316.2. Personnel certification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17416.3. Performance monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17516.4. Data quality surveillance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17616.5. Site visits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

DIADS-2 Handbook 16. Quality assurance

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16.1. Clinic certification

The general requirement for clinic certification is to complete the Clinic Certification (CC)form. The purpose of the form is to:

C Document that each clinical site has the Institutional Review Board approval necessary forparticipation in DIADS-2

C Walk clinic personnel through a list of the facilities, equipment, and supplies that areneeded to complete DIADS-2 procedures

Upon completion, this form should be faxed to the CC at (443) 287-5797. Once approved, acertification grid, documenting the clinic certification, will be sent to the clinic.


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16.2. Personnel certification

The functions that require personnel certification are:C Director or other study physicianC Coordinator or study nurseC Outcomes rater, including CSDD and dAD • Outcomes rater (non-CSDD and non-dAD ratings)C Caregiver psychosocial intervention administrator• Neuropsych administrator

The general requirements for personnel certification are as follows:C Read the DIADS-2 ProtocolC Read relevant sections of the DIADS-2 HandbookC Complete the Personnel Certification (PC) form (a form that indicates who is requesting

certification, the functions requested, and assurance of integrity in the data collectionprocess)

C Attend the DIADS-2 training meeting and complete a knowledge assessment

Certain functions have additional requirements for certification. These include:• Outcomes rater for CSDD and dAD: Rate CSDD and dAD video for interater reliability• Caregiver psychosocial intervention administrator: Participate in caregiver psychosocial

intervention training through the CO• Neuropsych administrator: Train on neuropsychological assessments by the DIADS-2

psychologist in CO

Alternative training will be provided for those who begin working on the study after the initialDIADS-2 training meeting.

It is advisable to certify two people for each function so that there is backup during illness,vacation, or other absence. A staff member may be certified for more than one function.

When a person meets all certification requirements for the function(s) designated, thecertification coordinator at the CC will issue the staff member a unique, 3 character alpha-numericpersonal identification number (ID). Each staff member will have a single ID, even if certified formore than one function.

The general forms related to staff certification are:PC: Personnel CertificationKA: Abridged Knowledge Assessment


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16.3. Performance monitoring

C The CC will maintain real-time records of randomization at all clinical sites. As part of therandomization procedure, sites will fax the treatment assignment obtained from theDIADS-2 randomization envelope to the CC. Based on these faxes, the CC will generateenrollment reports that will provide a count of patients enrolled at each clinic

C Approximately every 6 months, the CC will generate reports summarizing the performanceof all clinical sites. These reports will include information on enrollment and thepercentage of expected visits for which documentation has been entered into the DIADS-2data system. Also, for those visits for which data have been entered, the report will showthe percentage of missed visits, the completeness of data collection, and protocoldeviations. Performance reports will be reviewed by the Steering Committee which willmake decisions regarding actions to be taken in the event that a clinic is performing poorly


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16.4. Data quality surveillance

General procedures• Assurance of data accuracy will occur routinely through two main procedures:

- Monthly checks for completeness and edits- Form audits

• In addition, detection of problems may occur during data analysis. For example, inpreparing reports for Steering Committee and Data and Safety Monitoring Board meetings,problems may be discovered. Outliers and unusual variations or patterns in the data areexamined and may reveal problems

• Quality assurance of data analysis is achieved by independent replication of key analyseswithin the CC and review of reports by multiple individuals before distribution

Data entry checks• The data system will contain checks during the data entry process of range, logic, and

consistency of items within forms

Monthly checks for completeness and edits• On a monthly basis, after receipt of data transmittals from the clinical sites, the CC will

generate a database report of:- Number of patients enrolled- Missed visits- Incomplete visits (missing or pending forms)- Missed specimen collections or shipments- Edits (see below)

• Edits are run on the database of the keyed forms monthly; checks for missing, out-of-range,unusual and inconsistent values, and cross-form checks are some of the types of checksperformed- A listing of queries is sent to each clinical site for resolution- The clinical site must respond to each query on the listing and make appropriate edits

to the forms (initialed and dated)- Forms with edits are to be sent to the CC along with a completed Forms Edit List (FE)

form- Items that cannot be corrected (e.g., missing values, unusual measures) are to be

marked with a data entry code directly on the form (see section 14.4); these items areexcluded from future queries upon receipt of the documentation of this change

- A hard copy of the edits, with each resolution, should be kept in a notebook located atthe clinical site

16.4. Data quality surveillance


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Form audits• Sites are to send copies of all patient forms for the first 3 months after the initial patient

randomization for review by the CC• On a periodic basis, the CC selects and requests that copies of forms and neuropsychology

test booklets for specific patients be sent by each clinical site to the CC for auditing• Audited forms are compared with the database; discrepancies are noted and queried• Audited paper forms are also inspected for other problems, which are noted and queried• Each clinical site will be required to resolve discrepancies from the audit report and fax the

resolutions to the CC within 5 days• The CC will generate a summary report of the audit discrepancies by clinical site to be

distributed to all DIADS-2 centers• Discrepancy rates over time by clinical site are reported to the Steering Committee


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16.5. Site visits

PurposeC Conduct an audit of selected patient dataC Review documentation and procedures for the trialC Review study drug kit accounting recordsC Tour facilitiesC Discuss with clinic personnel any problems that have occurred or that are expected to occur

in conducting the trial

Clinic preparationThe following should be available or accessible:• IRB communications organized with original approval letters, revision approvals, annual

renewals, safety reports and any communications regarding concerns or special requests fromthe IRB

• Signed and dated consent forms for all patients, including the date and signature of a witness• Documents including the DIADS-2 Protocol, Handbook, Forms, PPMs, and Directory• Study forms for data audit• Study drugs and study drug accounting logs

Conducting site visitsAt least one person from the CO and one from the CC will attend the site visit. During the

course of the site visit, the following will be reviewed:

IRB Documentation• Original approval• Annual renewals (if applicable)• IRB submissions (including safety reports)• Approval for updated consent forms and protocol

Documents• Directory• Forms Notebook• Handbook• PPMs• Protocol• Database Manual• Randomization envelopes• Unmasking envelopes

16.5. Site visits


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Enrollment and retention• Status• Recruitment strategies• Problems• Losses to follow-up

Personnel• Certification status• Personnel changes• Back-up

Clinical management• Adverse event reporting procedures• Study procedures• Clinic coordination• Clinic concerns or problems

Patient files• Security• Organization• Consent statements

Specimen shipment• Comparison of specimens expected and received• Shipping procedures and problems• Shipping supplies

Protocol performance• Protocol deviations

Forms and data management• Monthly form status report• Source documentation• Data audit (selected patients)• Eligibility criteria• Adverse events• Death reports

Study drug• Comparison of shipments and receipts• Drug storage and security• Drug accounting record

16.5. Site visits


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Previous site visit report• Action items follow-up• Data audit follow-up

Site visit follow-up• A list of action items is compiled at the end of the site visit to identify items which require

further action• The CC will send a written report to the clinical site• The procedure for site visit action item follow-up is:

- Action items will be listed at the end of the site visit report- Clinical sites will be required to respond to action items within 30 days of receipt of the

site visit report; responses should be in writing and sent to the CC- The CC will be required to respond to the action items within 30 days of the completion

of the site visit report

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17. Appendices

17.1. Research Consent for Cognitively Impaired Adults . . . . . . . . . . . . . . . . . . . . . . . . . . . 18217.2. Minority recruitment training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18817.3. Patient information about study medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189

DIADS-2 Handbook 17. Appendices

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17.1. Research Consent for Cognitively Impaired Adults

Recommendations for Institutional Review Boards (IRBs) and Investigators

1. OVERVIEWIndividuals with cognitive impairment are considered a vulnerable population. In this

document, the term "cognitive impairment" refers to dementia, delirium, or more focal cognitivesyndromes as defined in the DSM-IV. Hence, research involving these individuals requires specialcare in design, review, and actual conduct. The purpose of these recommendations is to assistinvestigators and IRBs in identifying key considerations for research involving cognitively impairedpersons. Several basic points should be kept in mind.

Cognitive impairment is not always associated with the lack of capacity for informed consent toresearch. Exclusion from research of otherwise eligible persons with cognitive impairment for thatreason alone, whether or not they lack the capacity to consent to research, is discriminatory andviolates the ethical principle of justice. Individuals who cannot themselves consent to participate inresearch due to cognitive impairment may be enrolled in research projects if the following fourconditions are all met:

• The research offers a reasonable prospect of a direct health-related benefit to theindividual; if there is no reasonable prospect of a direct health-related benefit to theindividual, then the research must pose no more than a minor increment aboveminimal risk, as determined by the IRB, and is likely to yield generalizable knowledgeabout the participant's disorder or condition.

• Informed consent for research is provided by someone who, under state or federal law,has the legal authority to make such decisions for the patient. If other persons havingclose relationships with the individual with cognitive impairment are readily available,it is ethically appropriate for them to be consulted and to provide surrogate consentregarding the research participation, even if they are not legally authorizedrepresentatives.

• And the individual with cognitive impairment assents if capable to participation, ordoes not dissent.

• Enrollment into research of a cognitively impaired individual who is unable to giveconsent generally should not occur if the research presents greater than a minorincrement over minimal risk and does not offer a reasonable prospect of ahealth-related benefit directly resulting from the research procedures. Investigatorsand IRBs should pay close attention to identifying and minimizing the risks of theresearch that are not justified by potential benefits to the participants. For example, aclinical trial that compares two medications may include multiple blood draws that arenot clearly indicated for the benefit of the participant but are clearly indicated forassuring that the research gathers generalizable knowledge.

17.1. Resource document: Research Consent for Cognitively Impaired Adults


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The greater the risks of research procedures that are not justified by potential benefits to theparticipants, the more ethically challenging it is to enroll a non-competent participant in the research.In general, an IRB should assure that risks that are not justified by potential benefits to the subjectsare no more than a minor increment over minimal risk, and that they are justified by the importanceof the knowledge to be gained from the research. When assessing whether a risk is minimal (or aminor increment above minimal), the IRB should use the definitions supplied in the Common Rule.One exception to this general rule may be made if:

a. the condition causing cognitive impairment is the object of study, so that the researchcould not otherwise be carried out without the involvement of individuals unable toconsent; and

b. the individual has given a research advance directive that authorizes a proxy toprovide consent for enrollment in research of this kind.

2. AT-RISK POPULATIONSWhen applying for IRB approval, all investigators should consider the risk of clinically

significant cognitive impairment among potential participants eligible for their study. Aninvestigator who is trying to determine whether the study population is at risk of incapacity related tocognitive impairment might ask a clinician experienced in the care of this population (if theinvestigator is not), "In this population of patients, do you typically look to a family member orsomeone else to make clinical decisions for or along with the patient, because of impairments in thepatient's cognition?"

IRBs should include in their application forms a "check-off box" in the section on "vulnerablepopulations" where investigators are asked to address this issue. The issue should also be addressedin the special section of the protocol as well using the format of this guideline. Certain populationsthat are a target of clinical investigation have been reported in the literature to have high rates ofcognitive impairment. By way of example, these include patients with Alzheimer's disease andrelated disorders, brain disease, patients with certain psychiatric conditions, hospitalized patientswith congestive heart failure, patients with AIDS, acutely ill emergency room patients, intensive carepatients, nursing home residents, assisted living residents, and individuals of very advanced age.

3. ASSESSMENT3.1. SCREENING OF AT-RISK POPULATIONS FOR COGNITIVE IMPAIRMENT

When research involves individuals at risk for clinically significant cognitive impairment,investigators should consider whether to specify a screening procedure in their protocols and, if theydecide not to do so, they must justify this decision to the IRB. In general, screening for cognitiveimpairment reduces participant burden, as it allows investigators to identify individuals who havesignificant cognitive impairment and who may be unable to consent to the research. Screening forcognitive impairment should not be confused with screening for incapacity to consent to research.Whether or not to use a screening procedure in a given research study, and what the procedure and its"cut-offs" should be, is up to the investigator to develop with the approval of the IRB. Screeningshould not be confused with capacity assessment (see Section 3.2).



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3.2. ASSESSING CAPACITY FOR CONSENT TO A SPECIFIC RESEARCH PROJECTThe protocol should describe, to the IRB's satisfaction, how the investigator would conduct a

capacity assessment and the nature of the assessment (i.e., whether a formal assessment instrumentwill be used). The rigor of the capacity assessment process should relate to the risks presented by theresearch. For minimal risk research, informal capacity assessment by qualified members of theresearch team would ordinarily suffice. For higher risk research, consideration should be given tothe use of an independent (i.e., not part of the research team), qualified professional to assessformally the potential subject's capacity to consent.

At a minimum, the investigator, or IRB approved designee, must review and discuss the researchproject, and the consent document, with the potential participant and decide whether he or she is ableto:

(1) understand the nature of the research and of his or her participation;(2) appreciate the consequences of the participation;(3) show a) the ability to consider alternatives, including the option not to participate, and b)

considers the consequences of participation; and(4) show the ability to make a reasoned choice.

This discussion should include oral and written descriptions of research, its significance, and thesubject's options. Both for persons with dementia, because of health literacy concerns, and becausepersons with dementia may come from culturally and linguistically disadvantaged diversebackgrounds, the vocabulary and syntax should be simple and avoid medical jargon. In the consentdocument, the type font and size should be easily readable by older subjects. Key elements of thediscussion (i.e. purpose, procedures, risks, benefits, alternatives) should be presented sequentially, tohelp the potential subject understand and deal individually with each element.

4. ACTION IF CAPACITY IS IMPAIRED4.1. PERMISSION AND ASSENT

If a potential participant is determined to lack capacity to consent to the specific researchproject, the investigator ordinarily must obtain permission from a proxy (see section 4.2), with bothactual capacity and legal authority to give it, and assent from the participant. Permission means theproxy's informed consent to the proposed participation. Assent is defined in section 4.4. Permissionor assent need not be obtained if an IRB, in accordance with ethical and regulatory standards forminimal risk research, has waived the requirement.



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4.2. IDENTIFYING A PROXYPersons with cognitive impairments must rely on proxy decision-makers - usually a spouse,

child, caregiver, or other trusted individual - for decisions of everyday life or medical care. Researchparticipation is not an exception to this necessary and beneficial dependence on others. Wherepossible, permission should be sought from someone who, under state law, has the right to be theparticipant's legally authorized representative. While the exact order may vary from state to state, thefollowing priority ranking is consistent with most state laws. If a potential proxy is not available at agiven priority level, the investigator should seek to identify a proxy from the next level down:

(1) legal guardian;(2) proxy (research agent) named in the participant's research-specific advance directive;(3) proxy (health care agent) named in an advance directive or durable power of attorney for

health care;(4) family member or other surrogate identified by the state law on health care decisions.

Example: In Maryland, spouse, adult children, parents, adult siblings, other relative orfriend.

4.3 PERMISSION FROM THE PROXYPermission for participation in a research project should be consistent with the proxy's legally

defined role and with the types of research consistent with surrogate consent as outlined in section 1of this document. Example: A guardian may give permission only if this is allowed by the court,either in the order appointing the guardian or a special order. Example: A health care surrogate maygive permission if participation in the research offers a reasonable prospect of direct medical benefit,even if the research also includes procedures unrelated to potential benefits. Custom may alsorecognize proxy permission for participation in some research with no expected benefits.

Disagreements among proxies with equal priority should be resolved informally, wheneverpossible, and, if necessary, through more formal means as identified in law or policy. Example: InMaryland, disagreements among surrogates are to be referred to a facility's ethics committee.

The informed consent form should include instruction to the proxy to base his or her decisionson the participant's expressed wishes or, in the absence of expressed wishes, what the participantwould have desired in light of his or her prognosis, values, and beliefs. If the participant's wishes areunknown and cannot be inferred, the decision should be based on the participant's best interests. Theinstructions should also include a statement that the proxy should consider how much the subjectwould have granted the proxy leeway or freedom to choose for the subject.

4.4 ASSENT FROM THE PARTICIPANTIf the participant is capable of providing affirmative agreement to participate, the participant

should be informed in the presence of the proxy that he or she is about to be enrolled in a researchstudy. The procedures, risks, benefits, and alternatives involved should be explained in a simplefashion. The participant should then be asked if he or she agrees to be in he research, and theresponse should be recorded.



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If the participant is incapable of providing affirmative agreement to participate, then assent (ordissent) should be judged behaviorally based on cooperativeness with study procedures (e.g., does heor she refuse to have blood drawn, take pills, or lie still for an imaging study?). Dissent for anystudy-related procedure should be respected, and consistent dissent may be a basis for removal fromthe research study.

If at any time after the participant is enrolled in the study through proxy permission, theparticipant regains the capacity to provide informed consent, the investigator must obtain theparticipant's informed consent for continued participation in the research.

5. CAPACITY IMPAIRMENT IN THE COURSE OF RESEARCH5.1. RISK OF LOSS OF CAPACITY

If at the time of enrollment a participant who has the capacity to consent is known to be at riskfor loss of that capacity due to cognitive impairment, the investigator must, to the IRB's satisfaction

(1) show a plan for reassessment of cognitive capacity and capacity to consent if there is aclinically significant change in cognitive function that could reasonably change thesubject's current status as either competent or not competent;

(2) offer the participant the opportunity to appoint a proxy (research agent, see 4.2 above) tomake ongoing consent decisions regarding the research project should the participant'scapacity to consent become impaired during the course of the project; and

(3) when applicable, ask the participant to give guidance to her or his proxy about theconditions under which she or he would and would not want to participate in the presentand future protocols, in the event of loss of capacity.

5.2. APPARENT LOSS OF CAPACITYIf a participant who gave consent personally appears to lose capacity during the study, the

investigator must:(1) formally assess the participant's capacity to consent (see Section 3.2); and(2) if capacity is impaired, obtain permission for further research participation from a proxy

(see section 4.2).

5.3. INTERMITTENT CAPACITYIn cases of intermittent capacity, periodic re-evaluations are indicated. The proxy need not be

called on as long as, in the judgment of the investigator, all decisions can be safely and appropriatelydelayed until the participant's decisional capacity returns.



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6. DOCUMENTATIONProper documentation of the process above must be kept in the participant's study records.

Reassessment of consent and assent and associated documentation should occur on a regular basisduring the course of the study, using a time schedule set by the investigator with the IRB's approval.Documentation is to include assessment of cognitive capacity, assessment of capacity to consent,proxy identification and permission (if applicable), and assent.


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17.2. Minority recruitment training

Target audience: Clinical site directors, coordinators, and other staffTime devoted: Annual half/day training Faculty: Adrian Mosley, MSW

Objectives: To educate research teams about:1) Issues regarding the recruitment of minority populations into clinical trials with specialemphasis on barriers

2) How to work with community leaders and organizations to find out their needs with regard tothe role of research as a component of the community health care

3) How to make contacts in the community and identify the local barriers to researchparticipation, for example the perception of the institution doing the study

4) How to develop community partnerships that will overcome barriers to research participationand facilitate lasting relationships for the purpose of continuing research participation

5) Ways of identifying the barriers that individual participants face that affect their continuedparticipation in research. For example, problems with transportation, access to care, and soforth and how to overcome them

6) Helping the caregivers of minority participants identify their needs and providing them withproblem solving assistance so that they can better take care of the patients for whom they areresponsible

Format: Seminar and workshopThe workshop will focus on the nitty-gritty of enhancing minority recruitment will be discussed

in an open format, around case studies (vignettes). In these workshops, site coordinators will discusstheir experiences with recruitment from ethnic and racial minority groups, barriers they have faced,strategies they have tried, their fears and concerns for the future, and what would be helpful to themto enhance participation.


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17.3. Patient information about study medication

DEPRESSION IN ALZHEIMER’S DISEASE STUDY-2

General instructionsYou are asked to take a pill provided by the study team once a day for up to 24-weeks. The pill maycontain SERTRALINE, (pronounced: SER tra leen), also known as Zoloft, or placebo, an inactivesubstance. Both types of pills will look exactly alike. Neither you nor your study team will knowwhat is in the pills provided to you. Your pills will have the same contents all through the study.When you first start in the study, you will take two 25 mg pills once a day. A week later you willincrease the dose to four 25 mg once a day. This is the intended study dose of the medication. Invery rare instances, your doctor may adjust the dose to 75 mg or 125 mg once a day.

At each study visit, you will be provided with a medication supply that will be enough to last untilyour next visit. We ask that you take great care to take the medication as prescribed. At eachfollow-up visit, we ask that you return the pill bottles with any unused portions of the studymedication. It is really important that you bring back these study bottles and the unused pills.PLEASE DO NOT THROW AWAY ANY UNUSED PILLS.

Below we provide you some information about the study medication and how to use it. If you haveany questions, be sure to ask the study doctor or nurse. If you have any questions after hours that areurgent, or any side effects develop that are worrisome, please call your study team on the 24-hournumber they have given you.

What is sertraline?Sertraline is in a class of drugs called selective serotonin reuptake inhibitors. Sertraline affectschemicals in the brain that may become unbalanced and cause depression, panic or anxiety, obsessiveor compulsive symptoms, or other psychiatric symptoms.

Sertraline is used to treat depression, obsessive-compulsive disorder, panic disorder, posttraumaticstress disorder (PTSD), and premenstrual dysphoric disorder (PMDD).

Sertraline may also be used for purposes other than those listed in this medication guide.

How should I take sertraline?Take sertraline exactly as directed by the study doctor. If you do not understand these directions, askyour study nurse, or doctor to explain them to you.

Take each tablet with water.

Try to take sertraline at the same time each day.

Sertraline may be taken with or without food.



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Do not stop taking sertraline without first talking to your doctor. It may take 4 weeks or more foryou to start feeling better and you may experience unpleasant side effects if you stop taking sertralinesuddenly.

Store sertraline at room temperature away from moisture and heat.

What happens if I miss a dose?Take the missed dose as soon as you remember. However, if it is almost time for the next regularlyscheduled dose, skip the missed dose and take the next one as directed. Do not take a double dose ofthis medication unless otherwise directed by your doctor.

What happens if I overdose?Seek emergency medical attention.

Symptoms of a sertraline overdose include nausea, vomiting, tremor, seizures, agitation, drowsiness,hyperactivity, and enlarged pupils.

What should I avoid while taking sertraline?Use caution when driving, operating machinery, or performing other hazardous activities. Sertralinemay cause dizziness or drowsiness. If you experience dizziness or drowsiness, avoid these activities.

Use alcohol cautiously. Alcohol may increase drowsiness or dizziness while taking sertraline.

What are the possible side effects of sertraline?If you experience any of the following serious side effects, stop taking sertraline and contact yourdoctor immediately or seek emergency medical treatment:

• an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips,tongue, or face; or hives);

• an irregular heartbeat or pulse; • low blood pressure (dizziness, weakness); • high blood pressure (severe headache, blurred vision); or chills or fever.

If you experience any of the following less serious side effects, continue taking sertraline and talk toyour doctor:

• headache; • tremor, nervousness, or anxiety; • nausea, diarrhea, dry mouth, or changes in appetite or weight; • sleepiness or insomnia; or • decreased sex drive, impotence, or difficulty having an orgasm.

Side effects other than those listed here may also occur. Talk to the study doctor about any sideeffect that seems unusual or that is especially bothersome.



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What other drugs will affect sertraline?Do not take sertraline if you have taken a monoamine oxidase inhibitor (MAOI) such asisocarboxazid (Marplan), phenelzine (Nardil), or tranylcypromine (Parnate) during the last 2 weeks.Serious, and sometimes fatal, reactions have occurred when these medicines have been used together.

Do not take sertraline if you are taking pimozide (Orap). A dangerous drug interaction could result.

Before taking sertraline, tell the study doctor if you are taking any of the following medicines:• a benzodiazepine such as diazepam (Valium), alprazolam (Xanax), chlordiazepoxide

(Librium), clorazepate (Tranxene), temazepam (Restoril), triazolam (Halcion), andothers;

• a tricyclic antidepressant such as amitriptyline (Elavil), imipramine (Tofranil), doxepin(Sinequan), nortriptyline (Pamelor), and others;

• a phenothiazine including chlorpromazine (Thorazine), thioridazine (Mellaril),fluphenazine (Prolixin), mesoridazine (Serentil), perphenazine (Trilafon),prochlorperazine (Compazine), and others;

• lithium (Lithobid, Eskalith, others) or clozapine (Clozaril); • almotriptan (Axert), frovatriptan (Frova), sumatriptan (Imitrex), naratriptan (Amerge),

rizatriptan (Maxalt), or zolmitriptan (Zomig); • carbamazepine (Tegretol) or phenytoin (Dilantin); • warfarin (Coumadin); • digoxin (Lanoxin); • cimetidine (Tagamet, Tagamet HB); or • bupropion (Wellbutrin, Zyban).

You may not be able to take sertraline, or you may require a dosage adjustment or special monitoringduring treatment if you are taking any of the medicines listed above.

Drugs other than those listed here may also interact with sertraline. Talk to your doctor andpharmacist before taking any prescription or over-the-counter medicines, including vitamins andherbal products.

Remember, keep this and all other medicines out of the reach of children, never share your medicineswith others, and use this medication only for the indication prescribed.