Clinical Trial Protocol...Short title: DBS for memory& thinking in Parkinson's Sponsor code: 11/0516 Protocol Version 3.0 29/09/2012 1 1 Clinical Trial Protocol 2 Full title of trial

Short title: DBS for memory& thinking in Parkinson's Sponsor code: 11/0516

Protocol Version 3.0 29/09/2012 1

Clinical Trial Protocol 1 2

Full title of trial Double blind, randomised, single centre, crossover pilot trial of bilateral Nucleus Basalis of Meynert Deep Brain stimulation (as an adjunctive treatment to conventional Globus pallidum Deep Brain stimulation) to improve cognitive deficits in patients with Parkinson's disease.

Short title DBS for thinking and memory problems in Parkinson’s.

Version and date of protocol Version 3, 29/09/2012

Sponsor: University College London (UCL)

Funder (if applicable): Brain Research Trust

Trial device Deep Brain Stimulation

Phase of trial Phase 2

Trial sites(s) NHNN

Chief investigator: Dr Thomas Foltynie, Senior Lecturer & Honorary Consultant Neurologist, Box 146, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG

Sponsor Representative: Mr Dave Wilson UCLH/UCL/Royal Free JRO University College London Gower Street, WC1E 6BT

Postal address: Joint UCLH/UCL Biomedical Research and Development (R&D) Unit, (1st Floor, Maple House), Ground Floor, Rosenheim Wing, 25 Grafton Way, London WC1E 6DB.

3

Downloaded From: https://jamanetwork.com/ by a Non-Human Traffic (NHT) User on 02/11/2020



Signatures 4

The Chief investigator and the sponsor have discussed this protocol. The investigators agree to 5 perform the investigations and to abide by this protocol except in case of medical emergency or 6 where departures from it are mutually agreed in writing (as an urgent safety measure under 7 section 10.3.6 requirements). 8

The investigator agrees to conduct the trial in compliance with the protocol, GCP, the Data 9 Protection Act (1998), the Trust Information Governance Policy (or other local 10 equivalent),Research Governance Framework, (2005), the Sponsor’s SOPs and other regulatory 11 requirements as appropriate. 12

13

Chief investigator

Dr Thomas Foltynie

National Hospital for Neurology & Neurosurgery

Signature Date

Sponsor Representative Mr Dave Wilson, UCLH/UCL/Royal Free JRO UCL Gower Street WC1E 6BT

UCL Signature Date 14

15




Contents 16

Signatures .................................................................................................................................... 2 17

Contents ...................................................................................................................................... 3 18

List of abbreviations ................................................................................................................... 5 19

1 Summary ............................................................................................................................ 8 20

2 Introduction ...................................................................................................................... 11 21

2.1 Background ...............................................................................................................11 22

2.2 Preclinical data ..........................................................................................................12 23

2.3 Clinical data ..............................................................................................................12 24

2.4 Investigational device(s) ...........................................................................................12 25

2.5 Device Marketing.......................................................................................................14 26

2.6 Clinical and technical Data to Date...........................................................................14 27 2.5 Rationale and risks/benefits ......................................................................................14 28

3 Objectives ........................................................................................................................ 15 29

4 Trial design ...................................................................................................................... 16 30

4.1 Overall design ...........................................................................................................16 31

5 Selection of Subjects ........................................................................................................ 20 32

5.1 Inclusion criteria .......................................................................................................20 33

5.2 Exclusion criteria ......................................................................................................20 34

5.3 Concomitant medication ...........................................................................................20 35

6 Recruitment ...................................................................................................................... 21 36

7 Study procedures and schedule of assessments ............................................................... 21 37

7.1 Informed consent procedure .....................................................................................21 38

7.2 Screening and eligibility assessment ........................................................................22 39

7.3 Screening assessments ..............................................................................................22 40

7.4 Baseline assessments ................................................................................................22 41

7.5 Surgical procedures ...................................................................................................23 42

7.6 Derivation of DBS parameters...................................................................................23 43




7.7 Randomisation procedures ........................................................................................23 44

7.8 Blinding.....................................................................................................................24 45

7.9 Emergency unblinding ..............................................................................................24 46

7.10 Subsequent assessments ............................................................................................24 47

7.11 Flowchart of study assessments ................................................................................26 48

7.12 Methods.....................................................................................................................29 49

7.12.1 Laboratory procedures ......................................................................................29 50

7.12.2 Radiology or other procedures ..........................................................................30 51

7.13 Definition of end of trial...............................................................................................30 52

8 Compliance ......................................................................................................................30 53

9 Recording and reporting of adverse events and reactions ............................................... 31 54

9.1 Definitions.................................................................................................................31 55

9.2 Notification and reporting Adverse Events or Reactions..........................................31 56 10 Data management and quality assurance ......................................................................... 33 57

11 Record keeping and archiving ......................................................................................... 33 58

12 Statistical Considerations ................................................................................................. 34 59

12.1 Endpoints ..................................................................................................................34 60

12.1.1 Primary endpoints .............................................................................................34 61

12.1.2 Secondary endpoints .........................................................................................34 62

12.2 Sample size and recruitment .....................................................................................35 63

12.2.1 Sample size calculation .....................................................................................35 64

12.3 Statistical analysis plan .............................................................................................35 65

13.3.2 Primary endpoint analysis .................................................................................35 66

13.3.3 Secondary endpoint analysis .............................................................................35 67

13 Name of Committees involved in trial ............................................................................. 36 68

14 Ethics................................................................................................................................ 36 69

15 Finance ............................................................................................................................. 36 70

16 Insurance .......................................................................................................................... 36 71

17 Publication policy ............................................................................................................ 37 72

18 Statement of compliance .................................................................................................. 37 73




19 References ........................................................................................................................ 37 74

75

List of abbreviations 76

AE Adverse Event 77

AR Adverse Reaction 78

ASR Annual Safety Report 79

BDS Blessed Dementia Scale 80

CA Competent Authority 81

CANTAB Cambridge Neuropsychological Test Automated Battery 82

CI Chief Investigator 83

CPT Continuous Performance Test 84

CRF Case Report Form 85

CRO Contract Research Organisation 86

CTA Clinical Trial Authorisation 87

CVLT-II California Verbal Learning Test-II 88

DBS Deep Brain Stimulation 89

DMC Data Monitoring Committee 90

DRS-2 Dementia Rating Scale-2 91

EC European Commission 92

EMEA European Medicines Agency 93

EU European Union 94

EudraCT European Clinical Trials Database 95

fMRI Functional Magnetic Resonance Imaging 96

GA General Anaesthesia 97

GCP Good Clinical Practice 98

GFQ Freezing of Gait Questionnaire 99

GMP Good Manufacturing Practice 100

GPi Globus Pallidus pars Interna 101




HAM-D and HAM-A Hamilton scale for Depression, Anxiety 102

IB Investigator Brochure 103

ICF Informed Consent Form 104

MEG Magnetoencephalography 105

MHRA Medicines and Healthcare products Regulatory Agency 106

MMSE Minimental State Examination 107

MRC Medical Research Council 108

NBM Nucleus Basalis of Meynert 109

NHS R&D National Health Service Research & Development 110

NPI Neuropsychiatric Inventory 111

PASAT Paced Auditory Serial Addition Test 112

PD Parkinson’s disease 113

PI Principal Investigator 114

PIS Participant Information Sheet 115

PRL Probabilistic Reinforcement Learning 116

QA Quality Assurance 117

QC Quality Control 118

RCT Randomised Control Trial 119

REC Research Ethics Committee 120

SAR Serious Adverse Reaction 121

SAE Serious Adverse Event 122

SDR Spatial Delayed response 123

SOP Standard Operating Procedure 124

SmPC Summary of Product Characteristics 125

SRM Short Recognition Memory 126

SSA Site Specific Assessment 127

SSAR Suspected Serious Adverse Reaction 128

STN Subthalamic Nucleus 129

SUSAR Suspected Unexpected Serious Adverse Reaction 130




TMG Trial Management Group 131

TMT Trail Making Test 132

TSC Trial Steering Committee 133

MDS-UPDRS Unified Parkinson’s disease Rating Scale 134

WAIS Wechsler Abbreviated Scale of Intelligence 135

136




Trial personnel 137

Chief Investigator (CI) Thomas Foltynie 138

e-mail: [email protected] 139 tel: 0203 108 0026 fax: 0203 108 0142 140

141

Sponsor’s representative Dave Wilson 142 e-mail: [email protected] 143 tel: 02034475199 fax: 0207 3809937 144

145

Routine local laboratories John Land 146 e-mail: [email protected] 147 tel: 020-7829-8768 fax: [fax no.] 148

149

Imaging Professor Tarek Yousry 150

Head of Department Professor Linda Greensmith 151

Sobell Department of Motor Neuroscience, National 152 Hospital for Neurology and Neurosurgery, Queen square, 153 London, WC1E 3BG 154

Email; [email protected] 155

156




157

1 Summary 158

Title: Double blind, randomised, single centre, crossover pilot trial of bilateral Nucleus Basalis of Meynert Deep Brain stimulation (as an adjunctive treatment to conventional Globus Pallidum Deep Brain Stimulation) to improve cognitive deficits in patients with Parkinson's disease.

Short title: DBS for thinking & memory problems in Parkinson's.

Trial device: Medtronic PC Deep Brain Stimulation device

Phase of trial: Phase II

Objectives: Primary Objective-

To evaluate the effectiveness of human NBM DBS at improving a short battery of cognitive deficits (including but not restricted to deficits in attention and working memory) in PD patients referred for DBS treatment for coexisting motor impairments.

Secondary Objectives-

To confirm the safety and tolerability of NBM DBS and its impact on activities of daily living, motor performance, broader assessments on cognitive ability, mood, behaviour, non-motor symptoms and quality of life among patients with moderate PD using standard validated tools of assessment.

To identify whether NBM DBS leads to any changes in functional imaging of cortical blood flow will be obtained using fMRI.

To identify whether NBM DBS leads to any changes in cortical activity using magnetoencephalography.

Type of trial: Phase II, double blind, randomised, crossover, single site trial in Parkinson’s disease.

Trial design and methods:

We will perform a pilot study to evaluate the effectiveness of human NBM DBS at improving cognitive deficits in PD patients referred and eligible for conventional DBS treatment for coexisting motor impairments. Six patients with PD with both motor fluctuations and cognitive impairments (including but not restricted to deficits in attention and working memory) will have bilateral electrodes




implanted to ensure that superficial contacts lie in the conventional motor GPi target, while the deepest electrical contacts lie in the NBM- (see figure 1). We will place electrodes using our conventional image guided, stereotactic frame-based procedure currently used in patients at NHNN. Patients will be randomised into 2 groups in a crossover trial design to have 6 week periods of NBM stimulation switched on or switched off separated by a 2 week washout period, following which the patient will cross over to have the opposite condition for a further 6 weeks- see timeline. At the end of the crossover period, all patients will be invited for continued follow up with stimulation switched on and will have neuropsychological evaluations at 6 monthly intervals. Patients will be given the option of receiving additional conventional stimulation to the motor GPi, through the higher contacts of each electrode, at the end of the crossover period.

Trial duration per participant:

20 weeks

Estimated total trial duration:

90 weeks

Planned trial sites: Single-site

Total number of participants planned:

6

Main inclusion criteria:

All patients will meet Queen Square brain bank criteria for the diagnosis of PD and will have motor fluctuations (off periods and/or L-dopa induced dyskinesias) in response to medications that are known to improve with GPi DBS and will be appropriate candidates for GPi DBS aside from the coexistence of cognitive impairment.

Patients will be aged between 35 and 80 years.

Patients will be able to give informed consent. Consent by proxy will also be obtained from the primary carer.

Patients will meet criteria for PD dementia. Patients will have an MMSE score between 26 and lower cutoff of 21 to restrict the sample to those with mild dementia and cognitive impairment. This will be equivalent to an age and education adjusted scaled score of greater than 5 and lower than 9 (mildly impaired range) on the




Mattis Dementia Rating Scale-2.

Patients will have only minimal atrophy on pre-operative brain MRI scans.

Patients will be living at home and will have a carer living with them e.g. their spouse.

Able to comply with trial protocol and willing to attend clinic necessary visits

Statistical methodology and analysis:

The primary outcome measure will be the difference in performance on the selected short battery of tests of attention, working memory, executive function and processing speed (see below for details) between ON stimulation and OFF stimulation conditions.

The primary outcome measure will be analysed using the Wilcoxon matched pairs signed rank test. The mean difference in the primary outcome and an estimate of its variance will be determined from our results and these data will be used for formal sample size calculations for future studies.

159

160

2 Introduction 161

2.1 Background 162

While traditionally viewed as a movement disorder, cognitive impairments are present in up to 163 36% of patients with Parkinson’s disease (PD) even at the time of diagnosis1. In a multicentre 164 pooled analysis of 1346 PD patients, variable types of cognitive deficits were seen particularly in 165 association with older age, longer disease duration and increased motor severity, and include 166 isolated deficits in attention, executive function, memory, or visuospatial function as well as 167 patients with deficits in multiple domains2. Cognitive deficits in attention underlie the 168 phenomenon of dopa refractory gait freezing, a major cause of disability in PD patients3. Up to 169 80% of PD patients will ultimately develop dementia, and the natural history of the progression 170 of specific cognitive impairments to dementia in PD has been the subject of detailed population 171 based studies4;5. 172

The patho-physiological causes of cognitive impairment in PD are diverse being influenced by 173 neuro-degeneration occurring in subcortical dopaminergic and cholinergic neurons, non-174 physiological dopamine replacement and/or anti-cholinergic medications, comorbid conditions 175




affecting brain function, and neuro-degeneration of cortical neurons themselves due to alpha-176 synuclein positive, Lewy body pathology6. Cognitive processing involves the intact functioning 177 of cortical-subcortical neuronal loops. Abnormal activity in one brain region due to its 178 involvement in a pathological process may therefore have widespread physiological effects on 179 other interconnected brain regions in advance of their involvement in the neurodegenerative 180 process. 181

2.2 Preclinical data 182

The Nucleus Basalis of Meynert is the major source of cortical and limbic Acetyl-Choline (ACh) 183 and there is extensive evidence of the importance of the NBM and ACh in cognition7 8;9. When 184 the NBM is electrically stimulated in the rodent, cortical ACh is released, there is EEG activation 185 and facilitation of a range of cognitive tasks10-12. Stimulation of the NBM in non-human primates 186 (NHP) allows more sophisticated evaluation of the functions and projections of this nucleus and 187 confirms its importance in normal cognitive function13. Lesions in this area result in deficits in 188 cognitive function in both rodent14 and NHP models15. Furthermore, use of ACh antagonists such 189 as scopolamine have been widely used to model age- and dementia-related cognitive deficits in 190 human and animal models16;17. 191

2.3 Clinical data 192

Deep Brain Stimulation surgery is an accepted treatment for the motor complications of chronic 193 PD18;19. Chronic stimulation of the subthalamic nucleus (STN) or globus pallidus pars interna 194 (GPi) can lead to substantial improvements in motor function, and in the complications of 195 chronic oral PD treatment, and the quality of life of the patient20. Disturbance of the activity in 196 functional circuits explains why stimulation of the STN (the most common target to treat the 197 motor complications of PD) leads to deterioration in verbal fluency and executive ability, among 198 patients with limited cognitive reserves, because of the cognitive cortical-subcortical projections 199 that pass through the associative territory of the STN21. This represents a major barrier in the 200 application of DBS to help many patients with advanced PD. 201

The NBM lies beneath the GPi in each hemisphere and can be reached with a DBS electrode via 202 the same trajectory to target the GPi, but a few millimetres deeper. The proximity of the NBM to 203 the conventional GPi target thus makes it an appealing structure to stimulate and evaluate 204 therapeutic effects. To date, there has been a single report of a patient with cognitive impairment 205 in association with PD who had DBS electrodes inserted into the NBM with subsequent 206 improvements in attention, concentration and alertness22;23. There is therefore limited but 207 encouraging data on the possibility of using DBS as a treatment for cognitive impairments in PD, 208 in particular stimulation of the NBM. 209




2.4 Investigational device 210

Deep Brain stimulation device(s) to be used in this study is manufactured by Medtronic. Their 211 PC device and 1.3mm diameter leads will be used. This can deliver a wide range of amplitude of 212 stimulation, pulse width and frequency. 213

214 The stimulation system consists of three implantable components: 215 216

Lead - the lead is a thin insulated wire with four electrodes at the tip that is implanted in the 217 brain. 218

Extension - The lead is connected to an extension, a thin, insulated wire that is threaded under 219 the skin from the head, down the neck and into the upper chest. 220

Neurostimulator - The extension is connected to a neurostimulator, a small, sealed device 221 similar to a cardiac pacemaker that contains a battery and electronics. The neurostimulator is 222 implanted beneath the skin in the chest or abdominal wall. It produces the electrical pulses 223 needed for stimulation. These electrical pulses are delivered through the extension and through 224 the lead to the GPi in the brain. 225

External components of the system include a physician programmer (used to adjust 226 neurostimulator parameters) After the trial is over the patient will be provided with a hand-held 227 patient controller that can be held over the neurostimulator to check the battery status and to 228 adjust the electrical parameters where necessary. 229

The Stimulator System is implanted by a functional neurosurgeon, a neurosurgeon who 230 specialises in central nervous system function. Under a general anaesthetic the neurosurgeon 231 fixes a stereotactic frame to the head and maps the brain using a magnetic resonance imaging 232 (MRI) to localise the target within the brain. Two leads are inserted through small holes drilled 233 through the skull and implanted in the targeted site deep within the brain. Electronic equipment 234 that analyses the electrical properties of the brain may be used to help with this targeting process. 235 Once the lead has been placed at the target, the extension wires and neurostimulator are 236 implanted. Further MRI or CT scans may be obtained during or after the procedure to confirm 237 placement of the electrodes within the desired target area. 238

The extension is passed under the skin of the scalp and neck, into the trunk to connect the lead to 239 the neurostimulator. An incision of about 3 inches is made under the collar-bone or in the 240 abdomen, a pocket is made just under the skin in which to implant the neurostimulator. 241

Battery longevity varies, depending on how much electrical energy is required to help improve 242 symptoms. At the expected therapeutic settings, the battery should last an average of two to 243 seven years. A simple surgical procedure is used to replace the neurostimulator and carries much 244 less risk than the initial implantation of the whole device. When it needs to be changed, the old 245




neurostimulator is replaced by an entirely new neurostimulator that is connected to the original 246 cables and electrode leads. 247

Most people will not feel the stimulation directly but may feel the effects of stimulation 248 indirectly if it reduces some of their symptoms. Some people may feel a brief tingling sensation 249 when the device is first turned on. 250

251

2.5 Device marketing and current use 252 253 The Medtronic PC device is CE marked for the use of Deep Brain stimulation of patients with 254 Parkinson’s disease or Dystonia. The CE-marking certificate is included in Appendix 2 255

256

2.6 Clinical and technical Data to Date 257 258

DBS has been in use for the treatment of patients with Movement Disorders since 1989 with 259 many thousands of publications demonstrating its effectiveness. The devices that will be used as 260 part of this study received their CE mark in 2010. Deep Brain Stimulation for the treatment of 261 patients with Parkinson’s disease and Dystonia has been the subject of evaluations by the 262 National Institute of Health and Clinical Excellence. 263

http://www.nice.org.uk/nicemedia/pdf/cg035fullguideline.pdf 264

http://www.nice.org.uk/IPG188 265

This trial will not be used for commercialisation of these products and therefore does not require 266 MHRA approval in accordance with the guidelines issued on their website- 267

http://www.mhra.gov.uk/Howweregulate/Devices/Clinicaltrials/index.htm#l5 268

2.7 Rationale and risks/benefits 269

Hypotheses that will be tested in this study are as follows; 270 271

1. Pathological activity in the NBM is responsible for the deficits of attention and/or other 272 cognitive impairments in PD patients. 273

2. Deficits in attention/ other cognitive impairments in PD patients may be acutely reversed 274 by NBM stimulation that can be achieved via the same electrodes encompassing the 275 traditional GPi target for relief of motor symptoms. 276

3. NBM stimulation leads to changes in activity in a network of cortical and subcortical 277 regions. 278




4. Objective clinical measures, together with objective physiological measures of local field 279 potential recordings, magneto-encephalography and functional imaging will consistently 280 reflect improvements in cognitive and motor performance. 281

5. Improvements in attention and/ or other cognitive impairments in PD patients will 282 translate to functional benefits in day to day functioning, gait freezing, and quality of life. 283

Risks v benefits- 284

When the study stops, the DBS stimulator will still be in the participant’s brain. At that point, 285 the participant still has a choice about whether to have it switched on or off and can discuss this 286 with the doctors/ researchers about the level of the stimulation, and the choice or combinations of 287 electrical contacts through which stimulation is administered to maximise benefits for both 288 movement and cognition. We would not normally remove stimulators after a study, except in 289 exceptional circumstances. 290

291

The complication rates of DBS surgery are roughly; 292

2% haemorrhage (this includes death) 293

5% infection 294

2% provocation of seizures 295

296 The surgical procedure itself does not differ in any way from its specified indication for 297 which it is CE marked, namely high frequency stimulation of the Internal globus pallidum, 298 aside from in these patients the electrodes will be advanced a few millimeters deeper along 299 the same trajectory through the brain, so that the active contacts encompass both the GPi 300 and the NBM. 301

302

Participation in this trial will require the patients to make additional trips to the hospital. While 303 additional trips to hospital will be burdensome, patients will benefit from the access to 304 experienced PD clinical advice at each visit. 305

In addition to undergoing a clinical examination and assessment, patients will be helped to 306 complete all the questionnaires. 307

3 Objectives 308

Primary Objective- 309




To evaluate the effectiveness of human NBM DBS at improving a short battery of cognitive 310 deficits (including but not restricted to deficits in attention and working memory) in PD patients 311 referred for DBS treatment for coexisting motor impairments. 312

Secondary Objectives- 313

To confirm the safety and tolerability of NBM DBS and its impact on activities of daily living, 314 motor performance, broader assessments on cognitive ability, mood, behaviour, non-motor 315 symptoms and quality of life among patients with moderate PD using standard validated tools of 316 assessment. 317

To identify whether NBM DBS leads to any changes in functional imaging of cortical blood flow 318 will be obtained using FDG PET and /or fMRI. 319

To identify whether NBM DBS leads to any changes in cortical activity using 320 magnetoencephalography. 321

4 Trial design 322

4.1 Overall design 323

This is a non-commercial trial of a CE marked device used to provide bilateral Deep Brain 324 Stimulation to the Nucleus Basalis of Meynert. 325

We will perform a pilot study to evaluate the effectiveness of human NBM DBS at improving 326 cognitive deficits in PD patients referred for DBS treatment for coexisting motor impairments. 327 Six patients with PD with both motor fluctuations and cognitive impairments (including but not 328 restricted to deficits in attention and working memory) will have bilateral electrodes implanted to 329 ensure that superficial contacts lie in the conventional motor GPi target, while the deepest 330 electrical contacts lie in the NBM- (see figure 1). We will place electrodes using our 331 conventional image guided, stereotactic frame-based procedure currently used in patients at 332 NHNN. The surgery will follow our conventional NHS practice in all ways other than the deeper 333 insertion of the electrodes. During the 1 week between electrode insertion and implantation of 334 the battery (IPG), recordings from the electrodes will be taken in the MEG scanner. Patients will 335 be randomised into 2 groups in a crossover trial design to have 6 week periods of NBM 336 stimulation switched on or switched off separated by a 2 week washout period, following which 337 the patient will cross over to have the opposite condition for a further 6 weeks- see timeline. At 338 the start and end of each period the patient will have a cognitive assessment to evaluate the acute 339 and chronic effects of the stimulation in comparison to the off stimulation condition. Functional 340 Imaging scans (fMRI) will be performed in each patient at baseline and at the end of each 341 blinded ON or OFF stimulation period. At the end of the crossover period, all patients will be 342 invited for continued follow up with stimulation switched on and will have neuropsychological 343




evaluations at 6 monthly intervals. Patients will be given the option of receiving additional 344 conventional stimulation to the motor GPi, through the higher contacts of each electrode, at the 345 end of the crossover period. All patients will continue to have optimal conventional PD treatment 346 administered throughout the trial period. 347

348




349

350

351

352

353

354

355

356

357

358

359

360

361

362

Figure 1 363

364

4.2 Schematic diagram(s) of overall trial design. 365




366

6 weeks NBM stimulation ON/OFF

6 weeks NBM stimulation OFF/ON

Electrode implantation & Post op MRI

Derivation of DBS Parameter Session- 1/52

Washout

MEG, LFP recording

Baseline MRI, DTI, Detailed Neuro-psychology, Motor, NMS & Gait assessment

Condition 1 Detailed Neuropsychology, Motor, NMS & Gait assessment

Condition 2 Detailed Neuropsychology, Motor, NMS & Gait assessment

Cognitive subtests to assess acute change in performance

Cognitive subtests to assess acute change in performance

IPG implantation

1 12 14

Washout

6

Open label GPi DBS +/- NBM DBS

20 weeks

fMRI fMRI fMRI

4


Short title: DBS for memory& thinking in Parkinson's- pilot trial Sponsor code: 11/0516

Protocol Version 3.0 19/Oct/2011 Page 20 of 39

5 Selection of Subjects 367

5.1 Inclusion criteria 368

All patients will meet Queen Square brain bank criteria for the diagnosis of PD and will have 369 motor fluctuations (off periods and/or L-dopa induced dyskinesias) in response to medications 370 that are known to improve with GPi DBS 24, and will be appropriate candidates for GPi DBS 371 aside from the coexistence of cognitive impairment. 372

Patients will be aged between 35 and 80 years. 373

Patients will be able to give informed consent. Consent by proxy will also be obtained from 374 the primary carer. 375

Patients will meet criteria for PD dementia25. Patients will have a MMSE score between 26 376 and lower cutoff of 21 to restrict the sample to those with mild dementia and cognitive 377 impairment. This will be equivalent to an age and education adjusted scaled score of greater 378 than 5 and lower than 9 (mildly impaired range) on the Mattis Dementia Rating Scale-2. 379

Patients will have only minimal atrophy on pre-operative brain MRI scans. 380

Patients will be living at home and will have a carer living with them e.g. their spouse 381

Able to comply with trial protocol and willing to attend clinic necessary visits 382

5.2 Exclusion criteria 383

Diagnosis or suspicion of other cause for parkinsonism or dementia. 384

Known abnormality on CT or MRI brain imaging considered likely to compromise 385 compliance with trial protocol. 386

Prior intra-cerebral surgical intervention for Parkinson’s disease including Deep Brain 387 stimulation, lesional surgery, growth factor administration, gene therapy or cell transplant. 388

5.3 Concomitant medication 389

Trial participants will be permitted to use any licensed PD medication throughout the course 390 of the trial that is recommended by their referring Neurologist. Patients will be given advice 391 in any necessary minor adjustments to their pre-existing PD drug therapy at each of their 392 visits and note made of L-dopa equivalent doses at each visit. 393

. 394




6 Recruitment 395

Patient contact will only be made once the study receives documented main REC approval, 396 any relevant regulatory approval, Local Trust R&D approval, signed site agreement and the 397 site has been initiated by the Sponsor. 398

Patients will be recruited from the National Hospital for Neurology & Neurosurgery, London. 399 Patients attending their routine follow up appointments will be informed about the trial by 400 their Neurologist and given a Patient Information sheet. Each potential patient will be pre-401 screened according to the inclusion/exclusion criteria. At the individual’s request, their 402 contact details will be passed to the trial Investigator. 403

7 Study procedures and schedule of assessments 404

7.1 Informed consent procedure 405

All patients will have had greater than 24 hours between the Patient Information sheet being 406 given and Informed Consent being sought. All potential participants will be assessed for their 407 capacity to provide informed consent by an experienced neuropsychologist independent from 408 the trial group. Providing the patient has been judged to have capacity to provide consent 409 following adequate explanation of the aims, methods, anticipated benefits and potential 410 hazards of the study, the chief Investigator, or a person delegated by the Investigator will 411 obtain written informed consent from each subject prior to participation in the trial. 412

All potential patients/subjects will be properly informed as to the purpose of the trial and the 413 potential risks and benefits known, or that can be reasonably predicted or expected. All 414 personnel obtaining consent from patients will have up to date GCP training. The Investigator 415 or designee will explain the patients are under no obligation to enter the trial and that they can 416 withdraw at any time during the trial, without having to give a reason. 417

A copy of the signed Informed Consent will be given to the participant. The original signed 418 form will be retained at the study site and a third copy will be filed in the patients hospital 419 notes. Only the consent form approved by the relevant trial ethics committee will be used. 420

Each patient wishing to participate in the trial and who provides informed consent will be 421 evaluated with the inclusion/exclusion criteria for eligibility. A thorough review of medical 422 records for each patient will be necessary to review treatment history and ensure the patient 423 meets all the inclusion/exclusion criteria. This review will take place after the patient signs 424 the informed consent. 425

If new safety information results in significant changes in the risk/benefit assessment, the 426 consent form will be reviewed and updated if necessary. All subjects, including those already 427 being treated, will be informed of the new information, given a copy of the revised form and 428 will give their consent to continue in the study. 429




7.2 Screening and eligibility assessment 430

As part of their informed consent, the contact details of the research team will be given to 431 each patient. Each patient will have a review of their demographics and data regarding their 432 PD history, medication history, family history, previous imaging, previous genetic tests, and 433 previous drug compliance issues. The Queen Square Brain Bank criteria will thus be applied 434 and their current PD medication regime will be noted. Each patient will be aware that, if 435 eligible, they will have DBS electrodes surgically implanted and that they will then have a 436 50% chance of being allocated randomly to active stimulation during the first or second 3 437 month period. They will then be invited for an in-person evaluation to confirm eligibility. 438

7.3 Screening assessments 439

Each patient will have an up to date structural MRI brain scan and a Levodopa challenge, 440 (including the Unified Parkinson’s disease rating scale (MDS-UPDRS) identical to the routine 441 NHS assessment of DBS eligibility. The patient will undergo brief cognitive assessment with 442 the mini-mental state examination (MMSE), and the Mattis Dementia Rating scale-2. The 443 results of these tests will be discussed with the patient during a multidisciplinary appointment 444 including the patient, their carer, their Neurologist and a member of the neurosurgical team, 445 and a decision taken on their eligibility for recruitment. 446

7.4 Baseline Assessments 447

The patient will be given the Parkinson’s disease quality of life questionnaire (PDQ39), 448 SCOPA Sleep, SCOPA AUT, Non Motor symptoms questionnaire (NMS quest) & Smell 449 Identification test self-assessment forms to complete and bring with them to their baseline 450 evaluation. This will comprise a detailed neuropsychological battery to be completed within 451 one month prior to surgery and will consist of the following; 452

MMSE 453

Mattis Dementia Rating Scale-2 454

National Adult Reading Test 455

Wechsler Abbreviated Scale of Intelligence (Vocabulary, Matrices) 456

Episodic memory measures (California Verbal Learning Test-II, Short Recognition 457 Memory for Faces) 458

Working memory index of WAIS-III (Letter number sequencing, Digit Span, 459 Arithmetic) 460

Attention (Continuous Performance Test, Spatial Delayed response, Posner’s covert 461 attention test) 462

Executive function (Verbal fluency, Trail Making Test, Probabilistic Reinforcement 463 Learning) 464




Processing speed (Symbol Search and Digit Symbol coding of WAIS-III; simple and 465 choice RT of CANTAB) 466

Florida Apraxia Screening test 467

EQ5D 468

Neuropsychiatric Inventory (an interview schedule for use with the carer) 469

The Blessed Dementia Scale (an interview schedule for use with the carer) 470

Clinician rated measures of mood (HAM-D and HAM-A, Starkstein Apathy Scale). 471

In addition to cognitive assessments, standard PD gait evaluations -quantitative gait analysis, 472 Gait & Falls Questionnaire, will be performed by fully trained individuals. 473

Pre-operative structural MR imaging will be performed including DTI to allow connectivity 474 analysis according to our standard current practice for DBS. Functional Imaging using fMRI 475 will also be performed at baseline and at the end of each 6 week stimulation period. (FMRI 476 will only be used if the patient is judged to have the motor and cognitive ability to control 477 head movement while lying in the scanner in accordance with our existing research policy). 478 This will allow an in vivo evaluation of the widespread cortical effects resulting from NBM 479 Stimulation, and represents a vital aspect of the clinical research. 480

7.5 Surgical procedure 481

The surgery will be performed according to NHS standard clinical practice. The surgery will 482 be performed in general anaesthesia using MR imaging to visualise and target the NBM. The 483 NBM lies just below the GPi and electrodes will be implanted (one in each hemisphere) to 484 include the deepest electrical contacts in NBM and more superficial contacts in GPi using 485 Medtronicl wide spaced electrodes- see figure 1.The accuracy of electrode implantation will 486 be confirmed with a post operative MRI scan. The implanted electrodes will be externalised 487 for a period of 1 week during which the patient will undergo a short period of simultaneous 488 local field potential (LFP) recording and magneto- encephalographic (MEG) recording at rest 489 and during a brief period of cognitive testing26. The implantable pulse generator will be 490 placed 1 week after electrode implantation in general anaesthesia. 491

7.6 Derivation of DBS parameters 492

DBS will be switched on only 4 weeks after surgery to ensure all surgical swelling has 493 resolved. Each DBS contact will be tested in turn individually and all subjective patient 494 reports and objective observations of positive and negative effects will be noted for each 495 contact at a range of stimulation frequencies (20-130 Hz). The contacts/ frequencies with the 496 highest ratio between positive and negative effects will be selected for future stimulation at an 497 amplitude threshold just below that associated with patient awareness of the effects of 498 stimulation. In the absence of a clear advantage of one contact, then the post operative 499




imaging will be used to select the contacts with the optimal anatomical location. In the 500 absence of a clear advantage of any specific frequency, then 130Hz will be used. 501

The stimulation pulse width will be kept at 60 microseconds in all patients. 502

7.7 Randomisation procedures 503

Each patient will be randomised to have stimulation ON first or OFF first using previously 504 created randomisation lists. The patient will not be aware of the order of their stimulation 505 allocation. Randomisation lists will be created by the JRO and held independently from the 506 DBS team. All randomisation procedures will take place during working hours. 507

7.8 Blinding 508

All the clinical scores done after 6 weeks on-stimulation and 6 weeks off-stimulation will be 509 double-blind, the patient and the clinician directly involved in the scoring will not be aware of 510 the condition of stimulation. 511

The clinician doing the programming will spend the same time adjusting the stimulator of the 512 patient at the start of the on or off-stimulation period. The electrical parameters will be 513 selected in a way that does not induce any lasting side-effect perceived by the patient. 514

7.9 Emergency unblinding 515

All participants will have contact details for the DBS team, which is the standard practice for 516 all patients undergoing DBS therapy for any indication. In the event that unblinding of the 517 state of stimulation becomes clinically relevant, the CI will be asked to reveal the stimulation 518 status. All adverse events reported by patients will be recorded. Adverse reactions (likely 519 related to the stimulation) will lead to unblinding of the stimulation status, and open label 520 adjustment of the stimulation to alleviate the adverse event will be performed. 521

7.10 Subsequent assessments 522

An abbreviated cognitive assessment comprising the; 523

CVLT-II 524

Verbal Fluency 525

Simple & Choice RT (CANTAB) 526

Digit span 527

Posner’s covert attention test 528

will be performed during the first week after surgery, 1 day after each change in condition and 529 at the end of each washout period. This shorter battery of selected tests is amenable to 530 repeated administration (possibility of parallel versions and less affected by practice) will be 531




used to assess cognition before and after each cross-over phase of the study to identify acute 532 stimulation effects. This short battery includes tests of attention, working memory, episodic 533 memory, executive function and processing speed. 534

At the end of each 6 week period of stimulation, a battery of assessments identical to the 535 baseline assessments (aside from measures of IQ) will be repeated by individuals unaware of 536 stimulation condition namely; 537

The patient will be sent the Parkinson’s disease quality of life questionnaire (PDQ39), 538 SCOPA Sleep, SCOPA AUT, & Smell Identification test self-assessment forms to complete 539 and bring with them to their follow up evaluations. 540

MMSE 541

Mattis Dementia Rating Scale-2 542

Episodic memory measures (California Verbal Learning Test-II, Short Recognition 543 Memory for Faces) 544

Working memory index of WAIS-III (Letter number sequencing, Digit Span, 545 Arithmetic) 546

Attention (Continuous Performance Test, Spatial Delayed response, Posner’s covert 547 attention test) 548

Executive function (verbal fluency, Trail Making Test, Probabilistic Reinforcement 549 Learning) 550

Processing speed (Symbol Search and Digit Symbol coding of WAIS-III; simple and 551 choice RT of CANTAB) 552

Florida Apraxia Screening test 553

EQ5D 554

Neuropsychiatric Inventory (an interview schedule for use with the carer) 555

The Blessed Dementia Scale (an interview schedule for use with the carer) 556

Clinician rated measures of mood (HAM-D and HAM-A, Starkstein Apathy Scale). 557

In addition to cognitive assessments, standard PD evaluations -The Unified Parkinson’s 558 disease rating scale (MDS-UPDRS), Non Motor symptoms questionnaire (NMS quest), 559 quantitative gait analysis, Gait & Falls Questionnaire, will be performed by fully trained 560 individuals. 561

Functional Imaging using fMRI will again be performed at the end of each 6 week stimulation 562 period. (FMRI will only be used if the patient is judged to have the motor and cognitive 563 ability to control head movement while lying in the scanner in accordance with our existing 564 research policy). 565

Adverse events and concomitant medications will be recorded at each visit. 566




7.11 Flowchart of study assessments 567

Timing of assessment Activities during assessment

Forms to be completed

Initial discussion during Outpatient clinic visit

Participant education re trial. Patient Information sheet given. Research team contact details given

DBS Eligibility Patient questions answered & formal assessment of capacity. Patient signs Informed consent -Demographic data re PD -medication history -L-dopa response -Family history -Imaging -Previous genetic tests Structural MRI Brain scan L-dopa challenge MDS-UPDRS MMSE DRS-2

Consent Form Patient Demographics PD background Information Inclusion/Exclusion criteria MDS-UPDRS On/ Off meds MMSE DRS-2

Baseline Assessments PDQ39, SCOPA Sleep, SCOPA AUT Smell Identification test (to be given to patient and brought to baseline evaluation)

Standard NHS blood tests reviewed prior to baseline evaluation to ensure patient eligibility. MMSE

DRS-2

NART

WASI (Vocabulary, Matrices)

CVLT-II

SRM (Faces)

WAIS-III (Letter number sequencing, Digit Span, Arithmetic)

CPT, SDR, Posner’s covert attention test

Verbal fluency, TMT, PRL

PDQ39,

SCOPA Sleep,

SCOPA AUT

MMSE

DRS-2

NART

WASI

CVLT-II

SRM (Faces)

WAIS-III

CPT, SDR, PCAT


FAST

EQ5D

NPI

BDS

HAM-D, HAM-A, SAS.




WAIS-III Symbol Search and Digit Symbol coding

Simple and choice RT of CANTAB)

FAST

EQ5D

NPI

BDS

HAM-D, HAM-A, SAS.

MDS- UPDRS, NMS quest,

Quantitative gait analysis, GFQ.

fMRI

MDS-UPDRS,

NMS quest,

GFQ fMRI datasheet

AE

Con Meds

Post electrode insertion MEG, LFP recording AE First week Post IPG surgery

CVLT-II

Verbal Fluency

Simple & Choice RT (CANTAB)

Digit span

Posner’s covert attention test

CVLT-II Verbal fluency form Digit span form PCAT form AE

4 weeks post electrode insertion

DBS parameter evaluation Randomisation

DBS parameters to be used Randomisation outcome


CVLT-II

Verbal Fluency


Digit span


to be completed before and 1 day after stimulation set to condition 1


Con Meds

End of condition 1 Assessments (12 weeks post electrode insertion)

PDQ39, EQ5D, SCOPA Sleep, SCOPA AUT, Smell Identification test (to be given to patient and brought to baseline evaluation)

MMSE

PDQ39,

SCOPA Sleep, SCOPA AUT

MMSE




DRS-2

CVLT-II

SRM (Faces)






FAST

EQ5D

NPI

BDS

HAM-D, HAM-A, SAS.

MDS-UPDRS, NMS quest,


fMRI

DRS-2

CVLT-II

SRM (Faces)

WAIS-III

CPT, SDR, PCAT


FAST

EQ5D

NPI

BDS

HAM-D, HAM-A, SAS.

MDS-UPDRS,

NMS quest,

GFQ

fMRI datasheet

AE

Con Meds


CVLT-II

Verbal Fluency


Digit span


to be completed before and 1 day after stimulation set to condition 2


Con Meds

End of condition 2 Assessments (20 weeks post electrode insertion)

PDQ39, EQ5D, SCOPA Sleep, SCOPA AUT, Smell Identification test (to be given to patient and brought to baseline evaluation)

PDQ39,

SCOPA Sleep, SCOPA AUT




MMSE

DRS-2

CVLT-II

SRM (Faces)






FAST

EQ5D

NPI

BDS

HAM-D, HAM-A, SAS.

MDS-UPDRS, NMS quest,


fMRI

MMSE

DRS-2

CVLT-II

SRM (Faces)

WAIS-III

CPT, SDR, PCAT


FAST

EQ5D

NPI

BDS

HAM-D, HAM-A, SAS.

MDS-UPDRS,

NMS quest,

GFQ

fMRI datasheet AE

Con Meds

7.12 Methods 568

7.12.1 Laboratory procedures 569

All patient blood samples will be analysed by the standard accredited hospital routine 570 laboratories of the National Hospital for Neurology and Neurosurgery and UCLH. 571




7.12.2 Radiology or other procedures 572

All patients will have structural MRI scans performed to assess eligibility, and as part of their 573 DBS surgery according to standard NHS practice at NHNN. DTI scans will also be performed 574 according to our ongoing research protocol- REC approval number 10/H0706/68. fMRI scans 575 will be performed at baseline and at the end of each condition according to our ongoing 576 research protocol 09/H0716/51. 577

All imaging will take place at the NHNN under the supervision of the CI or delegated 578 members of the DBS clinical team. Analysis of scans will be performed by an experienced 579 trained individual. 580

7.13 Definition of end of trial 581

The end of the trial will be the date of the last visit by the last participant. 582

7.14 Discontinuation/withdrawal of participants and ‘stopping rules’ 583

Appropriate symptomatic treatment for common adverse effects of DBS surgery, and or 584 general anaesthesia will be provided, including nausea, vomiting, pain, transient confusion. 585 Rare adverse effects of DBS surgery including intracerebral haemorrhage, infection, or 586 provocation of seizures will also be treated symptomatically using standard NHS care. 587

Patients wishing to discontinue participation with the trial will be free to do so. The reasons 588 for withdrawal will be sought from all individuals and recorded. Adverse events will be 589 recorded systematically throughout the trial and from all patients wishing to withdraw. 590 Appropriate medical advice and treatment will be made available to any individuals 591 experiencing adverse events from trial participation. 592

The trial will be stopped prematurely if there are doubts regarding the safety or scientific 593 validity of its continuation, in accordance with the principles of Good Clinical Practice and 594 the Medicines for Human Use (Clinical Trials) Regulations 2004 Part 4. 595

8 Assessment of compliance 596

The patients will not have the facility to turn the DBS system on or off. Adverse reactions 597 (considered by the CI to be related to the DBS) will lead to unblinding of the patients. Open 598 label adjustments to DBS parameters will be made by the trial team to allow continued open 599 label participation. 600




9 Recording and reporting of adverse events and reactions 601

9.1 Definitions 602

Adverse Event (AE) 603

An AE is any untoward medical occurrence in a subject to whom a medicinal product or 604 device has been administered, including occurrences which are not necessarily caused by or 605 related to that product. An AE can therefore be any unfavourable and unintended sign 606 (including an abnormal laboratory finding), symptom or disease temporarily associated with 607 the use of a device or Investigational Medicinal Product (IMP), whether or not considered 608 related to the device. 609

610

Adverse Reaction (AR) 611 An AR is any untoward and unintended response in a subject to a device, which is related to 612 any administration of the device. All adverse events judged by either the reporting 613 investigator or the Sponsor as having a reasonable causal relationship to a device qualify as 614 adverse reactions. The expression reasonable causal relationship means to convey in general 615 that there is evidence or argument to suggest a causal relationship. 616

617

Serious Adverse event (SAE) or Serious Adverse Reaction (SAR) 618 619

Serious Adverse Event (SAE) 620

An SAE/ SAR fulfils at least one of the following criteria: 621

Is fatal – results in death (NOTE: death is an outcome, not an event) 622

Is life-threatening 623

Requires inpatient hospitalisation or prolongation of existing hospitalization 624

Results in persistent or significant disability/incapacity 625

Is a congenital anomaly/birth defect 626

627

Suspected unexpected Serious Adverse Reaction (SUSAR) 628 629

The definition of a SUSAR is any suspected unexpected adverse reaction related to a device 630 that is both unexpected and serious. In this case the event is not outlined in the manufacturer 631 guide to the device or in the protocol. 632

633




9.2 Notification and reporting Adverse Events or Reactions 634 635

AEs and ARs will be recorded in the CRF of each patient and the AE/ AR log. 636

637

9.3 Notification and Reporting of Serious Adverse Events/SUSAR 638 639

As the device used in this project are licensed in the UK and used within their marketing 640 authorization, the EXPECTED SARs will be RECORDED in the subjects’ notes/CRF. No 641 SAE forms will be completed and sent to the sponsor. Trust reporting requirements for events 642 and incidents will be followed. 643

UNEXPECTED Serious Adverse Event (SAE’s) will be recorded in the subjects’ notes/CRF, 644 the sponsor SAE form and reported to the UCL/UCLH/RF Joint Biomedical Research (JRO) 645 Unit as soon as possible. The co-investigators listed in this protocol will be authorized to sign 646 the SAE forms in the absence of the PI. Suspected Unexpected Serious Adverse Reactions 647 (SUSAR’s) during the trial will be reported to the JRO and the main REC within one working 648 day of the PI or co-investigator becoming aware of the event. NHS Trust reporting 649 requirements for events and incidents will be followed. 650

651

9.4 Identification of SAE’s/SUSARs 652 653 Expected SAEs include; 654

Infection of surgical wounds and/or DBS hardware 655 Epileptic seizures 656 Intra-cranial haemorrhage 657 658

SAEs may be related to the surgery (e.g. bleeding in the brain, which could cause a stroke, 659 possibly leading to weakness of the opposite side of the body and speech problems), the 660 device (infection necessitating removal of the stimulator, malfunction including disconnection 661 of the stimulator). Although these events are rare (e.g. infection: 1%; bleeding <1%; lead 662 fracture <1% in specialised centres across UK), they may be serious when they do occur. 663 There is also a risk of epilepsy or having a convulsive fit with any brain operation (estimated 664 at 0.6% for DBS surgery). The risk of death from surgery is again below 1 in a hundred. 665

9.4.1 Notification of deaths 666

All deaths will be immediately (within one working day of the CI becoming aware of the 667 death) reported to the sponsor irrespective of whether the death is related to disease 668 progression, the implantation of the device, or an unrelated event. 669




10 Data management and quality assurance 670

10.1 Confidentiality 671

All data will be handled in accordance with the Data Protection Act 1998. 672

The Case Report Forms (CRFs) will not bear the subject’s name. The subject’s initials, date 673 of birth and trial identification number, will be used for identification. 674

10.2 Data collection tools and source document identification 675

Case report forms will be designed and produced by the investigator, according to the 676 sponsor’s CRF template. The final version will be approved by the sponsor. All data will be 677 entered legibly in black ink with a ball-point pen. If an error is made, the error will be 678 crossed through with a single line in such a way that the original entry can still be read. The 679 correct entry will then be clearly inserted, and the alterations will be initialled and dated by 680 the person making the alteration. Overwriting or use of correction fluid will not be 681 permitted.’ 682

10.3 Data handling and analysis 683

A Microsoft Access database will be specifically designed for data entry and storage. 684 Numerical limits (e.g. valid values 0-4) will be put in place to prevent erroneous data being 685 entered. This database will be stored on a single UCL computer with secure server backup to 686 prevent data loss in case of hardware failure. This computer will have restricted access, will 687 be username and password protected, and will be kept in a secure University research facility. 688

The CI will delegate responsibility for data entry and quality to a named individual who will 689 be part of the trial team. The CI will be responsible for data analysis which will be done 690 independently of data entry. 691

All data storage will adhere to Data Protection Act 1998. 692

11 Record keeping and archiving 693

The Chief Investigator is responsible for the secure archiving of trial documents and the trial 694 database. 695

The site files, CRFs and consent forms, and the trial database will be retained for 10 years 696 after completion of the study. Data will be stored to enable additional retrospective subgroup 697 analyses to be performed or to look at long term follow up outcomes, should future data 698 indicate that this may be of interest or importance. 699

These data will be stored in a secure University Research facility. 700




12 Statistical Considerations 701

Dr Foltynie has been formally trained in Epidemiology and Biostatistics at the University of 702 Cambridge (MPhil 2000), and has taken the statistical decisions in the design of the protocol. 703 Additional statistical advice has been sought through the UCL JRBU. 704

12.1 Endpoints 705

12.1.1 Primary endpoints 706

Differences between each item of the abbreviated cognitive battery scores between patients 707 after 6 weeks ON stimulation and 6 weeks OFF stimulation. 708

CVLT-II 709

Verbal Fluency 710

Simple & Choice RT (CANTAB) 711

Digit span 712

Posner’s covert attention test 713

12.1.2 Secondary endpoints 714

Difference between the following assessments between patients ON stimulation and OFF 715 stimulation in: 716

717 MMSE 718

DRS-2 719

SRM (Faces) 720

WAIS-III (Letter number sequencing, Arithmetic) 721

CPT, SDR 722

TMT, PRL 723

WAIS-III Symbol Search and Digit Symbol coding 724

FAST 725

EQ5D 726

NPI 727

BDS 728

HAM-D, HAM-A, SAS. 729

MDS-UPDRS, NMS quest, 730




PDQ39, 731

SCOPA Sleep, 732

SCOPA AUT, 733

Smell Identification test 734

735

Quantitative gait analysis 736

GFQ. 737

738

fMRI 739

12.2 Sample size and recruitment 740

12.2.1 Sample size calculation 741

Six patients will be recruited to this pilot study. There has only been a single case report of 742 NBM DBS in humans and therefore there is not sufficient prior data to perform sample size 743 calculations. Following completion of this trial, a refined estimate of the potential efficacy of 744 NBM DBS can then be used in the design and sample size calculation in a future larger trial. 745 This pilot data will also provide evidence of safety of NBM DBS in this patient group. 746

12.3 Statistical analysis plan 747

12.3.1 Primary endpoint analysis 748

. 749

Every effort will be made to ensure that missing data for the primary outcomes is kept to a 750 minimum. In view of the small sample size, a non-parametric test e.g the Wilcoxon matched 751 pairs signed rank test will be used to assess differences between scores ON and OFF 752 stimulation. No subgroup analyses are planned. The mean difference in the primary outcome 753 and an estimate of its variance will be determined from our results and these data will be used 754 for formal sample size calculations for future studies 755

12.3.2 Secondary endpoint analysis 756

Each of the secondary outcome measures will be analysed using the Wilcoxon matched pairs 757 signed rank test. Every effort will be made to ensure that missing data is kept to a minimum 758 for all secondary endpoints. However the tests will be arranged such that missing data due to 759 fatigue will have minimal impact on the scientific interpretation of the data. 760




13 Name of Committees involved in trial 761

A Trial Management Group (TMG) will be created to supervise the conduct of the trial. This 762 will comprise the chief investigator, two collaborating senior principal investigators, and the 763 research fellow coordinating data collection and data entry. 764

14 Ethics 765

This trial will be conducted in accordance with the Seoul revision of the Declaration of 766 Helsinki (2008), the principles of Good Clinical Practice according to the EU directive 767 2005/28/EC (GCP Directive) and The Medicines for Human Use (Clinical Trials) Regulations 768 Statutory Instruments 2004/1031 and 2006/1938 in the UK. 769

The sponsor will ensure that the trial protocol, patient information sheet, consent form, GP 770 letter and submitted supporting documents have been approved by main REC prior to any 771 patient recruitment. The protocol and all agreed substantial protocol amendments, will be 772 documented and submitted for ethical approval prior to implementation. 773

15 Finance 774

All patients participating in this trial will be eligible and appropriate for pallidal (GPi) DBS 775 for the treatment of the motor aspects of the Parkinson’s disease. The DBS systems will 776 therefore be funded by the patient’s PCT as this indication is NICE approved. 777

All other aspects of the trial will be funded by the Brain Research Trust- ref -PAR11141 778

15 Southampton Place 779

London 780

WC1A 2AJ 781

0207 404 9982 782

Registered charity number 1137560 783

www.brt.org.uk 784

16 Insurance 785

Standard NHS Indemnity arrangements apply for providing indemnity and/or compensation in 786 the event of a claim by, or on behalf of participants for negligent harm. 787

UCL will provide non-negligent insurance cover. 788




17 Publication policy 789

The results of this pilot trial will be submitted for publication in a peer reviewed journal, in 790 addition to reports at appropriate specialist conferences. 791

18 Statement of compliance 792

The trial will be conducted in compliance with the protocol, GCP and the applicable 793 regulatory requirement(s). 794

19 References 795

Reference List 796

797 (1) Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident 798

cohort of Parkinson's patients in the UK. The CamPaIGN study. Brain 2004; 127(Pt 799 3):550-560. 800

(2) Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J et 801 al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. 802 Neurology 2010; 75(12):1062-1069. 803

(3) Naismith SL, Shine JM, Lewis SJ. The specific contributions of set-shifting to 804 freezing of gait in Parkinson's disease. Mov Disord 2010; 25(8):1000-1004. 805

(4) Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. Evolution of 806 cognitive dysfunction in an incident Parkinson's disease cohort. Brain 2007; 130(Pt 807 7):1787-1798. 808

(5) Williams-Gray CH, Evans JR, Goris A, Foltynie T, Ban M, Robbins TW et al. The 809 distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the 810 CamPaIGN cohort. Brain 2009; 132(Pt 11):2958-2969. 811

(6) Farlow MR, Cummings J. A modern hypothesis: The distinct pathologies of dementia 812 associated with Parkinson's disease versus Alzheimer's disease. Dement Geriatr Cogn 813 Disord 2008; 25(4):301-308. 814

(7) Weinberger NM. Experience-dependent response plasticity in the auditory cortex: 815 Issues, characteristics, mechanisms and functions. In: Parks TN, Rubel E.W., Popper 816 AN, editors. Plasticity of the auditory system . New York: Springer-Verlag.; 2004. 817 173-228. 818

(8) Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL. Basal 819 forebrain lesions in monkeys disrupt attention but not learning and memory. J 820 Neurosci 1994; 14(1):167-186. 821

(9) Voytko ML. Cognitive functions of the basal forebrain cholinergic system in 822 monkeys: memory or attention? Behav Brain Res 1996; 75(1-2):13-25. 823

(10) Jimenez-Capdeville ME, Dykes RW, Myasnikov AA. Differential control of cortical 824 activity by the basal forebrain in rats: a role for both cholinergic and inhibitory 825 influences. J Comp Neurol 1997; 381(1):53-67. 826




(11) Montero-Pastor A, Vale-Martinez A, Guillazo-Blanch G, Marti-Nicolovius M. Effects 827 of electrical stimulation of the nucleus basalis on two-way active avoidance 828 acquisition, retention, and retrieval. Behav Brain Res 2004; 154(1):41-54. 829

(12) Miasnikov AA, Chen JC, Weinberger NM. Behavioral memory induced by 830 stimulation of the nucleus basalis: effects of contingency reversal. Neurobiol Learn 831 Mem 2009; 91(3):298-309. 832

(13) Santos-Benitez H, Magarinos-Ascone CM, Garcia-Austt E. Nucleus basalis of 833 Meynert cell responses in awake monkeys. Brain Res Bull 1995; 37(5):507-511. 834

(14) Hasselmo ME, Sarter M. Modes and models of forebrain cholinergic neuromodulation 835 of cognition. Neuropsychopharmacology 2011; 36(1):52-73. 836

(15) Voytko ML. Cognitive functions of the basal forebrain cholinergic system in 837 monkeys: memory or attention? Behav Brain Res 1996; 75(1-2):13-25. 838

(16) Voytko ML, Olton DS, Richardson RT, Gorman LK, Tobin JR, Price DL. Basal 839 forebrain lesions in monkeys disrupt attention but not learning and memory. J 840 Neurosci 1994; 14(1):167-186. 841

(17) Klinkenberg I, Blokland A. The validity of scopolamine as a pharmacological model 842 for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav 843 Rev 2010; 34(8):1307-1350. 844

(18) Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D et al. Electrical 845 stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl J Med 846 1998; 339(16):1105-1111. 847

(19) Foltynie T, Hariz MI. Surgical management of Parkinson's disease. Expert Rev 848 Neurother 2010; 10(6):903-914. 849

(20) Foltynie T, Zrinzo L, Martinez-Torres I, Tripoliti E, Petersen E, Holl E et al. MRI-850 guided STN DBS in Parkinson's disease without microelectrode recording: efficacy 851 and safety. J Neurol Neurosurg Psychiatry 2010. 852

(21) Witt K, Daniels C, Reiff J, Krack P, Volkmann J, Pinsker MO et al. 853 Neuropsychological and psychiatric changes after deep brain stimulation for 854 Parkinson's disease: a randomised, multicentre study. Lancet Neurol 2008; 7(7):605-855 614. 856

(22) Freund HJ, Kuhn J, Lenartz D, Mai JK, Schnell T, Klosterkoetter J et al. Cognitive 857 functions in a patient with Parkinson-dementia syndrome undergoing deep brain 858 stimulation. Arch Neurol 2009; 66(6):781-785. 859

(23) Barnikol TT, Pawelczyk NB, Barnikol UB, Kuhn J, Lenartz D, Sturm V et al. Changes 860 in apraxia after deep brain stimulation of the nucleus basalis Meynert in a patient with 861 Parkinson dementia syndrome. Mov Disord 2010; 25(10):1519-1520. 862

(24) Follett KA, Weaver FM, Stern M, Hur K, Harris CL, Luo P et al. Pallidal versus 863 subthalamic deep-brain stimulation for Parkinson's disease. N Engl J Med 2010; 864 362(22):2077-2091. 865

(25) Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA et al. Diagnostic 866 procedures for Parkinson's disease dementia: recommendations from the movement 867 disorder society task force. Mov Disord 2007; 22(16):2314-2324. 868




(26) Litvak V, Jha A, Eusebio A, Oostenveld R, Foltynie T, Limousin P et al. Resting 869 oscillatory cortico-subthalamic connectivity in patients with Parkinson's disease. Brain 870 2011; 134(Pt 2):359-374. 871

872 873


Documents

Clinical Trial Protocol...Short title: DBS for memory& thinking in Parkinson's Sponsor code: 11/0516 Protocol Version 3.0 29/09/2012 1 1 Clinical Trial Protocol 2 Full title of trial