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Stiefel, a GSK company

Calcipotriene Foam 0.005%, U0267-302 Clinical Study Report

Page 1

STIEFEL CONFIDENTIAL

A Multicenter, Randomized, Double-Blind, Phase 3 Study of the Safety and Efficacy of

Emulsion Formulation Calcipotriene Foam, 0.005%, versus Vehicle Foam in Subjects

with Plaque-type Psoriasis

Clinical Study Report U0267-302

Version 1.0

13 Aug 2009

Sponsored by:

Stiefel, a GSK company (“Stiefel”)

3160 Porter Drive

Palo Alto, CA 94304

USA

Conducted by:

Stiefel

3160 Porter Drive

Palo Alto, CA 94304

USA

THIS DOCUMENT CONTAINS CONFIDENTIAL AND/OR TRADE SECRET

INFORMATION THAT IS DISCLOSED ONLY IN CONNECTION WITH THE

LICENSING AND/OR REGISTRATION OF PRODUCTS FOR STIEFEL OR ITS

AFFILIATED COMPANIES. THIS DOCUMENT SHOULD NOT BE DISCLOSED

OR USED, IN WHOLE OR IN PART, FOR ANY OTHER PURPOSE WITHOUT

THE PRIOR WRITTEN CONSENT OF STIEFEL.



Page 2


1 TITLE PAGE

A Multicenter, Randomized, Double-Blind, Phase 3 Study of the Safety and Efficacy

of Emulsion Formulation Calcipotriene Foam, 0.005%, versus Vehicle Foam in

Subjects with Plaque-type Psoriasis

Name of Investigational

Product

Emulsion Formulation Calcipotriene Foam 0.005%

Indication Plaque-type psoriasis

Sponsor Stiefel.

Protocol/Study Number U0267-302

Development Phase 3

Study Initiation Date 22 April 2008 (first subject, first visit)

Study Completion Date 26 December 2008 (last subject, last visit)

Sponsor’s Responsible

Medical Officer

, MD

Executive Director, Global Clinical Research

Stiefel.

Responsible Signatory , MD

Executive Director, Global Clinical Research

Stiefel.

Date of the report 13 Aug 2009

This study was performed in accordance with Good Clinical Practices, including guidelines outlined by the

International Conference on Harmonisation.



Page 3


2 SYNOPSIS

NAME OF SPONSOR/COMPANY:

Stiefel. INDIVIDUAL STUDY

TABLE REFERRING TO

PART OF THE DOSSIER

(FOR NATIONAL

AUTHORITY USE

ONLY)

NAME OF FINISHED PRODUCT:


Volume:

Page:

NAME OF ACTIVE INGREDIENT:

Calcipotriene

Title of study: A Multicenter, Randomized, Double-Blind, Phase 3 Study of the Safety and Efficacy of

Emulsion Formulation Calcipotriene Foam, 0.005%, versus Vehicle Foam in Subjects with Plaque-type

Psoriasis

Investigators: A complete list of investigators who participated in this multicenter study is presented within

appendix 16.1.4, List and Description of Investigators and Other Important Participants in the Study.

Study centers: This study was conducted at 12 study centers in the United States. A complete list of the

names and addresses of study centers that participated in this multicenter study are presented within

appendix 16.1.4, List and Description of Investigators and Other Important Participants in the Study.

Publication (reference): None

Study initiation/completion dates:

First subject, first visit: 22 Apr 2008

Last subject, last visit: 26 Dec 2008

Phase of

Development: 3

Objectives: To evaluate the safety and efficacy of Emulsion Formulation Calcipotriene Foam compared to

vehicle foam in subjects with plaque-type psoriasis.

Methodology: This was a multicenter, randomized, double-blind, phase 3 study comparing calcipotriene

foam to vehicle foam in subjects with plaque-type psoriasis. Application areas included psoriatic areas of the

body excluding those on the face and scalp. If new psoriatic lesions appeared during the treatment period,

they were dosed as well. Subjects were randomized to 1 of 2 groups in a 2:1 ratio (calcipotriene foam: vehicle

foam). All study product was administered twice daily (morning and evening) for 8 weeks. Visits occurred at

baseline, week 2, week 4, and week 8. Stiefel personnel, investigators, subjects, and nurses/coordinators were

blinded to the study product assignment.

Number of subjects (planned and analyzed):

Planned: 327

Enrolled: 330

Treated: 323

Analyzed: Intent to treat (ITT) analysis set: 323

Per protocol (PP) analysis set: 261



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Diagnosis and Main Criteria for Inclusion: Subjects meeting all of the following criteria were eligible for

enrolment:

1. Male or female subjects at least 12 years old and in good general health.

2. Mild to moderate plaque-type psoriasis, as defined by an Investigator’s Static Global Assessment (ISGA) score of 2 or 3 at baseline.

3. Mild to moderate plaque-type psoriasis involving 2% to 20% of total body surface area (BSA) (excluding the face and scalp).

4. Identification of a target lesion (>2 cm²) on the trunk or extremities with a score of 2 or 3 on a 0 to 5 scale for each of erythema, scaling, and plaque thickness. Lesions on palms/soles, knees,

elbows, and intertriginous areas were not used as the target lesion site.

Test Product, Dose and Mode of Administration, Batch No.:

Calcipotriene foam containing 0.005% calcipotriene in an emulsion formulation foam vehicle, applied to

affected areas of skin twice daily, batch ZLS-C.

Duration of Study: Eight weeks.

Reference Therapy, Dose and Mode of Administration, Batch No.:

Vehicle foam with identical ingredients and packaging as calcipotriene foam but without the active ingredient

calcipotriene, applied to affected areas of skin twice daily, batch ZLP-C.

Criteria for Evaluation:

Primary Efficacy Endpoint: The proportion of subjects who achieved the following at week 8:

An ISGA score of clear (0) or almost clear (1), and

A minimum improvement in the ISGA score of 2 grades from baseline to week 8.

Subjects with missing efficacy evaluations at week 8 were considered to be treatment failures.



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Criteria for Evaluation (continued):

Key Secondary Efficacy Endpoints: The proportion of subjects who achieved each of the following at week 8:

A target lesion score of 0 or 1 for erythema and at least a 2-grade improvement from baseline.

A target lesion score of 0 or 1 for scaling and at least a 2-grade improvement from baseline.

A target lesion score of 0 for plaque thickness.

An ISGA score of 0 or 1.

In addition, the primary endpoint was analyzed by baseline ISGA score.

Additional Efficacy Endpoints:

Mean percent reduction in the percent of BSA involvement of psoriasis at each visit.

The change in Dermatology Life Quality Index (DLQI) or Children's DLQI (CDLQI) from baseline to week 8.

The proportion of subjects who had a Subject's Global Assessment (SGA) score of 0 or 1 at each visit.

The primary and all key secondary endpoints by visit.

Safety was assessed by evaluation of adverse events (AEs), vital signs, pregnancy, and concocmitant

medications.

Statistical Methods:

The primary efficacy endpoint was analyzed to test the superiority of calcipotriene foam over vehicle foam

using the Cochran-Mantel-Haenszel (CMH) procedure stratified by study center with a 2-sided 0.05

significance level. Consistency of the results across investigative centers for the primary endpoint was verified

using the Breslow-Day test of homogeneity of the odds ratios, using a 0.10 significance level. The ITT

analysis set (all subjects who received study product) was used for the primary endpoint analysis; subjects

with missing week 8 efficacy evaluations were considered to be treatment failures. Two additional sensitivity

analyses were performed for the primary endpoint, 1 using the PP analysis set and the other using the ITT

analysis set where subjects with missing week 8 efficacy assessments had their last non-missing response

carried forward.

The first 4 key secondary efficacy endpoints were analyzed using the CMH procedure stratified by study

center. In the event that the primary analysis was significant at the 0.05 level, the Holm stepwise closed

testing procedure was used to control multiplicity.

The final key secondary endpoint was primary endpoint by baseline ISGA. It was analyzed using the CMH

procedure stratified by study center with a two-sided 0.05 significance level.

The additional efficacy endpoints were analyzed by analysis of covariance (percent reduction in BSA

involvement, change in DLQI) or by the CMH procedure (SGA score).



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SUMMARY – CONCLUSIONS

Demographic and Baseline Characteristics: The mean subject age was 47.8 years (range, 12 to 88 years);

48% of subjects were male and 91% were White. There were no meaningful differences between the

treatment groups in baseline disease characteristics.

Efficacy Results: Primary endpoint: The primary efficacy endpoint was the percentage of subjects in the ITT analysis set with

treatment success, defined as having an ISGA score of clear (0) or almost clear (1) at week 8 and a minimum

improvement in the ISGA score of 2 grades from baseline to week 8. In the ITT analysis set, the proportion of

subjects achieving treatment success was higher in the calcipotriene foam group than in the vehicle foam

group (27% of subjects versus 16%); this difference was statistically significant (P = 0.016).

An additional analysis examined the primary endpoint in the PP analysis set In the PP analysis set, treatment

success was achieved by 32% of calcipotriene foam group subjects and 16% of vehicle foam group subjects

(P = 0.004).

An additional sensitivity analysis of the primary endpoint was performed on the ITT analysis set using last

observation carried forward (LOCF). Sixty subjects (28%) in the calcipotriene foam group achieved treatment

success compared with 17 subjects (16%) in the vehicle foam group (P = 0.010, CMH test stratified by pooled

center).

At the request of the FDA, a post hoc sensitivity analysis of the primary endpoint was performed on the ITT

analysis set. This analysis included only those subjects who had a non-missing week 8 efficacy evaluation.

Fifty-eight subjects (31%) in the calcipotriene foam group achieved treatment success compared with

17 subjects (18%) in the vehicle foam group (P = 0.010).

Key secondary endpoints: The analysis of 4 key secondary endpoints in the ITT analysis set gave results

consistent between these endpoints: in each analysis, more subjects in the calcipotriene foam group achieved

the endpoint than in the vehicle foam group. For 1 endpoint (a target lesion score of 0 or 1 for scaling and at

least a 2-grade improvement from baseline at week 8), the difference between groups was considered to be

statistically significant after multiplicity testing (P = 0.004). These analyses in the PP analysis set gave

similar results. Analysis of a final key secondary endpoint in the ITT analysis set showed that for subjects

with a baseline ISGA score of 3 (moderate), more subjects in the calcipotriene foam group achieved the

primary endpoint than in the vehicle foam group (32% versus 17%, P = 0.015). The results for the PP analysis

set were similar (38% versus 19%, P = 0.013).

Additional efficacy analyses: The analysis of primary and secondary endpoints by time point, and of

reduction in percent BSA involvement by time point showed that, for both analyses and all time points, the

calcipotriene foam group showed greater improvement than the vehicle foam group.

Quality-of-life/Pharmacoeconomic Results: Two additional analyses addressed quality-of-life (QOL) endpoints: proportion of subjects with an SGA score

of 0 or 1 by time point, and change in DLQI from baseline to end of treatment. Neither of these analyses

showed a difference between the treatment groups.



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Safety Results: Adverse events were no more frequent in the calcipotriene foam group than in the vehicle foam group (18% of

subjects vs. 20% respectively), and the 2 treatment groups did not differ meaningfully in the distribution of

AEs according to system organ class (SOC). In the calcipotriene foam group, the most common AEs were

application site-related, while in the vehicle foam group the most common AEs were in the Infections and

Infestations SOC (only 1 of which was at the application site). Adverse events considered by the investigator

to be related to the study product occurred with similar frequencies in the calcipotriene foam group (6% of

subjects) and the vehicle foam group (5%). Adverse events rated as severe in intensity were reported in 2% of

subjects in each treatment group.

There were no deaths during this study. Only one subject experienced an SAE, deafness unilateral, which was

considered to be not related to study product. This subject was in the vehicle foam group.

Seven subjects (3%) in the calcipotriene foam group and 1 subject (1%) in the vehicle foam group

discontinued the study due to AEs. Within both groups, all of the AEs resulting in discontinuation were

application site-related.

Conclusions: Calcipotriene foam appears to be effective, safe, and well-tolerated when used for 8 weeks for

treatment of plaque-type psoriasis in areas excluding the face and scalp in the population studied.

Date of the report: 13 Aug 2009



Page 8


3 TABLE OF CONTENTS

1 TITLE PAGE ................................................................................................................ 2

2 SYNOPSIS .................................................................................................................... 3

3 TABLE OF CONTENTS .............................................................................................. 8

3.1 List of In-Text Tables ......................................................................................... 12

4 LIST OF ABBREVIATIONS ..................................................................................... 14

5 ETHICS....................................................................................................................... 16

5.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ...... 16

5.2 Ethical Conduct of Study .................................................................................... 16

5.3 Subject Information and Consent ........................................................................ 17

5.4 Compliance Statement ........................................................................................ 17

6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ................. 18

7 INTRODUCTION ...................................................................................................... 19

8 STUDY OBJECTIVES ............................................................................................... 21

9 INVESTIGATIONAL PLAN ..................................................................................... 22

9.1 Overall Study Design and Plan ........................................................................... 22

9.2 Discussion of Study Design ................................................................................ 22

9.3 Selection of Study Population ............................................................................. 22

9.3.1 Inclusion Criteria ................................................................................................ 22

9.3.2 Exclusion Criteria ............................................................................................... 23

9.3.3 Removal of Subjects from Therapy or Assessment ............................................ 24

9.3.3.1 Subject Discontinuation .............................................................................. 24

9.3.3.2 Subject Dropout .......................................................................................... 24

9.3.3.3 Screen Failures ............................................................................................ 24

9.4 Study Product(s) .................................................................................................. 25

9.4.1 Study Products Administered ............................................................................. 25

9.4.2 Dose Modification .............................................................................................. 25

9.4.3 Identity of Study Product(s) ................................................................................ 25

9.4.4 Method of Assigning Subjects to Groups ........................................................... 26

9.4.5 Selection of Doses in the Study .......................................................................... 26

9.4.6 Blinding ............................................................................................................... 26

9.4.7 Unblinding .......................................................................................................... 26

9.4.8 Prior and Concomitant Therapy .......................................................................... 26

9.4.8.1 Prohibited Concomitant Therapies ............................................................. 27

9.4.8.2 Permitted Concomitant Therapies............................................................... 27

9.4.9 Treatment Compliance ........................................................................................ 27

9.5 Efficacy and Safety Variables ............................................................................. 27

9.5.1 Efficacy Evaluations ........................................................................................... 27

9.5.2 Laboratory Evaluations ....................................................................................... 28

9.5.3 Safety Evaluations .............................................................................................. 28

9.5.4 Schedule of Study Procedures ............................................................................ 28

9.5.5 Interim Visits and Post-Study Visits ................................................................... 32



Page 9


9.5.6 Primary Efficacy Endpoint ................................................................................. 32

9.5.7 Key Secondary Efficacy Endpoints .................................................................... 32

9.5.8 Additional Efficacy Endpoints ............................................................................ 33

9.6 Data Quality Assurance ...................................................................................... 33

9.6.1 Study Monitoring ................................................................................................ 33

9.6.2 Source Data Verification ..................................................................................... 34

9.6.3 Quality Assurance Audits ................................................................................... 34

9.6.4 Direct Access, Data Handling, and Record-Keeping .......................................... 34

9.6.4.1 Case Report Forms ...................................................................................... 34

9.6.4.2 Data Protection............................................................................................ 34

9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size34

9.7.1 Statistical and Analytical Plans ........................................................................... 35

9.7.1.1 Primary Efficacy Endpoint ......................................................................... 35

9.7.1.2 Key Secondary Efficacy Endpoints ............................................................ 35

9.7.1.3 Additional Efficacy Endpoints .................................................................... 36

9.7.1.4 Safety Analysis ........................................................................................... 36

9.7.2 Determination of Sample Size ............................................................................ 37

9.7.3 Analysis Sets ....................................................................................................... 37

9.8 Changes in the Conduct of the Study or Planned Analyses ................................ 38

10 STUDY SUBJECTS ................................................................................................... 39

10.1 Disposition of Subjects ....................................................................................... 39

10.2 Protocol Deviations ............................................................................................. 39

11 EFFICACY EVALUATION ...................................................................................... 41

11.1 Data Sets Analyzed ............................................................................................. 41

11.2 Demographic and Other Baseline Characteristics .............................................. 41

11.2.1 Demographics ..................................................................................................... 41

11.2.2 Disease Characteristics ....................................................................................... 43

11.2.3 Concomitant Medications ................................................................................... 44

11.3 Measurements of Dosing/Application Compliance ............................................ 46

11.4 Efficacy Results and Tabulations of Individual Subject Data ............................ 47

11.4.1 Analysis of Efficacy ............................................................................................ 47

11.4.1.1 Primary Efficacy Endpoint ..................................................................... 47

11.4.1.2 Key Secondary Efficacy Endpoints ........................................................ 50

11.4.1.3 Additional Efficacy Analyses ................................................................. 53

11.4.2 Statistical/Analytical Issues ................................................................................ 58

11.4.2.1 Adjustments for Covariates..................................................................... 58

11.4.2.2 Handling of Dropouts or Missing Data ................................................... 58

11.4.2.3 Interim Analyses and Data Monitoring................................................... 59

11.4.2.4 Multicenter Studies ................................................................................. 59

11.4.2.5 Multiple Comparisons/Multiplicity ........................................................ 59

11.4.2.6 Use of an Efficacy Subset of Subjects .................................................... 59

11.4.2.7 Examination of Subgroups ...................................................................... 60

11.4.3 Tabulation of Individual Response Data ............................................................. 60



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11.4.4 Product Dose, Product Concentration, Relationships to Response, and

Mechanism of Action .......................................................................................... 60

11.4.5 By-Subject Displays ............................................................................................ 60

11.4.6 Efficacy Conclusions .......................................................................................... 60

12 SAFETY EVALUATION .......................................................................................... 62

12.1 Extent of Exposure .............................................................................................. 62

12.2 Adverse Events ................................................................................................... 64

12.2.1 Brief Summary of Adverse Events ..................................................................... 64

12.2.2 Display of Adverse Events .................................................................................. 64

12.2.3 Analysis of Adverse Events ................................................................................ 65

12.2.3.1 Adverse Events by Relationship to Study Product ................................. 65

12.2.3.2 Severe Adverse Events ........................................................................... 67

12.2.4 Listing of Adverse Events by Subject ................................................................. 68

12.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 68

12.3.1 Deaths ................................................................................................................. 68

12.3.2 Other Serious Adverse Events ............................................................................ 68

12.3.3 Other Significant Adverse Events ....................................................................... 68

12.3.3.1 Adverse Events Leading to Discontinuation........................................... 68

12.3.4 Listing of Deaths, Other Serious Adverse Events, and Other Significant

Adverse Events ................................................................................................... 69

12.3.5 Narratives of Deaths, Other Serious Adverse Events, and Certain Other

Significant Adverse Events ................................................................................. 69

12.3.6 Analysis and Discussion of Deaths, Other Serious Adverse Events, and

Other Significant Adverse Events ....................................................................... 69

12.4 Clinical Laboratory Evaluation ........................................................................... 69

12.5 Vital Signs, Physical Findings, and Other Observations Related to Safety ........ 69

12.6 Safety Conclusions .............................................................................................. 71

13 DISCUSSION AND OVERALL CONCLUSIONS ................................................... 72

13.1 Discussion ........................................................................................................... 72

13.2 Overall Conclusions ............................................................................................ 72

14 TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED

IN THE TEXT ............................................................................................................ 73

14.1 Subject Disposition and Demographic Data ....................................................... 73

14.2 Efficacy Data....................................................................................................... 74

14.3 Safety Data .......................................................................................................... 75

14.4 Other Data ........................................................................................................... 76

14.5 Narratives of Deaths, Other Serious and Significant Adverse Events ................ 77

14.5.1 Deaths ................................................................................................................. 77

14.5.2 Other Serious Adverse Events ............................................................................ 77

15 REFERENCE LIST .................................................................................................... 78

16 APPENDICES ............................................................................................................ 79

16.1 Study Information ............................................................................................... 80

16.1.1 Protocol and Protocol Amendments ................................................................... 80



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16.1.2 Sample Case Report Form .................................................................................. 81

16.1.3 List of Independent Ethics Committees (IECs)/Institutional Review Boards

(IRBs) and Sample Consent Forms/Subject Information Sheets ........................ 82

16.1.4 List and Description of Investigators and Other Important Participants in the

Study ................................................................................................................... 83

16.1.5 Signatures of Principal or Coordinating Investigator(s) or Sponsor’s

Responsible Medical Officer .............................................................................. 84

16.1.6 Listing of Subjects Receiving Investigational Product(s) from Specific

Batches ................................................................................................................ 85

16.1.7 Randomization Scheme and Codes ..................................................................... 86

16.1.8 Audit Certificates ................................................................................................ 87

16.1.9 Documentation of Statistical Methods ................................................................ 88

16.1.9.1 Statistical Analysis Plan .......................................................................... 89

16.1.9.2 Additional Analyses ................................................................................ 90

16.1.10 Documentation of Inter-laboratory Standardization Method and Quality

Assurance Procedures ......................................................................................... 91

16.1.11 Publications Based on the Study ..................................................................... 92

16.1.12 Important Publications Referenced in the Report ........................................... 93

16.2 Subject Data Listings .......................................................................................... 94

16.2.1 Discontinued Subjects ......................................................................................... 94

16.2.2 Protocol Deviations ............................................................................................. 95

16.2.3 Subjects Excluded from the Efficacy Analysis ................................................... 96

16.2.4 Demographic Data .............................................................................................. 97

16.2.5 Compliance and/or Product Concentration Data ................................................ 98

16.2.6 Individual Efficacy Response Data ..................................................................... 99

16.2.7 Adverse Event Listings ..................................................................................... 100

16.2.8 Listing of Individual Laboratory Measurements .............................................. 101

16.2.9 Other Safety Data .............................................................................................. 102

16.2.10 Other Data ..................................................................................................... 103

16.3 Case Report Forms ............................................................................................ 104

16.3.1 CRFs for Deaths, Other Serious Adverse Events, and Withdrawals for an

Adverse Event ................................................................................................... 104

16.3.2 Other CRFs Submitted ...................................................................................... 105

16.4 Individual Subject Data Listings (US Archival Listings) ................................. 106



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3.1 List of In-Text Tables

Table 1: Schedule of Study Procedures ........................................................................... 29

Table 2: Disposition of Subjects (ITT Analysis Set) ....................................................... 39

Table 3: Summary of Reasons for Exclusion from Per Protocol Analysis Set

(All Randomized Subjects) ............................................................................... 40

Table 4: Subject Demographics (ITT Analysis Set) ........................................................ 41

Table 5: Baseline Disease Characteristics (ITT Analysis Set) ........................................ 43

Table 6: Concomitant Medications by ATC Classification Used by ≥5% of Subjects

in Either Treatment Group (ITT Analysis Set) ................................................. 45

Table 7: Number of Study Product Applications (ITT Analysis Set) ............................. 46

Table 8: Primary Efficacy Endpoint: Subjects with Treatment Success at Week 8

(ITT Analysis Set) ............................................................................................. 47


(PP Analysis Set) ............................................................................................... 48

Table 10: Sensitivity Analysis of Primary Efficacy Endpoint: Subjects with

Treatment Success at Week 8 (LOCF, ITT Analysis Set) ................................ 49


(Subjects with Non-Missing Week 8 Evaluation, ITT Analysis Set) ............... 50

Table 12: Analysis of Key Secondary Endpoints (ITT Analysis Set) ............................... 51

Table 13: Analysis of Key Secondary Endpoints (PP Analysis Set) ................................. 52

Table 14: Subjects Achieving Treatment Success by Baseline ISGA Score

(ITT Analysis Set) ............................................................................................. 52

Table 15: Subjects Achieving Treatment Success Analyzed by Baseline ISGA Score

(PP Analysis Set) ............................................................................................... 53

Table 16: Primary and Key Secondary Efficacy Endpoints by Time Point

(ITT Analysis Set) ............................................................................................. 54

Table 17: Change in Percent Body Surface Area Involvement by Time Point

(ITT Analysis Set) ............................................................................................. 56

Table 18: Proportion of Subjects with a Subject's Global Assessment Score of 0 or

1 by Time Point (ITT Analysis Set) .................................................................. 57

Table 19: Change in Dermatology Life Quality Index from Baseline to End of

Treatment (ITT Analysis Set) ........................................................................... 58

Table 20: Duration of Study Treatment (ITT Analysis Set) .............................................. 62

Table 21: Total Amount of Study Product Used (ITT Analysis Set) ................................ 63

Table 22: Mean and Median Daily Study Product Usage (ITT Analysis Set) .................. 63

Table 23: Summary of Treatment-Emergent Adverse Events Experienced by

>1 Subject in Either Group by System Organ Class and Preferred Term

(ITT Analysis Set) ............................................................................................. 64

Table 24: Summary of Subjects with Study Product-Related Treatment-Emergent

Adverse Events by System Organ Class and Preferred Term

(ITT Analysis Set) ............................................................................................. 66

Table 25: Summary of Treatment-Emergent Adverse Events Rated Severe in Intensity

(ITT Analysis Set) ............................................................................................. 67



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Table 26: Adverse Events Leading to Discontinuation (ITT Analysis Set) ...................... 68

Table 27: Vital Sign Changes from Baseline to Week 8/End of Treatment

(ITT Analysis Set) ............................................................................................. 70



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4 LIST OF ABBREVIATIONS

AE adverse event

ANCOVA analysis of covariance

ATC anatomical therapeutic chemical

BSA body surface area

CDLQI Children’s Dermatology Life Quality Index

CFR Code of Federal Regulations

CMH Cochran-Mantel-Haenszel

CRF case report form

DLQI Dermatology Life Quality Index

FDA Food and Drug Administration

GCP Good Clinical Practice

HIPAA Health Insurance Portability and Accountability Act

ICH International Conference on Harmonisation

ICF informed consent form

IEC Independent Ethics Committee

IND Investigational New Drug

IRB Institutional Review Board

ISGA Investigator's Static Global Assessment

ITT intent to treat

IUD intrauterine device

LC/MS/MS liquid chromatography/mass spectrometry/mass spectrometry

LOCF last observation carried forward

MedDRA Medical Dictionary for Regulatory Activities

PP per protocol

PUVA psoralen combined with exposure to ultraviolet light A

QOL quality of life

SAE serious adverse event

SD standard deviation

SDV source data verification



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SGA Subject’s Global Assessment

SOC system organ class

SOP standard operating procedure

TEAE treatment-emergent adverse event

UVB ultraviolet light B

US United States

WHODrug World Health Organization Drug Dictionary



Page 16


5 ETHICS

5.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

The protocol and informed consent/assent form for this study were approved by each

investigator's governing IRB (including a central IRB where appropriate) before the study

was initiated; documentation of this approval was provided to Stiefel. The IRB was required

to comply with current Food and Drug Administration (FDA) regulations (21 Code of

Federal Regulations 56).

Other investigator responsibilities relative to the IRB included the following:

1. Submit to the IRB for review any advertisements that will be used to recruit subjects.

2. Submit to the IRB for review any patient information documentation (eg, patient information sheets).

3. During the conduct of the study, submit progress reports to the IRB, if required, and request re-review of the study at least once a year.

4. Report, in writing, to the IRB any serious adverse event (SAE) that occurred during the study.

5. If Stiefel notified the investigator about SAEs reported in other studies or at other study sites using this study product, report that information, in writing, to the IRB.

6. Inform the IRB of any changes in the protocol or informed consent/assent form and obtain IRB approval of the changes prior to implementing these changes.

7. Provide the IRB with any other information it requested before or during the conduct of the study.

8. Maintain a file of study-related information, including correspondence with the IRB and with Stiefel.

9. Within 3 months of study completion, provide the IRB with a final report on the study.

NOTE: Copies of all communications between the investigator and the IRB regarding the

study were provided to Stiefel.

A copy of the protocol is provided in appendix 16.1.1; a list of IECs/IRBs is provided in

appendix 16.1.3.

5.2 Ethical Conduct of Study

This study was performed according to the recommendations made in the Declaration of

Helsinki (South Africa, 1996) and with the laws and regulations of the country in which the

study was conducted.



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For studies conducted in the United States (US) or under a US Investigational New Drug

(IND) Application, the investigator ensured that the basic principles of “Good Clinical

Practice” as outlined in the current version of 21 CFR, subchapter D, part 312,

“Responsibilities of Sponsors and Investigators,” part 50, “Protection of Human Subjects,”

and part 56, “Institutional Review Boards,” were adhered to.

5.3 Subject Information and Consent

The written informed consent form (ICF)/assent form was signed by each subject or

parent/guardian at the first (baseline) study visit, prior to any study procedures. The

investigator was responsible for the content of the informed consent/assent form, but the

content was reviewed by Stiefel and approved by the IRB. It was understood that the

process by which the investigator obtains informed consent/assent was a matter solely within

the investigator-subject relationship and did not involve Stiefel. However, the informed

consent/assent must have complied with FDA regulations (21 CFR 50.20–50.27). It also

included any additional information required by local laws relating to institutional review.

The investigator was also responsible for obtaining informed consent/assent from each

subject participating in the study. All pertinent aspects of the study were explained to the

subject/legal guardian before he or she signed and dated the informed consent/assent.

Informed consent/assent must have been obtained from the subject before any activity or

treatment was undertaken that was not part of routine care. This included, but was not

limited to, the performance of diagnostic or therapeutic procedures and the administration of

the first dose of the study product.

It was documented in the source that written informed consent/assent for each subject was

obtained prior to performing any screening procedures (21 CFR 312.62).

Copies of the ICF and assent form are provided in appendix 16.1.3.

5.4 Compliance Statement

It was the responsibility of the investigator to conduct this study in strict compliance with

this protocol and FDA regulations and all applicable laws and regulations.



Page 18


6 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

A list of investigators who participated in the study, along with corresponding site addresses,

is presented in appendix 16.1.4. The curricula vitae for the investigators who participated in

this study are included in appendix 16.1.4. The signature of the sponsor’s responsible

medical officer is presented in appendix 16.1.5.

List of Suppliers:

Study Product: Fisher Clinical Services

7554 Schantz Road

Allentown, PA 18106

Photography:

Canfield Scientific, Inc.

263 Passaic Avenue

Fairfield, NJ 07004-2524

Central IRB:

Local IRBs:

Data Management:

ICON

1700 Pennbrook Parkway

North Wales, PA 19454



Page 19


7 INTRODUCTION

Psoriasis is a noncontagious skin disorder, most often appearing as inflamed, thickened skin

covered with silvery white scales and involving areas of the scalp, trunk, and limbs. The

most common type of psoriasis is plaque psoriasis, characterized by raised lesions on the

scalp, trunk, and limbs. An estimated 4 to 5 million people suffer from psoriasis in the US,

with approximately 150,000 new cases of psoriasis occurring annually.1

Psoriasis, though rarely life-threatening, can cause significant morbidity and disruption in a

person’s life. Topical medications may be used alone in mild to moderate psoriasis or in

combination with systemic agents in moderate or severe psoriasis. Topical vitamin D

analogs remain one of the most widely used therapeutic modalities for psoriasis.2

Laboratory

research has shown that subjects with psoriasis have a shortened epidermal cell cycle:

normally, keratinocytes require 28 to 44 days to migrate from the basal cell layer of the

epidermis to the stratum corneum; in subjects with psoriasis, this migration takes only

4 days.3 Vitamin D3 and its analogs inhibit keratinocyte proliferation and induce terminal

differentiation.4

Calcipotriene, also called calcipotriol, is a synthetic vitamin D3 derivative that has been used

effectively for many years for the treatment of plaque-type psoriasis. Topical calcipotriene

(Dovonex) was first approved in the US in 1993 for the reversal of the abnormal

keratinocyte changes seen in psoriasis. Calcipotriene is as potent as 1,25(OH)2D3, the

naturally occurring active form of vitamin D, in regulating cell proliferation and cell

differentiation, but is much less active than 1,25(OH)2D3 in its effect on calcium

metabolism. Calcipotriene is currently approved in 3 different dosage forms for topical use:

a cream, an ointment, and a solution for scalp application, all at a strength of 0.005%.5,6,7

The current study investigated a new calcipotriene formulation, Calcipotriene Emulsion

Formulation Foam 0.005% (hereafter referred to as calcipotriene foam), which delivers the

active ingredient calcipotriene in a ethanol-free, aqueous-based emulsion formulation foam.

Adequate and well-controlled studies of subjects treated with the currently marketed version

of calcipotriene ointment and cream (Dovonex Ointment/Dovonex Cream) have

demonstrated improvement usually beginning after 2 weeks of therapy. This improvement

continued in subjects using Dovonex Ointment once daily and twice daily. After 8 weeks of

twice daily use of Dovonex Ointment, approximately 56% of subjects were evaluated as

being clear or almost clear using the Physician’s Global Assessment (compared to

approximately 8% in the vehicle control group). Over 400 subjects have been treated in

open-label studies for over 1 year. In controlled clinical studies, the most frequent adverse

reactions reported for Dovonex Ointment were burning, itching, and skin irritation, which

occurred in approximately 10% to 15% of subjects. Erythema, dry skin, peeling, rash,

dermatitis, worsening of psoriasis, including development of facial/scalp psoriasis were

reported in 1% to 10% of subjects. Other adverse experiences reported in less than 1% of

subjects included skin atrophy, hyperpigmentation, hypercalcemia, and folliculitis.5,6

http://www.drugs.com/PDR/Dovonex_Ointment.html##



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Elevated albumin-adjusted serum calcium has also been observed in subjects who used very

high doses of calcipotriene (>200 g/week).8

Two clinical studies using calcipotriene foam have been conducted. One multicenter phase 2

study (CAL.201) enrolled 101 subjects with mild to moderate plaque-type psoriasis. All

subjects were dosed twice daily for 8 weeks with either calcipotriene foam, vehicle foam,

Dovonex Ointment (active control), or vehicle ointment. Efficacy was defined as an

Investigator's Static Global Assessment (ISGA) score of clear or almost clear and a

minimum improvement in the ISGA score of 2 grades from baseline to week 8 (or early

termination). Treatment success was observed in 17% of subjects treated with calcipotriene

foam, 35% of subjects treated with Dovonex Ointment, 3% of subjects treated with vehicle

foam, and 0% of subjects treated with vehicle ointment.

The second study was a bioavailability study (CAL.203) conducted in 32 subjects with

psoriasis. Subjects were randomized equally to either 2 weeks of administration of

calcipotriene foam or Dovonex Ointment. In order to achieve maximal exposure, subjects

were instructed to apply approximately 3.5 g of study product twice daily (morning and

evening) and to cover all affected areas (except for the face and scalp). Six of the 32

subjects had measurable levels of calcipotriene (at least 10 pg/mL) at various time points

during the study; 1 subject in the calcipotriene foam group had a measurable level on day 8,

and 5 subjects in the Dovonex Ointment group had measurable levels on days 8 and 15. All

measured calcipotriene levels were below 25 pg/mL. These results are consistent with the

results of a radioabsorption assay that evaluated the systemic exposure and elimination of

calcipotriene in subjects treated with Dovonex Ointment.5,6,7

Safety in both studies was evaluated based on reported adverse events (AEs) and

measurement of serum albumin-adjusted calcium levels. Neither study reported clinically

meaningful changes in serum calcium in any treatment group. There were no severe AEs,

deaths, or other SAEs in either study. Treatment-emergent adverse events (TEAEs) were

infrequent and did not differ in nature or frequency between treatment groups.



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8 STUDY OBJECTIVES

The primary objectives of this study were to evaluate the safety and efficacy of calcipotriene

foam compared with vehicle foam in subjects with plaque-type psoriasis.



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9 INVESTIGATIONAL PLAN

9.1 Overall Study Design and Plan

This was a multicenter, randomized, double-blind, phase 3 study comparing calcipotriene

foam with vehicle foam in subjects with plaque-type psoriasis. Application areas included

psoriatic areas of the body excluding those on the face and scalp. If new psoriatic lesions

appeared during the treatment period, these were to have been dosed as well. Approximately

327 male and female subjects with plaque-type psoriasis as defined by an ISGA score of 2 or

3 were to have been enrolled. A subject’s extent of psoriasis must have involved 2% to 20%

body surface area (BSA), excluding the face and scalp. Subjects must have had a target

lesion >2 cm² on the trunk or extremities with a score of 2 or 3 for each of erythema, scaling,

and plaque thickness. Lesions on palms/soles, knees, elbows, and intertriginous areas could

not be used as a target lesion site.

Subjects were randomized to 1 of 2 dose groups in a 2:1 (calcipotriene foam:vehicle foam)

ratio.

Stiefel personnel, investigators, subjects, and nurse/coordinators were blinded to the study

product assignment. Visits occurred at baseline, week 2, week 4 and week 8.

9.2 Discussion of Study Design

The double-blinded, placebo controlled design of this study is standard when the objective is

to demonstrate the superior efficacy of an active study product over an inactive comparator

or placebo. The homogeneity of the study population was maximized by requiring all

subjects to meet certain disease characteristic criteria at entry and by randomly assigning

subjects to the 2 treatment groups. The inactive comparator used, vehicle foam, did not

contain calcipotriene but was otherwise identical to the active study product, permitting

between-group differences to be attributed to the presence or absence of calcipotriene. The

double-blinding removed the chance of bias.

9.3 Selection of Study Population

9.3.1 Inclusion Criteria

Subjects were eligible to participate in the study if they met all of the following criteria:

1. Male or female subjects at least 12 years old and in good general health.

2. Mild to moderate plaque-type psoriasis, as defined by an ISGA score of 2 or 3 at baseline(rating scale presented in appendix 3 of the protocol [appendix 16.1.1]).

3. Mild to moderate plaque-type psoriasis involving 2% to 20% of total BSA (excluding the face and scalp).

4. Identification of a target lesion (>2 cm²) on the trunk or extremities with a score of 2 or 3 on a 0 to 5 scale for each of erythema, scaling, and plaque thickness; the rating scale is



Page 23


presented in appendix 2 of the protocol (appendix 16.1.1). Lesions on palms/soles,

knees, elbows, and intertriginous areas were not used as the target lesion site.

5. The ability and willingness to follow all study procedures, attend all scheduled visits, and successfully complete the study.

6. The ability to understand and sign a written ICF and a Health Insurance Portability and Accountability Act (HIPAA) authorization form, which must have been obtained prior to

participation in this study. The HIPAA authorization may have been incorporated in the

informed consent form.

9.3.2 Exclusion Criteria

Subjects were excluded from participation in the study if they met any of the following

criteria:

1. Had participated in any previous Phase 1 or 2 calcipotriene foam study.

2. Known allergy or other adverse reaction to calcipotriene or other vitamin D analogs or to any component of the study formulations.

3. History of hypercalcemia or of vitamin D toxicity.

4. Diagnosis of generalized pustular or erythrodermic exfoliative psoriasis.

5. Other serious skin disorder or any chronic medical condition that was not well controlled.

6. Use of nonbiologic systemic anti-psoriatic therapy (eg, corticosteroids, psoralen combined with exposure to ultraviolet light A [PUVA], ultraviolet light B [UVB],

retinoids, methotrexate, cyclosporine, other immunosuppressive agents) or biologic

therapy (eg, alefacept, etanercept, efalizumab) within 4 weeks of enrollment.

7. Use of topical therapies that have a known beneficial effect on psoriasis, including but not limited to corticosteroids, retinoids, vitamin D derivatives, tar, or anthralin, within

2 weeks of enrollment.

8. Systemic medications for other medical conditions that are known to affect psoriasis (eg, lithium, beta-adrenergic blockers) within 4 weeks of enrollment.

9. Use of any investigational therapy within 4 weeks of enrollment.

10. Pregnant women, women who were breast feeding, or sexually active women of childbearing potential who were not practicing an acceptable method of birth control

(birth control pill, patch, implant, barrier with spermicidal jelly, intrauterine device

[IUD], etc.), as determined by the investigator. An acceptable method of birth control



Page 24


must have been used during the entire study in sexually active women of childbearing

potential. A woman of childbearing potential was defined as one who was biologically

capable of becoming pregnant. Abstinence was considered to be a medically acceptable

form of contraception.

11. Current drug or alcohol abuse (drug screening not required).

12. A history of any immunocompromising disease.

13. Any other condition which, in the judgment of the investigator, would have put the subject at unacceptable risk for participation in the study.

9.3.3 Removal of Subjects from Therapy or Assessment

9.3.3.1 Subject Discontinuation

A subject could have voluntarily withdrawn from the study at any time he or she chose.

Subjects could have withdrawn from study product usage, but may have agreed to return for

week 8/early termination visit evaluations. If the subject withdrew consent for any further

participation in the study, no further study evaluations were performed and no attempts were

made to collect additional data. The investigator could have elected, at any time, to

withdraw a subject for reasons related or unrelated to the study product or study procedures.

In either event, full details were documented in the case report form (CRF). Subjects who

could not complete the study for administrative reasons (eg, non-compliance, failure to meet

visit schedule) were discontinued from the study.

Any subject who became pregnant during the study was to be immediately discontinued

from study activities. The subject or subject’s partner who became pregnant during the

study was to be followed for safety evaluations and outcome of pregnancy.

9.3.3.2 Subject Dropout

When a subject withdrew from the study, the week 8/early termination visit evaluations were

to be performed, as described in section 9.5.4. The reason for any subject's premature

withdrawal from the study was to have been fully documented on the CRF. Subjects who

failed to attend a visit were contacted to find out if they had withdrawn themselves from the

study. If a subject stopped the study product (either at their own request or at the

investigator’s instruction), he/she was encouraged to return for week 8/early termination

visit evaluations.

9.3.3.3 Screen Failures

Subjects who signed the ICF but who discontinued or were withdrawn from the study before

study product administration were defined as screen failures.



Page 25


9.4 Study Product(s)

9.4.1 Study Products Administered

Subjects were instructed to self-apply study product twice daily (morning and evening) for

8 weeks, to continue to apply study product to areas originally affected by psoriasis in the

event of clearing, and to apply study product to any new lesions in the treatable area at the

first sign of flaring prior to the week 8 visit. The dose was the smallest amount of study

product necessary to cover all treatable lesions (excluding the face and scalp).

Subjects were instructed to dispense a small amount of foam and gently massage (rub) the

study product into the affected areas. All areas affected with psoriasis were to be treated

with the study product, with the exception of the face and scalp. Hands were to be washed

after the application of study product to avoid inadvertent transfer to the face and other body

parts. Treatable areas were not to be cleansed for at least 2 hours after study product

application. Study product was not to be applied within 4 hours prior to a scheduled study

visit.

9.4.2 Dose Modification

No modifications were permitted to the dosing regimen, except for study discontinuation as

outlined in section 9.3.3.

9.4.3 Identity of Study Product(s)

The study product, calcipotriene foam, contained 0.005% calcipotriene in an emulsion

formulation foam vehicle consisting of cetyl alcohol, stearyl alcohol, light mineral mil, white

petrolatum, isopropyl myristate, polyoxyl 20 cetostearyl ether, vitamin E (dl-α-tocopherol),

purified water, edetate disodium (dihydrate), sodium phosphate dibasic (anhydrous),

propylene glycol. Calcipotriene foam was packaged in a pressurized, polyamide imide-lined

aluminum can pressurized with a hydrocarbon (propane/butane) propellant.

The comparator, vehicle foam, had identical ingredients and packaging as calcipotriene foam

but without the active ingredient calcipotriene.

The following batch numbers were used:

Study Product Batch No. Expiry date

Calcipotriene foam ZLS-C January 2009

Vehicle foam ZLP-C January 2009

Note: Study product used in this study was not marked with an expiry date because stability

studies were ongoing. The expiry date of January 2009 is based on the manufacture date of

January 2008 for all product used in this study and the proposed 1 year shelf life that is

based on stability data available at the start of this clinical study. Because the study was

completed by January 2009, no update for the expiry date was required.



Page 26


Study product was stored at the site in a locked room or cabinet with limited access. At all

times, study product was stored at a controlled room temperature (20-25°C/68-77°F). Study

product temperature was monitored at the site using a hi/low thermometer or similar

recording device. Cans were not frozen or subjected to high temperature.

9.4.4 Method of Assigning Subjects to Groups

Subjects were randomly assigned to 1 of 2 groups in a 2:1 ratio (calcipotriene foam:vehicle

foam). The randomization schedule with study product assignments was generated prior to

the start of the study. There was no stratification. Study product kits were numbered in

sequential order and the contents (calcipotriene foam or vehicle foam) were based on the

randomization code. The study staff responsible for dispensing study product were

instructed to choose the next available study kit number as subjects were enrolled in order to

randomize the subject. The kit number was also used as the subject identification number.

The randomization scheme is provided in appendix 16.1.7.

Subjects were assigned sequential numbers upon assignment to study product.

9.4.5 Selection of Doses in the Study

The dose was the smallest amount of study product necessary to cover all treatable lesions

(excluding the face and scalp).

9.4.6 Blinding

The study was double-blinded to the use of calcipotriene foam or vehicle foam. When a

subject entered into the study, he/she was assigned a subject number that defined the type of

study product (calcipotriene foam or vehicle foam) the subject received. Calcipotriene foam

and vehicle foam were packaged in identically appearing containers so Stiefel personnel,

investigators, subjects, and nurse/coordinators did not know which type of study product the

subject received.

9.4.7 Unblinding

The blind was to be broken after all data had been collected from all subjects and validated

following applicable standard operating procedures (SOPs). There were 2 possible

exceptions to this; the blind could be broken by the investigator for all cases for which the

identification of the study product was required for determining medical treatment, or for

regulatory reporting purposes.

9.4.8 Prior and Concomitant Therapy

All concomitant medications taken by the subject were recorded, including over-the-counter

medications, vitamins, and natural supplements.



Page 27


9.4.8.1 Prohibited Concomitant Therapies

Other than the study product, no concomitant topical therapy or phototherapy to evaluable

psoriatic lesions (ie, all lesions except those on the face and scalp) was permitted.

No systemic therapies for the treatment of psoriasis were permitted during the study. The

introduction of medications or therapies for other medical conditions that are known to affect

psoriasis (eg, corticosteroids, PUVA, UVB, cyclosporine, azathioprine, methotrexate,

lithium, beta-blockers) was not permitted during the interval prior to entry into the study as

defined in the exclusion criteria and during the study (section 9.3.2). All drugs and therapies

listed in the exclusion criteria were also prohibited during the study. No other

investigational therapy was permitted during the study.

9.4.8.2 Permitted Concomitant Therapies

Bland emollients such as Eucerin Cream were permitted for application to evaluable

psoriatic lesions between applications of study product, but were not to have been used

within 4 hours before a scheduled study visit. Study product was to have been applied

before any emollients were used. Hands were to have been washed between applications of

study product and other emollients/cosmetics.

Subjects were permitted to use bland emollients such as Eucerin Cream for lesions on the

face and scalp.

The use of concomitant medications for other medical conditions (eg, hypertension, diabetes,

acute infections) was permitted during this study. The use of inhaled/intranasal steroids was

permitted prior to and during the conduct of the study if it was already being used by the

subject.

9.4.9 Treatment Compliance

Subjects were provided with detailed instructions concerning protocol requirements and

application of the study product at the baseline visit. Subjects received a Study Product

Compliance Log to document the date and time (morning or evening) of each missed study

product application. Subjects were asked at each visit about the number of missed

applications of the study product and the reason for missed applications. Additionally, study

product cans were collected and weighed at each subsequent visit to confirm study product

compliance.

9.5 Efficacy and Safety Variables

9.5.1 Efficacy Evaluations

The following efficacy measures were collected:

The ISGA assessed over all treatable areas, excluding the face and scalp at baseline, week 2, week 4, and week 8/early termination. This instrument provides a rating of

visual assessment of all evaluable lesions on a scale of 0 (clear) to 4 (severe). The ISGA

is presented in appendix 3 of the protocol (appendix 16.1.1).



Page 28


Evaluation of a designated target lesion on a 0 to 5 scale for erythema, scaling, and plaque thickness at baseline, week 2, week 4, and week 8/early termination. The

evaluation scale and criteria are presented in appendix 2 of the protocol

(appendix 16.1.1).

The Subject's Global Assessment (SGA) at baseline, week 2, week 4, and week 8/early termination. This instrument provides a subject's assessment of the status of all treatable

areas on a scale of 0 (skin is completely clear) to 5 (psoriasis is severe). The SGA is

presented in appendix 4 of the protocol (appendix 16.1.1).

The Dermatology Life Quality Index (DLQI, age ≥17) or Children's DLQI (CDLQI) (age



Page 29


Table 1: Schedule of Study Procedures

Assessment

Baseline

(Day 1)

Week 2

(Day 15 ± 2 days)

Week 4

(Day 29 ± 4 days)

Week 8/ET

(Day 57 ± 4 days)

Written informed

consent/assent/HIPAA

authorization

X

Concomitant medications query X X X X

Medical history/review of

systems

X

Vital signs measurements

(temperature, BP, pulse)

X X

Height and weight measurement X

Complete skin examination

(% BSA affected by psoriasis)

X X X X

ISGA X X X X

Evaluation of target lesion for

erythema, scaling and plaque

thickness

X X X X

Urine pregnancy test (all females

of childbearing potential)

X X

Adverse event query X X X

SGA X X X X

DLQI or CDLQI X X

Randomize subject to study

product

X

Weigh and dispense study

product

X X X

Collect and weigh study product X X X

Post-study questionnaire X

Abbreviations: BP = blood pressure; BSA = body surface area; CDLQI = Children's Dermatology Life Quality

Index; DLQI = Dermatology Life Quality Index; ET = early termination; HIPAA = Health Insurance

Portability and Accountability Act; ISGA = Investigator's Static Global Assessment; SGA = Subject's Global

Assessment.



Page 30


Baseline (day 1)

Subjects must have met all inclusion/exclusion criteria at the baseline visit.

1. Obtain written informed consent and HIPAA authorization prior to performing any study procedures. Minor assent was obtained as per IRB requirements and local regulations.

The date of consent/assent was recorded on the source document.

2. Query the subject for concomitant medication use.

3. Complete medical history/review of systems and confirm clinical diagnosis of plaque-type psoriasis.

4. Evaluate skin and record the extent of psoriatic involvement. Body surface area involvement of psoriasis was to be 2% to 20% (excluding the face and scalp).

5. Designate and grade a target lesion >2 cm² on the trunk or extremities. The target lesion must have had a score of 2 or 3 on a scale of 0 to 5 for each of erythema, scaling, and

plaque thickness. Lesions on palms/soles, knees, elbows, and intertriginous areas could

not be used as a target lesion site.

6. Conduct urine pregnancy test (for females of childbearing potential). If the subject was a minor, the investigator/designee may have queried the subject regarding sexual activity

and birth control method in private and not in the presence of the subject’s parent/legal

guardian.

7. Measure vital signs: temperature, blood pressure, pulse, height, and weight.

8. Complete the ISGA for areas treatable with study product (excluding the face and scalp). The ISGA score must have been 2 or 3 at baseline.

9. Administer the SGA.

10. Administer the DLQI (age ≥17 years) or CDLQI (age



Page 31


2. Evaluate and grade designated target lesion for erythema, scaling, and plaque thickness.

3. Examine the skin and record the extent of treatable psoriasis BSA involvement.

4. Complete the ISGA. Evaluations were assessed over all treatable areas.

5. Query subject for concomitant medications use.

6. Query subject for AEs.

7. Study product accountability: Retrieve previously dispensed container(s) and dispense study product container(s). Study product containers were weighed upon dispensation

and return. Subjects were queried regarding their compliance with study product.

8. Instruct subject to not apply study product within 4 hours before their next scheduled study visit.

9. Schedule week 4 visit.

Week 4 (day 29 ± 4 days)

The following procedures were conducted at this visit:





5. Query subject for concomitant medications use.

6. Query subject for AEs.

7. Study product accountability: Retrieve previously dispensed container(s) and dispense study product container(s). Study product containers were weighed upon dispensation

and return. Subjects were queried regarding their compliance with study product.

8. Instruct subject not to apply study product within 4 hours before their next scheduled study visit.

Week 8 (day 57 ± 4 days) or Early Termination

All subjects were required to complete the week 8/early termination visit evaluation,

regardless of their response to study product prior to week 8. The following procedures

were conducted at this visit:


2. Measure vital signs: temperature, blood pressure, pulse.



Page 32





6. Administer the DLQI (age ≥17 years) or CDLQI (age



Page 33


9.5.8 Additional Efficacy Endpoints

The following endpoints were analyzed by group:

Mean percent reduction in the percent of BSA involvement of psoriasis from baseline to week 8.

The proportion of subjects who had an SGA score of 0 or 1 at week 8.

The change in DLQI score from baseline to week 8. (The CDLQI was planned but not performed because of the small number of subjects [n = 5] in the age group that was

administered this instrument.)

The primary endpoint and all key secondary endpoints at each visit.

9.6 Data Quality Assurance

9.6.1 Study Monitoring

This study was closely monitored at all stages of its development from inception to

conclusion. A qualified representative of Stiefel or designee monitored the conduct of the

study. The study was monitored according to the International Conference on

Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and all applicable local

and national regulations.

Accuracy of the CRFs was authenticated by source data verification (SDV). Subject medical

notes were treated with absolute confidentiality.

Investigators were required to permit study-related monitoring, audits, IRB/IEC review, and

regulatory inspection(s), and to provide direct access to source data/documents.

Investigators were also required to permit such inspection of records and CRFs as was

deemed necessary by Stiefel for compliance with local and national regulations governing

the conduct of investigational studies.

Principal areas subjected to monitoring included:

Continued acceptability of the investigator's facilities.

Adherence to the study protocol.

Investigator's compliance with local and national regulations regarding his/her obligations (including those towards the IRB/IEC).

Maintenance of complete, consistent, and accurate records regarding clinical data and study product accountability.



Page 34


Verification of data entry on CRFs or into an electronic database, as applicable.

Case report form SDV.

9.6.2 Source Data Verification

Source documents for this study were any document on which study data were recorded for

the first time including the Subject Medical Notes, the Subject Study Diaries,

Consent/Assent Forms, and any other relevant documentation detailed in the source data

verification plan/monitoring plan.

Demographic data, inclusion and exclusion criteria, history of condition, informed

consents/assents, AEs, visit dates, and concomitant medications were to be source data

verified for all subjects.

Dispensing logs were to be routinely checked. The randomization code break envelopes or

labels were to be periodically inspected to check for any evidence that the study may have

been unblinded.

9.6.3 Quality Assurance Audits

In addition to study monitoring, the sponsor conducted routine quality assurance audits at

3 sites; the audit certificates can be found in appendix 16.1.8.

9.6.4 Direct Access, Data Handling, and Record-Keeping

9.6.4.1 Case Report Forms

The investigator was required to maintain adequate and accurate CRFs to record all

observations and other data relevant to the clinical investigation. These forms were to have

been completed in a neat, legible manner with permanent ink to ensure accurate

interpretation of data. A sample CRF is provided in appendix 16.1.2.

All required data were to be recorded in the CRFs in a timely manner. All CRF data must

have been submitted to Stiefel throughout and at the end of the study.

9.6.4.2 Data Protection

Stiefel complied with all applicable local and national laws and regulations relating to data

protection.

9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size

The statistical analysis plan is provided in appendix 16.1.9.



Page 35


9.7.1 Statistical and Analytical Plans

Summary statistics consist of numbers and percentages of responses in each category for

discrete measures; and descriptive statistics of means, medians, and standard deviations; and

minimum and maximum values for continuous measures.

Missing values for all primary and key secondary endpoints were counted as failures. An

additional sensitivity analysis was completed for the primary analysis only, where a subject’s

last non-missing response was carried forward. Missing values were not imputed for other

analyses.

Version 9.1.3 of the SAS statistical software package was used to generate all tabular

summaries, data listings, figures, and statistical analyses.

9.7.1.1 Primary Efficacy Endpoint

The primary endpoint was analyzed to test the superiority of calcipotriene foam over vehicle

foam. The hypothesis was tested using a Cochran-Mantel-Haenszel (CMH) procedure

stratified by study center with a two-sided 0.05 significance level. Consistency of the results

across investigative centers for the primary endpoint was verified using the Breslow-Day test

of homogeneity of the odds ratios, using a significance level of 0.1.

Centers enrolling fewer than 12 subjects were combined as one pooled center in the

analyses. In the event that pooling the centers with fewer than 12 still resulted in a pooled

center with less than 12, then the pooled center was combined with the next highest center

until all pooled centers had at least 12 subjects.

The intent to treat (ITT) analysis set was used for the primary analysis, including only

subjects who had an efficacy evaluation at week 8 (between study days 47 and 67); subjects

without an efficacy evaluation at week 8 were counted as treatment failures. Two additional

sensitivity analyses were completed for the primary endpoint: (1) using the per protocol (PP)

analysis set and (2) using the ITT analysis set but carrying forward earlier non-missing

responses for those subjects who did not have an efficacy evaluation at week 8 (between

study days 47 and 67).

9.7.1.2 Key Secondary Efficacy Endpoints

All but 1 of the key secondary efficacy endpoints were analyzed using the CMH procedure

stratified by study center. In the event that the primary analysis was significant at the

0.05 level, the Holm stepwise closed testing procedure was to be used to control multiplicity

for these 4 key secondary analyses.

The remaining key secondary efficacy endpoint, primary endpoint by baseline ISGA score,

was analyzed using the CMH procedure stratified by study center with a 2-sided 0.05

significance level.



Page 36


9.7.1.3 Additional Efficacy Endpoints

The additional efficacy endpoints of mean percent reduction in the percent of BSA at each

visit and the change in DLQI or CDLQI score from baseline to week 8 were analyzed using

analysis of covariance (ANCOVA) with baseline value, treatment, center, and interaction of

treatment-center. If the treatment-center interaction was not significant at the 0.1 level, this

interaction was to be excluded in the ANCOVA model.

The additional efficacy endpoint of proportion of subjects who had an SGA score of 0 or 1 at

each visit was tested using CMH procedure stratified by center.

The additional efficacy endpoint of all primary and key secondary efficacy endpoints by visit

was tested using the CMH procedure stratified by study center.

No further adjustment for multiplicity was made for the additional efficacy endpoints.

9.7.1.4 Safety Analysis

9.7.1.4.1 Summary of Study Product Compliance and Exposure

Summary statistics and a categorical summary are presented for both treatment duration and

days on study product. Additionally, a table is provided that includes the total amount, in

grams, of study product used. Study product usage was defined as the total container weight

dispensed minus the total container weight returned.

9.7.1.4.2 Adverse Events

Adverse events were coded using the Medical Dictionary for Regulatory Activities

(MedDRA), Version 11.0. Treatment-emergent AEs (TEAEs) were defined as those events

occurring during study treatment or up to 30 days after stopping study treatment. Treatment-

emergent AEs are summarized in the following tables:

Incidence of AEs.

Incidence of severe AEs.

Incidence of severe related AEs

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