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Study Protocol); PF-06651600 B7981006 Final Protocol Amendment 1, 26 October 2016 A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PARALLEL GROUP, PLACEBO-CONTROLLED, MULTI-CENTER STUDY TO ASSESS THE EFFICACY AND SAFETY PROFILE OF PF-06651600 IN SUBJECTS WITH MODERATE TO SEVERE ACTIVE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO METHOTREXATE Investigational Product Number: PF-06651600 Investigational Product Name: Not Applicable (N/A) United States (US) Investigational New 131274 Drug (IND) Number: European Clinical Trials Database 2016-002862-30 (EudraCT) Number: Protocol Number: B7981006 Phase: 2a Page 1 PF-06651600 B7981006 Final Protocol Amendment 1, 26 October 2016 Document History Document Version Date Summary of Changes and Rationale Amendment 1 26 October 2016 In the Schedule of Activities, and Section 7.2.12, added audiogram testing Rationale: To monitor for potential changes in hearing between baseline [between Visit 1 and Visit 2 (inclusive)] and at the end of the study [between Visit 7 and Visit 9 (inclusive)]. The following exclusion criteria has been added in Section 4.2: Have current or recent history of clinically significant severe or progressive hearing loss or auditory disease. Subjects with hearing aids will be allowed to enter the study provided their hearing impairment is considered controlled/ clinically stable. Rationale: This has been added to ensure that subject hearing for safety is fully evaluated prior to study entry. Several additional minor changes were made to protocol language for the purposes of clarification. Original protocol 31 August 2016 Not applicable (N/A) This amendment incorporates all revisions to date, including amendments made at the request of country health authorities and institutional review boards (IRBs)/ethics committees (ECs). Page 2 PF-06651600 B7981006 Final Protocol Amendment 1, 26 October 2016 TABLE OF CONTENTS LIST OF TABLES.....................................................................................................................7 LIST OF FIGURES ...................................................................................................................8 APPENDICES ...........................................................................................................................8 PROTOCOL SUMMARY.........................................................................................................9 SCHEDULE OF ACTIVITIES................................................................................................13 1. INTRODUCTION ...............................................................................................................18 1.1. Mechanism of Action/Indication.............................................................................19 1.2. Background and Rationale ......................................................................................19 1.3. Non-Clinical Pharmacokinetics, Metabolism of PF-06651600 ..............................19 1.4. Non-Clinical Safety Studies with PF-06651600 .....................................................20 1.5. Summary of Clinical Experience with PF-06651600 .............................................21 1.5.1. Summary of Clinical Safety of PF-06651600 ............................................22 1.5.2. Pharmacokinetics of PF-06651600.............................................................23 1.6. Summary .................................................................................................................25 1.6.1. Study Rationale...........................................................................................25 1.6.2. Dose Rationale............................................................................................25 1.6.3. Summary of Benefits and Risks .................................................................27 1.6.4. Additional Information ...............................................................................27 2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................27 3. STUDY DESIGN.................................................................................................................29 4. SUBJECT ELIGIBILITY CRITERIA.................................................................................30 4.1. Inclusion Criteria.....................................................................................................30 4.2. Exclusion Criteria....................................................................................................32 4.3. Lifestyle Requirements ...........................................................................................36 4.3.1. Contraception..............................................................................................36 4.4. Sponsor’s Qualified Medical Personnel..................................................................37 5. STUDY TREATMENTS.....................................................................................................38 5.1. Allocation to Treatment ..........................................................................................38 5.2. Breaking the Blind ..................................................................................................39 5.3. Subject Compliance.................................................................................................39 5.4. Investigational Product Supplies.............................................................................39 Page 3 PF-06651600 B7981006 Final Protocol Amendment 1, 26 October 2016 5.4.1. Dosage Form(s) and Packaging..................................................................39 5.4.2. Preparation and Dispensing ........................................................................40 5.5. Administration.........................................................................................................40 5.6. Investigational Product Storage ..............................................................................41 5.7. Investigational Product Accountability...................................................................41 5.7.1. Destruction of Investigational Product Supplies ........................................42 5.8. Background and Concomitant Treatment(s) ...........................................................42 5.8.1. Permitted Background Arthritis Therapy ...................................................42 5.8.2. Prohibited Background Arthritis Therapy ..................................................43 5.9. Rescue Medication ..................................................................................................46 6. STUDY PROCEDURES .....................................................................................................46 6.1. Screening.................................................................................................................47 6.2. Treatment Period .....................................................................................................47 6.3. Follow-up/End of Study..........................................................................................47 6.4. Subject Withdrawal/Early Withdrawal ...................................................................47 6.4.1. Withdrawal of Consent...............................................................................47 6.4.2. Lost to Follow-up .......................................................................................48 7. ASSESSMENTS..................................................................................................................48 7.1. Efficacy Assessments..............................................................................................48 7.1.1. American College of Rheumatology (ACR) Assessments.........................48 7.1.2. Tender/Painful Joint Count (68) .................................................................49 7.1.3. Swollen Joint Count (66)............................................................................49 7.1.3.1. Tender and Swollen Joint Counts (28)......................................50 7.1.4. Patient’s Assessment of Arthritis Pain (PAAP)..........................................50 7.1.4.1. Patient’s Global Assessment (PtGA) of Arthritis .....................50 7.1.4.2. Physician’s Global Assessment (PhGA) of Arthritis ................50 7.1.4.3. High Sensitivity C-Reactive Protein (CRP)..............................50 7.1.4.4. Erythrocyte Sedimentation Rate (ESR).....................................51 7.1.4.5. Health Assessment Questionnaire – Disability Index (HAQ-DI) ..........................................................................................51 7.1.5. Composite Efficacy Assessments Derived from the ACR Core Dataset..............................................................................................................51 7.1.5.1. Simple Disease Activity Index (SDAI) Assessment .................51 Page 4 PF-06651600 B7981006 Final Protocol Amendment 1, 26 October 2016 7.1.5.2. ACR Responder Analysis..........................................................51 7.1.6. Disease Activity Score (DAS) Assessments...............................................51 7.2. Safety and other Assessments .................................................................................52 7.2.1. Clinical Safety and Other Laboratory Tests ...............................................52 7.2.2. Physical Examination .................................................................................53
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