Study Protocol and Statistical Analysis Plan
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Clarification of Abatacept Effects in SLE with Integrated Biologic and Clinical Approaches (The ABC Study) [BMS PROTOCOL NUMBER: IM101-345 Joan T. Merrill, M.D. Clinical Pharmacology Research Program Oklahoma Medical Research Foundation 825 NE 13th St, MS 22 Oklahoma City, OK 73104 Telephone: 405-271-7805 Fax: 405-271-8797 Email: [email protected] [Protocol Version January 8, 2016] 1 ABC Trial – Version 1/08/2016 TABLE OF CONTENTS TITLE PAGE ...................................................................................................................................1 TABLE OF CONTENTS ..............................................................................................................2 PROTOCOL SYNOPSIS...……………………………………………………………………...5 1 INTRODUCTION ......................................................................................................9 1.1 Pathology of Systemic Lupus (SLE) ..........................................................................10 1.2 Relevance of Abatacept mechanism to SLE ...............................................................10 1.3 Summary of Results of Investigational Program ........................................................14 1.3.1 Pharmacology of Abatacept ........................................................................................14 1.3.2 Human Pharmacokinetics of Abatacept ......................................................................15 1.3.3 Clinical Safety of IV Abatacept in SLE and SC Form in RA ....................................20 1.3.3.1 Drug-Related Adverse Events ....................................................................................29 1.3.4 Clinical Efficacy of Abatacept Subcutaneous Formulation ........................................30 1.4 Overall Risk/Benefit Assessment ...............................................................................31 1.5 Research Hypothesis ...................................................................................................31 1.6 Study Rationale ...........................................................................................................32 2 STUDY OBJECTIVES ............................................................................................32 2.1 Primary Objective .......................................................................................................32 2.2 Secondary Objectives .................................................................................................32 3 ETHICAL CONSIDERATIONS ............................................................................33 3.1 Good Clinical Practice ................................................................................................33 3.2 Institutional Review Board/Independent Ethics Committee ......................................33 3.3 Informed Consent .......................................................................................................34 4 INVESTIGATIONAL PLAN ..................................................................................35 4.1 Study Design and Duration .........................................................................................35 4.2 Study Population .........................................................................................................37 4.2.1 Inclusion Criteria ........................................................................................................37 4.2.2 Exclusion Criteria .......................................................................................................38 4.2.3 Discontinuation of Subjects from Treatment ..............................................................39 5 TREATMENTS ........................................................................................................40 5.1 Study Treatment: Abatacept .......................................................................................40 5.1.1 Identification ...............................................................................................................40 5.1.2 Packaging and Labeling ..............................................................................................40 2 ABC Trial – Version 1/08/2016 5.1.3 Handling and Dispensing ............................................................................................40 5.2 Drug Ordering and Accountability .............................................................................41 5.2.1 Initial Orders ...............................................................................................................41 5.2.2 Re-Supply ...................................................................................................................41 5.3 Method of Assigning Subjects to a Treatment ...........................................................41 5.4 Selection and Timing of Dose for Each Subject .........................................................41 5.4.1 Dose Modifications .....................................................................................................41 5.5 Blinding/Unblinding ...................................................................................................42 5.6 Concomitant Treatments .............................................................................................42 5.6.1 Prohibited and/or Restricted Treatments ....................................................................42 5.6.2 Other Restrictions and Precautions .............................................................................42 5.7 Treatment Compliance ................................................................................................42 6 STUDY ASSESSMENTS AND PROCEDURES ...................................................43 6.1 Time and Events Schedule ..........................................................................................44 6.2 Study Materials ...........................................................................................................45 6.3 Safety Assessments .....................................................................................................45 6.3.1 Physical Examinations ................................................................................................45 6.3.2 Breast and Hematologic Cancer Screening ................................................................45 6.4 Efficacy Assessments .................................................................................................45 6.4.1 Primary Efficacy Assessment .....................................................................................45 6.4.2 Secondary Efficacy Assessments ...............................................................................46 6.5 Other Assessments ......................................................................................................47 7 ADVERSE EVENT REPORTING .........................................................................53 7.1 Adverse Events ...........................................................................................................53 7.1.1 Serious Adverse Events ..............................................................................................53 7.1.2 Nonserious Adverse Events ........................................................................................54 7.1.3 Assignment of Adverse Event Intensity and Relationship to Abatacept ....................54 7.2 Collection and Reporting ............................................................................................55 7.2.1 Serious Adverse Event Collecting and Reporting ......................................................55 7.2.2 Non-Serious Adverse Events (NSAEs) Collecting and Reporting .............................54 7.3 Laboratory Test Abnormalities ...................................................................................56 7.4 Overdose .....................................................................................................................56 7.5 Pregnancy ...................................................................................................................56 3 ABC Trial – Version 1/08/2016 7.6 Potential Drug-Induced Liver Injury (DILI) ...............................................................52 7.7 Other Safety Considerations ..................................................................................57 8 DATA MONITORING COMMITTEE ..................................................................57 9 STATISTICAL CONSIDERATIONS ....................................................................58 9.1 Sample Size Determination ........................................................................................58 9.2 Populations for Analyses ............................................................................................58 9.3 Endpoint Definitions ...................................................................................................59 9.4 Analyses ......................................................................................................................59 9.4.1 Demographics and Baseline Characteristics .............................................................59 9.4.2 Safety Analyses ..........................................................................................................59 9.4.3 Efficacy Analyses .......................................................................................................59 9.4.4 Other Analyses ............................................................................................................60