Ablynx Statistical Analysis Plan, Final Version 1.0 ALX0061-C204 Date Issued: 28FEB2018 Ablynx ALX0061-C204 A Phase II Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-range Finding Study to Evaluate the Safety and Efficacy of ALX-0061 Administered Subcutaneously in Subjects with Moderate to Severe Active Systemic Lupus Erythematosus 28FEB2018 Statistical Analysis Plan Final Version 1.0 1 Page 2 of 135 Ablynx Statistical Analysis Plan, Final Version 1.0 ALX0061-C204 Date Issued: 28FEB2018 TABLE OF CONTENTS LIST OF ABBREVIATIONS .................................................................................... 6 1 INTRODUCTION......................................................................................... 9 2 OBJECTIVES ............................................................................................ 10 2.1 PRIMARY OBJECTIVE ......................................................................................... 10 2.2 SECONDARY OBJECTIVES ................................................................................... 10 3 INVESTIGATIONAL PLAN......................................................................... 10 3.1 OVERALL STUDY DESIGN AND PLAN ...................................................................... 10 3.1.1 Sample Size ....................................................................................... 11 3.1.2 Blinding and Unblinding ....................................................................... 12 3.1.2.1 Study Drug Administration Blinding ................................................. 12 3.1.2.2 Blinding of Potentially Unblinding Parameters ................................... 12 3.1.2.3 Emergency Unblinding ................................................................... 12 3.2 STUDY ENDPOINTS .......................................................................................... 13 3.2.1 Primary Endpoint ................................................................................ 13 3.2.2 Secondary Endpoints ........................................................................... 13 4 GENERAL STATISTICAL CONSIDERATIONS.............................................. 16 4.1 ANALYSIS POPULATIONS .................................................................................... 19 4.1.1 All Screened Population ....................................................................... 19 4.1.2 All Randomized Population ................................................................... 19 4.1.3 Modified Intent-to-Treat (mITT) Population ............................................ 19 4.1.4 Per Protocol (PP) Population ................................................................. 19 4.1.5 Safety Population ................................................................................ 23 5 SUBJECT DISPOSITION ........................................................................... 23 5.1 DISPOSITION ................................................................................................. 23 5.2 ANALYSIS POPULATIONS .................................................................................... 24 5.3 PROTOCOL DEVIATIONS .................................................................................... 24 6 DEMOGRAPHICS AND BASELINE CHARACTERISTICS ............................... 24 6.1 DEMOGRAPHICS ............................................................................................. 24 6.2 BASELINE DISEASE CHARACTERISTICS ................................................................... 25 6.3 TOBACCO USAGE ............................................................................................ 26 6.4 MEDICAL HISTORY .......................................................................................... 26 6.5 ADDITIONAL SCREENING/BASELINE ASSESSMENTS .................................................... 26 7 TREATMENTS AND MEDICATIONS ........................................................... 26 7.1 PRIOR AND CONCOMITANT MEDICATIONS ................................................................ 26 7.1.1 Prior Medications ................................................................................ 27 7.1.2 Concomitant Medications ..................................................................... 27 7.2 STUDY TREATMENTS ........................................................................................ 27 8 EFFICACY ANALYSIS ............................................................................... 28 8.1 PRIMARY EFFICACY ENDPOINT ............................................................................. 29 8.1.1 Primary Analysis ................................................................................. 30 8.1.2 Assumption Testing ............................................................................. 34 8.1.3 Sensitivity Analysis ............................................................................. 34 8.1.4 Subgroup Analysis .............................................................................. 34 8.2 SECONDARY EFFICACY ENDPOINTS........................................................................ 35 8.2.1 mBICLA ............................................................................................. 35 8.2.2 BICLA ................................................................................................ 35 8.2.3 SRI ................................................................................................... 36 2 Page 3 of 135 Ablynx Statistical Analysis Plan, Final Version 1.0 ALX0061-C204 Date Issued: 28FEB2018 8.2.4 mSRI ................................................................................................ 36 8.2.5 SLEDAI-2K ......................................................................................... 37 8.2.6 mSLEDAI-2K ...................................................................................... 37 8.2.7 BILAG-2004 Improvement ................................................................... 37 8.2.8 BILAG-2004 Total Score ...................................................................... 38 8.2.9 BILAG-2004 Improvement by Individual Organ System ........................... 38 8.2.10 BILAG-2004 Systems Tally ................................................................... 38 8.2.11 PGA .................................................................................................. 39 8.2.12 Patient’s Global Assessment ................................................................. 39 8.2.13 Laboratory Efficacy Assessment ............................................................ 39 8.2.14 Treatment Failure ............................................................................... 40 8.2.15 BILAG-2004 Flare ............................................................................... 40 8.2.16 mSLEDAI-2K Flare (mSFI) ................................................................... 40 8.2.17 Prednisone Equivalent Total Daily Dose ................................................. 40 8.2.18 Reduction Rate in Steroids Intake Without Severe Flare ........................... 41 8.2.19 Discontinuation Rate in Steroids Intake without Severe Flare ................... 41 8.2.20 SF-36 Physical and Mental Component .................................................. 41 8.2.21 28-Joint Count.................................................................................... 42 8.2.22 CLASI ................................................................................................ 42 9 SAFETY ANALYSIS ................................................................................... 42 9.1 ADVERSE EVENTS ........................................................................................... 42 9.1.1 Incidence of Adverse Events................................................................. 43 9.1.2 Relationship of Adverse Events to Study Drug ........................................ 44 9.1.3 Severity of Adverse Event .................................................................... 44 9.1.4 Serious Adverse Events ....................................................................... 44 9.1.5 Adverse Events Leading to Treatment Discontinuation ............................. 44 9.1.6 Adverse Event of Special Interest (AESI) ............................................... 44 9.1.7 Death ................................................................................................ 45 9.2 CLINICAL LABORATORY EVALUATIONS .................................................................... 46 9.2.1 Haematology, Blood Chemistry, Lipid Profile and Coagulation ................... 46 9.2.2 Urinalysis ........................................................................................... 47 9.2.3 Laboratory Parameters of Special Interest ............................................. 47 9.2.4 Coombs’ test ...................................................................................... 47 9.2.5 INR ................................................................................................... 47 9.2.6 Antibodies .......................................................................................... 48 9.3 VITAL SIGN MEASUREMENTS .............................................................................. 48 9.4 PHYSICAL EXAMINATION .................................................................................... 49 9.5 ELECTROCARDIOGRAM ...................................................................................... 49 9.6 OTHER SAFETY DATA ......................................................................................