Title: A 12-Week, Phase 2 Randomized, Placebo-Controlled, Double-Blind Study to Assess the Efficacy, Safety, and Tolerability of Gemcabene in Subjects with Hypercholesterolemia Not Adequately Controlled on High-Intensity or Moderate-Intensity Stable Statin Therapy (ROYAL-1) NCT ID: NCT02634151 Approval Date: 10-Jul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onfidentiality Statement 7KLVGRFXPHQWFRQWDLQVFRQILGHQWLDODQGSURSULHWDU\LQIRUPDWLRQDQGLVQRWWR EHGLVWULEXWHGWRDQ\WKLUGSDUW\ &RQILGHQWLDO 3DJHRI Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017 1 TABLE OF CONTENTS 1 TABLE OF CONTENTS ...................................................................................................2 LIST OF TABLES .....................................................................................................................3 LIST OF APPENDICES ............................................................................................................3 2 SIGNATURE PAGE .........................................................................................................4 3 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................6 4 INTRODUCTION .............................................................................................................9 5 TRIAL OBJECTIVES .....................................................................................................10 5.1 Primary Objectives.................................................................................................10 5.2 Secondary Objectives.............................................................................................10 5.3 Exploratory Objectives ..........................................................................................10 6 STUDY DESIGN CONSIDERATIONS .........................................................................11 6.1 Study Design ..........................................................................................................11 6.2 Efficacy Measures ..................................................................................................12 6.3 Safety Measures .....................................................................................................13 7 STUDY POPULATIONS ................................................................................................14 7.1 Analysis Populations ..............................................................................................14 7.1.1 Full Analysis Set ..........................................................................................14 7.1.2 Per-Protocol Set ...........................................................................................14 7.1.3 Safety Analysis Set ......................................................................................14 8 CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ..15 9 OVERALL STATISTICAL CONSIDERATIONS .........................................................16 9.1 Sample Size Computation ......................................................................................16 9.2 General Conventions ..............................................................................................16 9.3 Baseline Definitions ...............................................................................................17 9.4 Handling of Missing Data ......................................................................................18 9.5 Interim Analysis .....................................................................................................18 9.6 Visit Windows .......................................................................................................18 10 STATISTICAL ANALYSIS METHODS .......................................................................20 10.1 Subject Disposition ................................................................................................20 10.2 Demographics and Baseline Characteristics ..........................................................20 10.3 Treatment Compliance and Exposure ....................................................................21 10.3.1 Treatment Compliance .................................................................................21 10.3.2 Treatment Exposure .....................................................................................22 11 EFFICACY PARAMETERS ...........................................................................................23 11.1 Primary Analysis ....................................................................................................23 Confidential Page 2 of 43 Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017 11.2 Secondary Analysis ................................................................................................23 11.3 Exploratory Analysis .............................................................................................25 11.4 Manuscript Analysis ..............................................................................................26 12 SAFETY AND TOLERABILITY ...................................................................................27 12.1 Adverse Events ......................................................................................................27 12.2 Clinical Laboratory Assessments ...........................................................................28 12.3 ECGs ......................................................................................................................30 12.4 Vital Signs and Weight ..........................................................................................31 12.5 Physical Examinations ...........................................................................................31 13 OTHER RELEVANT DATA ANALYSES/SUMMARIES ...........................................32 13.1 Medical History .....................................................................................................32 13.2 Prior and Concomitant Medications ......................................................................32 13.3 Concomitant Procedures ........................................................................................32 14 REFERENCES ................................................................................................................33 15 APPENDICES .................................................................................................................34 LIST OF TABLES Table 1. Overview of Study Periods .....................................................................................11 Table 2. Visit Windows for Assessments Done at Day 1, Weeks 2, 4, 8, and 12a ...............19 Table 3. Lab PCS Criteria .....................................................................................................29 Table 4. ECG PCS Criteria ...................................................................................................30 LIST OF APPENDICES Appendix 1. Schedule of Assessments and Procedures ..........................................................34 Appendix 2. Prior and Concomitant Medications and Smoking Status Date Imputation .......37 Appendix 3. ATC Categories and Descriptions of Hypertensive Treatments ........................38 Appendix 4. Sex-specific Framingham Risk Score algorithms ..............................................42 Appendix 5. Manuscript Analyses ..........................................................................................43 Confidential Page 3 of 43 *HPFDEHQH *HPSKLUH7KHUDSHXWLFV,QF 6WDWLVWLFDO$QDO\VLV3ODQ*(0 -XO\ 2 SIGNATURE PAGE 6WXG\7LWOH $:HHN3KDVH5DQGRPL]HG3ODFHER&RQWUROOHG 'RXEOH%OLQG6WXG\WR$VVHVVWKH(IILFDF\6DIHW\DQG 7ROHUDELOLW\RI*HPFDEHQHLQ6XEMHFWVZLWK+\SHUFKROHVWHUROHPLD 1RW$GHTXDWHO\&RQWUROOHGRQ+LJK,QWHQVLW\RU 0RGHUDWH,QWHQVLW\6WDEOH6WDWLQ7KHUDS\ 52<$/ 6WXG\1XPEHU *(0 PI 3UHSDUHG PI E\ PI 5HYLHZHG PI E\ PI PI $SSURYHG E\ *HPSKLUH7KHUDSHXWLFV,QF PI $SSURYHG E\ *HPSKLUH7KHUDSHXWLFV,QF &RQILGHQWLDO 3DJHRI Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017 Document History – Major changes compared to previous versions of the analysis plan Version Date Changes Final 1.0 17-Apr-17 N/A Amendment 1.0 10-Jul-17 Added that potentially clinically significant laboratory values, single occurrences, will also be summarized by statin-intensity stratum. Added information on imputing drug interruptions with partial start/stop dates to be 1 day in length along with technical comments regarding assignment. Added that we are summarizing days on treatment and days drug was interrupted for. Added 2 urinalysis parameters to PCS criteria. Updated PPS section. Edited text to reflect hsCRP and TG being analyzed using ranked ANCOVA. Confidential Page 5 of 43 Gemcabene Gemphire Therapeutics Inc. Statistical Analysis Plan: GEM-301 10 July 2017