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Statistical Analysis Plan for Clinical Study Report Ac-061A301 / Ac

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Statistical Analysis Plan for Clinical Study Report Ac-061A301 / Ac STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT AC-061A301 / AC-061A302 Two multi-center, randomized, double-blind studies to compare the efficacy and safety of cadazolid versus vancomycin in subjects with Clostridium difficile-associated diarrhea (CDAD) Purpose of Analysis Clinical Study Report Investigational Drug Cadazolid NCT Numbers NCT01987895 & NCT01983683 Protocol Numbers AC-061A301 / AC-061A302 Document Status / Version Number Final Version 3 Date 19 May 2017 Confidential Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. Cadazolid (ACT-179811) Statistical Analysis Plan AC-061A301/302, Clinical Study Doc No D-17.273 Confidential Report 19 May 2017, page 2/155 TABLE OF CONTENTS 1 INTRODUCTION .......................................................................................................13 2 STUDY DESIGN AND FLOW ..................................................................................14 2.1 Study design .................................................................................................14 2.2 Study visit and assessment schedule ............................................................16 3 OBJECTIVES .............................................................................................................19 3.1 Primary objective ..........................................................................................19 3.2 Secondary objectives ....................................................................................19 3.3 Other objectives ............................................................................................19 3.3.1 Objective of the meta-analysis of AC-061A301 and AC-061A302 .....................................................................................19 3.3.2 Exploratory objective ........................................................................19 3.3.3 Safety objective .................................................................................19 3.3.4 Objective of the re-treatment extension with cadazolid ...................19 4 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE STUDY PROTOCOL .................................................................................................20 4.1 Changes related to PRO validation ...............................................................20 4.2 Changes to the analyses planned in the study protocol ................................20 4.3 Changes in the conduct of the study / data collection ..................................21 4.3.1 Clarification on wording ...................................................................21 5 DEFINITIONS OF VARIABLES ..............................................................................21 5.1 Screening failures .........................................................................................22 5.1.1 Unmet eligibility criteria ...................................................................22 5.2 Subject characteristics ..................................................................................23 5.2.1 Demographics ...................................................................................23 5.2.2 Baseline disease characteristics ........................................................23 5.2.3 Other baseline characteristics ...........................................................25 5.2.4 Medical history .................................................................................26 5.2.5 Previous and concomitant therapies .................................................27 5.2.5.1 Previous therapies .................................................................... 27 5.2.5.2 Study concomitant therapies ................................................... 27 5.2.5.3 Specific therapies .................................................................... 27 5.2.6 Procedures .........................................................................................29 5.2.6.1 Concomitant procedures .......................................................... 30 5.2.6.2 Endoscopy and imaging since first dose of study drug ........... 30 Cadazolid (ACT-179811) Statistical Analysis Plan AC-061A301/302, Clinical Study Doc No D-17.273 Confidential Report 19 May 2017, page 3/155 5.3 Study treatment exposure and compliance ...................................................30 5.3.1 Exposure ...........................................................................................30 5.3.2 Compliance with study treatment .....................................................32 5.3.3 Study treatment discontinuation .......................................................32 5.3.4 Study treatment interruptions ............................................................32 5.4 Study withdrawal ..........................................................................................33 5.5 Efficacy variables .........................................................................................33 5.5.1 Primary efficacy variable: Clinical Cure ..........................................33 5.5.1.1 Derivation details .................................................................... 34 5.5.1.2 Clinical Failure ........................................................................ 36 5.5.2 Secondary efficacy variables ............................................................37 5.5.2.1 Sustained Cure ......................................................................... 37 5.5.2.2 Time to ROD ........................................................................... 44 5.5.2.3 Change from baseline in CDI-DaySyms PRO domain scores at Day 3 ........................................................................ 44 5.5.3 Other efficacy variables ....................................................................45 5.5.3.1 Investigator’s assessment of Early Treatment Response at Visit 2 .................................................................................. 45 5.5.3.2 Investigator’s judgment of Clinical Response at Visit 4 ......... 45 5.5.3.3 Investigator’s evaluation of Clinical Cure per protocol definition ................................................................................. 46 5.5.3.4 Investigator’s judgment of Sustained Response at Visit 5 ...... 46 5.5.3.5 Investigator’s evaluation of Sustained Cure per protocol definition ................................................................................. 46 5.5.3.6 Early Clinical Cure by Day 5 .................................................. 46 5.5.3.7 Normalization of bowel movements rate ................................ 46 5.5.3.8 Time to return to usual stools .................................................. 47 5.5.3.9 Recurrence rate and adjusted recurrence rate .......................... 47 5.5.3.10 Time to recurrence ................................................................... 48 5.5.3.11 Modified Sustained Cure ......................................................... 49 5.5.3.12 CDI-DaySyms PRO response rate at Day 3 ............................ 49 5.5.4 Microbiology variables .....................................................................49 5.5.4.1 Isolation of C. difficile ............................................................ 50 5.5.4.2 Typing of C. difficile ............................................................... 51 5.5.4.3 Susceptibility of C. difficile .................................................... 52 5.5.4.4 Change from baseline in susceptibility of C. difficile ............. 53 5.5.4.5 Isolation of vancomycin-resistant enterococci ........................ 54 5.5.4.6 Vancomycin-resistant enterococci quantitative culture .......... 55 5.5.4.7 Change from baseline in vancomycin-resistant enterococci quantitative culture at Visit 3 ............................... 55 Cadazolid (ACT-179811) Statistical Analysis Plan AC-061A301/302, Clinical Study Doc No D-17.273 Confidential Report 19 May 2017, page 4/155 5.5.4.8 Susceptibility of vancomycin-resistant enterococci to different antibiotics .................................................................. 55 5.5.5 Re-treatment extension variables ......................................................56 5.6 Safety variables .............................................................................................56 5.6.1 Adverse events ..................................................................................57 5.6.1.1 Frequency of treatment-emergent adverse events ................... 58 5.6.1.2 Intensity of adverse events ...................................................... 58 5.6.1.3 Relationship of adverse events ................................................ 58 5.6.2 Deaths ...............................................................................................58 5.6.2.1 All deaths ................................................................................. 58 5.6.2.2 Adverse events with fatal outcome ......................................... 58 5.6.3 Serious adverse events ......................................................................58 5.6.4 Non-serious adverse events ..............................................................59 5.6.5 Adverse events leading to discontinuation of study treatment .........59 5.6.6 Other significant adverse events .......................................................59 5.6.7 Vital signs and body weight ..............................................................59
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