STATISTICAL ANALYSIS PLAN - ... Statistical Analysis Plan 14-Aug-2017 SAR231893-EFC14280 - dupilumab...

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Transcript of STATISTICAL ANALYSIS PLAN - ... Statistical Analysis Plan 14-Aug-2017 SAR231893-EFC14280 - dupilumab...

  • Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be

    disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date

    of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity

    According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) Page 1

    STATISTICAL ANALYSIS PLAN

    A randomized, double blind, 52-week, placebo-controlled efficacy and safety study of Dupilumab, in patients with bilateral nasal polyposis on a background therapy

    with intranasal corticosteroids

    SAR231893(REGN668)-EFC14280

    STATISTICIAN:

    DATE OF ISSUE: 14-Aug-2017

    Total number of pages: 91

    (electronic 1.0)

    NCT Number:NCT02898454

  • Statistical Analysis Plan 14-Aug-2017 SAR231893-EFC14280 - dupilumab Version number: 1

    Property of the Sanofi Group - strictly confidential Page 2

    TABLE OF CONTENTS

    STATISTICAL ANALYSIS PLAN....................................................................................................................1

    TABLE OF CONTENTS..................................................................................................................................2

    LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5

    1 OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................8

    1.1 STUDY DESIGN AND RANDOMIZATION ......................................................................................8

    1.2 OBJECTIVES...................................................................................................................................8 1.2.1 Primary objectives............................................................................................................................8 1.2.2 Secondary objectives .......................................................................................................................9 1.2.3 Exploratory objectives ......................................................................................................................9

    1.3 DETERMINATION OF SAMPLE SIZE.............................................................................................9

    1.4 STUDY PLAN.................................................................................................................................11 1.4.1 Graphic study design......................................................................................................................11

    1.5 MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................12

    1.6 STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN......................12

    2 STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................13

    2.1 ANALYSIS ENDPOINTS................................................................................................................13 2.1.1 Demographic and baseline characteristics ....................................................................................13 2.1.2 Prior or concomitant medications...................................................................................................16 2.1.2.1 MFNS controller medication...........................................................................................................16 2.1.3 Efficacy endpoints ..........................................................................................................................17 2.1.3.1 Primary efficacy endpoint(s)...........................................................................................................17 2.1.3.2 Secondary efficacy endpoint(s) ......................................................................................................20 2.1.4 Safety endpoints.............................................................................................................................24 2.1.4.1 Adverse events variables ...............................................................................................................25 2.1.4.2 Deaths............................................................................................................................................27 2.1.4.3 Laboratory safety variables ............................................................................................................27 2.1.4.4 Vital signs variables........................................................................................................................28 2.1.4.5 Electrocardiogram variables...........................................................................................................28 2.1.4.6 Physical Examination .....................................................................................................................28 2.1.5 Pharmacokinetic variables .............................................................................................................29 2.1.6 Pharmacodynamic endpoints ........................................................................................30

    (electronic

    1.0)

  • Statistical Analysis Plan 14-Aug-2017 SAR231893-EFC14280 - dupilumab Version number: 1

    Property of the Sanofi Group - strictly confidential Page 3

    2.1.6.1 .............................................30 2.1.7 Health Related Quality-of-life endpoints.........................................................................................30 2.1.7.1 Euro-QOL-5D .................................................................................................................................30 2.1.8 Health economic endpoints............................................................................................................31

    2.2 DISPOSITION OF PATIENTS .......................................................................................................31 2.2.1 Randomization and drug dispensing irregularities .........................................................................32

    2.3 ANALYSIS POPULATIONS ...........................................................................................................33 2.3.1 Efficacy populations .......................................................................................................................34 2.3.1.1 Intent–to-treat population ...............................................................................................................34 2.3.2 Safety population............................................................................................................................34 2.3.3 Pharmacokinetics (PK) population .................................................................................................34 2.3.4 Anti-drug antibody population.........................................................................................................34

    2.4 STATISTICAL METHODS .............................................................................................................35 2.4.1 Demographics and baseline characteristics ..................................................................................35 2.4.2 Prior or concomitant medications...................................................................................................35 2.4.2.1 INCS/MFNS controller medication .................................................................................................36 2.4.3 Extent of investigational medicinal product exposure and compliance..........................................36 2.4.3.1 Extent of investigational medicinal product exposure ....................................................................36 2.4.3.2 Compliance ....................................................................................................................................37 2.4.4 Analyses of efficacy endpoints .......................................................................................................37 2.4.4.1 Analysis of primary efficacy endpoint(s).........................................................................................38 2.4.4.2 Analyses of key secondary efficacy endpoints...............................................................................44 2.4.4.3 Multiplicity issues............................................................................................................................46 2.4.4.4 Additional efficacy analyses ...........................................................................................................48 2.4.4.5 Analyses of exploratory efficacy endpoints ....................................................................................51 2.4.4.6 Missing data handling.....................................................................................................................52 2.4.5 Analyses of safety data ............................................................