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  • Statistical Analysis Plan Protocol: FLU-v 003 Version 2.0 16 February 2018

    1

    Clinical Study Protocol: FLU-v 003

    (WITH AMENDMENTS) A randomised, double-blind, placebo-controlled, single-centre phase

    IIb trial as part of the EU-funded UNISEC project to assess the immunogenicity and safety of different formulations and dosing

    regimens of FLU-v vaccine administered subcutaneously in healthy adults aged 18-60 years.

    STATISTICAL ANALYSIS PLAN

    Protocol No.: FLU-v 003 Clinical Phase: IIb Protocol Version and Date: 4.1 Dated 28 April 2017 Study Principal Investigator: Paul Groeneveld

    Isala Hospitals Isala Academy, department of Innovation and Science Dokter van Deenweg 1 8052 BP Zwolle The Netherlands

    Sponsor: PepTcell Limited (trading as SEEK) 45 Beech Street London EC2Y 8AD UK

    EudraCT number: 2015-001932-38 ClinicalTrials.gov Identifier: NCT0296208 Written by: Md. Atiqul Islam, PhD/ E. Hak, PhD/O.

    Pleguezuelos, PhD Document Status: v2.0 Date: March 20, 2018 Number of Pages: 95

  • Statistical Analysis Plan Protocol: FLU-v 003 Version 2.0 16 February 2018

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    Signature Page

    Statistical Analysis Plan for Clinical Study Protocol:

    A randomised, double-blind, placebo-controlled, single-centre phase IIb trial as

    part of the EU-funded UNISEC project to assess the immunogenicity and safety of

    different formulations and dosing regimens of FLU-v vaccine administered

    subcutaneously in healthy adults aged 18-60 years.

    Approved by:

    Coordinating investigator Prof. dr. Eelko Hak

    PharmacoTherapy, -Epidemiology & -

    Economics

    University of Groningen, The Netherlands

    Date: 16 February 2018 Signature ____________________

    Sponsor’s Representative Dr. Olga Pleguezuelos

    CSO & Project Manager, SEEK

    45 Beech Street, London, EC2Y 8AD,

    United Kingdom

    Date: _______________________ Signature ____________________

    Biostatistician Dr. Md. Atiqul Islam

    PharmacoTherapy, -Epidemiology & - Economics

    University of Groningen, The Netherlands

    Date _______________________ Signature ____________________

  • Statistical Analysis Plan Protocol: FLU-v 003 Version 2.0 16 February 2018

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    Contents List of Abbreviations ................................................................................................................................ 5

    1 Introduction ........................................................................................................................................... 6

    1.1 Scope .............................................................................................................................................. 6

    1.2 Trial Study Design .......................................................................................................................... 6

    1.3 Study Objectives ............................................................................................................................. 8

    1.3.1 Primary objectives ................................................................................................................... 8

    1.3.1.1 Th1 Cellular Immunogenicity ................................................................................................................. 8

    1.3.1.2 Safety ....................................................................................................................................................... 8

    1.3.2.1 Th2 cellular immunogenicity .................................................................................................................. 8

    1.3.2.2 IgM and IgG antibody responses ........................................................................................................... 10

    1.3.3 Exploratory objectives ........................................................................................................... 10

    1.3.3.1 Cellular immunogenicity ....................................................................................................................... 10

    1.3.3.2 IgG subclasses ....................................................................................................................................... 10

    1.3.3.3 Clinical Efficacy .................................................................................................................................... 11

    1.4 Schedule of visits .......................................................................................................................... 12

    2 Statistical Methods .............................................................................................................................. 14

    2.1 Data Management ......................................................................................................................... 14

    2.1.1 Coding ................................................................................................................................... 14

    2.2 Statistical Analysis Software ........................................................................................................ 14

    2.3 Data Collection and data sets ........................................................................................................ 15

    2.4 Handling of Missing Data ............................................................................................................. 15

    2.5 General Statistical Methods .......................................................................................................... 16

    2.6 Sample Size .................................................................................................................................. 16

    2.7 Study Populations ......................................................................................................................... 20

    2.7.1 Intention to Treat ................................................................................................................... 20

    2.7.2 Full Analysis Set .................................................................................................................... 20

    2.7.3 Per Protocol ........................................................................................................................... 20

    2.7.4 Safety ..................................................................................................................................... 21

    2.8 Level of Significance .................................................................................................................... 21

    2.9 Statistical Methods ....................................................................................................................... 21

    2.9.1 Primary endpoints .................................................................................................................. 21

    2.9.1.1 Cellular immunogenicity ....................................................................................................................... 21

    2.9.1.1.1 Th1 responses by Multiparametric Flow Cytometry .......................................................................... 21

    2.9.1.1.1.1 Data acceptance criteria Multiparametric Flow Cytometry .............................. 22

    2.9.1.1.1.2 Analyses with the accepted data sets ................................................................ 23

    2.9.1.1.2 INF- by ELISA ................................................................................................................................. 25

    2.9.1.1.2.1 Data acceptance criteria ELISA ....................................................................... 25

    2.9.1.1.2.2 Analysis with the accepted data sets ................................................................. 25

    2.9.1.2.1 Solicited Adverse Events: Post-vaccination diary cards..................................................................... 26

    2.9.1.2.2 Unsolicited Adverse Events ............................................................................................................... 26

    2.9.1.2.3 Serious Adverse Events ...................................................................................................................... 26

  • Statistical Analysis Plan Protocol: FLU-v 003 Version 2.0 16 February 2018

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    2.9.1.2.4 Analysis of AEs and SAEs ................................................................................................................. 27

    2.9.2.1 Immunoglobulin G (IgG) and M (IgM) specific for FLU-v .................................................................. 28

    2.9.2.2 Th2 responses: IL-4 ............................................................................................................................... 30

    2.9.3 Exploratory Endpoints ..................................................