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  • Forms

    Title Statistical Analysis Plan Template

    Code Version Effective Date Page

    FRM_ST03_032 01 23 Apr 2015 1 of 53

    Protocol Number: 4083-002 Final Version 2.0

    Document Date: 06 Oct 2017

    STATISTICAL ANALYSIS PLAN

    Protocol No. 4083-002

    A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Multiple

    Ascending Dose Study (Induction Therapy and Long-term Extension Therapy) of an

    Anti-OX40 Monoclonal Antibody (KHK4083) in Subjects with Moderately Active

    Ulcerative Colitis

  • Forms

    Title Statistical Analysis Plan Template

    Code Version Effective Date Page

    FRM_ST03_032 01 23 Apr 2015 2 of 53

    Protocol Number: 4083-002 Final Version 2.0

    Document Date: 06 Oct 2017

    STATISTICAL ANALYSIS PLAN

    Document Information

    Protocol Number: 4083-002

    Version: Final 2.0

    Document Date: 06 Oct 2017

    Prepared for: Kyowa Kirin Pharmaceutical Development, Inc.

    Prepared by: Hongsuk Song

    Senior Biostatistician, CROS NT

  • Forms

    Title Statistical Analysis Plan Template

    Code Version Effective Date Page

    FRM_ST03_032 01 23 Apr 2015 3 of 53

    Protocol Number: 4083-002 Final Version 2.0

    Document Date: 06 Oct 2017

    APPROVAL PAGE

    The Statistical Analysis Plan has been completed and reviewed and the contents are approved for

    use for the analysis.

    Lead Statistician details:

    Name: Hongsuk Song

    Job Role: Lead Statistician

    Company: CROS NT

    Signature:

    Date of signature: (DD Mmm YYYY)

    Sponsor Approver details:

    Name: Agron Collaku, Ph.D.

    Job Role: Senior Manager, Biostatistics

    Company: Kyowa Kirin Pharmaceutical Development, Inc.

    Signature:

    Date of signature: (DD Mmm YYYY)

    Sponsor Approver details:

    Name: June (Junfang) Li, Ph.D.

    Job Role: Vice President, Biometrics

    Company: Kyowa Kirin Pharmaceutical Development, Inc.

    Signature:

    Date of signature: (DD Mmm YYYY)

  • Forms

    Title Statistical Analysis Plan Template

    Code Version Effective Date Page

    FRM_ST03_032 01 23 Apr 2015 4 of 53

    Protocol Number: 4083-002 Final Version 2.0

    Document Date: 06 Oct 2017

    Contents Abbreviations ...................................................................................................................................... 6

    1. Introduction ................................................................................................................................. 8

    2. Study Objectives .......................................................................................................................... 8

    2.1 Primary objectives ..................................................................................................................... 8

    2.2 Secondary objectives ................................................................................................................. 9

    2.3 Exploratory objectives ............................................................................................................... 9

    3. Study Design ............................................................................................................................. 10

    3.1 General design and plan ........................................................................................................... 10

    3.2 Sample size justification .......................................................................................................... 16

    3.3 Randomization and blinding .................................................................................................... 16

    3.4 Efficacy endpoints ................................................................................................................... 16

    3.4.1 Primary endpoint .............................................................................................................. 16

    3.4.2 Secondary efficacy endpoints ........................................................................................... 17

    3.4.3 Exploratory efficacy endpoints ......................................................................................... 17

    3.5 Safety endpoints ....................................................................................................................... 18

    3.6 Other endpoints ........................................................................................................................ 18

    4. Statistical Analysis .................................................................................................................... 19

    4.1 General ..................................................................................................................................... 19

    4.2 Analysis sets ............................................................................................................................ 22

    4.3 Covariates ................................................................................................................................ 23

    4.4 Handling of missing and incomplete data ................................................................................ 23

    4.5 Changes in the planned analysis .............................................................................................. 23

    4.6 Data Review Meeting .............................................................................................................. 24

    4.7 Software ................................................................................................................................... 24

    5. Evaluation of Demographic and Baseline Characteristics ........................................................ 24

    5.1 Subject enrollment and disposition .......................................................................................... 24

    5.2 Protocol deviations .................................................................................................................. 25

    5.3 Demographics and baseline characteristics ............................................................................. 25

    5.4 Medical, diet and surgical history ............................................................................................ 25

    5.5 Prior and concomitant medications .......................................................................................... 26

    6. Evaluation of Treatment Exposure ............................................................................................ 26

    6.1 Exposure to investigational product ........................................................................................ 26

    6.2 Evaluation of pharmacokinetics ............................................................................................... 27

    6.3 Evaluation of immunogenicity ................................................................................................. 27

    7. Evaluation of Efficacy ............................................................................................................... 27

    7.1 Analysis of primary endpoint .................................................................................................. 28

    7.2 Analysis of secondary efficacy endpoints................................................................................ 30

  • Forms

    Title Statistical Analysis Plan Template

    Code Version Effective Date Page

    FRM_ST03_032 01 23 Apr 2015 5 of 53

    Protocol Number: 4083-002 Final Version 2.0

    Document Date: 06 Oct 2017

    7.3 Analysis of exploratory efficacy endpoints ............................................................................. 31

    7.4 Evaluation of pharmacodynamics ............................................................................................ 34

    8. Evaluation of Safety .................................................................................................................. 34

    8.1 Adverse events ......................................................................................................................... 34

    8.2 Clinical laboratory evaluation .................................................................................................. 35

    8.3 Vital signs and body weight ..................................................................................................... 35

    8.4 ECGs ........................................................................................................................................ 35

    8.5 Physical examination except body weight ............................................................................... 36

    9. Tables and Listings .................................................................................................................... 37

    9.1 Programs and tables quality control ......................................................................................... 37

    9.2 Programming conventions ....................................................................................................... 37

    9.3 Glucocorticoid .................................................................................