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Statistical Analysis Plan for Interventional Studies CCI NCT03697252 6WDWLVWLFDO$QDO\VLV3ODQIRU,QWHUYHQWLRQDO6WXGLHV 6SRQVRU1DPHKaruna Pharmaceuticals, Inc. 3URWRFRO1XPEHUKAR-004 3URWRFRO7LWOHA Phase 2, Randomized, Double-blinded Study to Assess the Safety, Tolerability, and Efficacy of KarXT in Hospitalized Adults with DSM-5 Schizophrenia 3URWRFRO9HUVLRQDQG'DWH ''0PP<<<< Version 4.0 Amendment 3/11Dec2018 Version 3.0 Amendment 2/24Aug2018 Version 2.0 Amendment 1/13Jun2018 Version 1.0 Final/17May2018 CCI $XWKRUVPPD , PPD Biostatistician PPD , Pharmacometrician 1RWLFHRI&RQILGHQWLDODQG3URSULHWDU\,QIRUPDWLRQ The information contained in this document is confidential belonging to Karuna Pharmaceuticals, Inc. Acceptance of this document constitutes agreement by the recipient that no information contained herein will be published or disclosed without prior written authorization from an official of Karuna Pharmaceuticals, Inc. However, this document may be disclosed to appropriate Institutional Review Board and Ethics Committees or duly authorized representatives of a national regulatory authority under the condition that they are requested to keep it confidential. In the event of an actual or suspected breach of this obligation, CCI should be notified promptly. SAP Version: Final v1.1 CCI , Effective Date 30-Apr-2018 Page of 6WDWLVWLFDO$QDO\VLV3ODQIRU,QWHUYHQWLRQDO6WXGLHV Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004 5HYLVLRQ+LVWRU\ 'DWH 9HUVLRQ (DD-Mmm-YYYY) 'RFXPHQW2ZQHU 5HYLVLRQ6XPPDU\ PPD Biostatistician V0.1 PPD PPD Initial Release Version PPD Biostatistician Address Karuna review comments V0.2 PPD PPD and update SAP per protocol amendment # 3 PPD Biostatistician Address Karuna review comments V1.0 PPD PPD Final version SAP CCI PPD Biostatistician V2.0 PPD PPD SAP Version: Final v2.0 CCI , Effective Date 30-Apr-2018 Page of PPD PPD PPD PPD PP PP PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD PPD CCI 6WDWLVWLFDO$QDO\VLV3ODQIRU,QWHUYHQWLRQDO6WXGLHV Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004 7DEOHRI&RQWHQWV Revision History..........................................................................................................................2 $SSURYDOV ..................................................................................................................................3 1. Glossary of Abbreviations...................................................................................................8 2. Purpose............................................................................................................................10 2.1. Responsibilities.....................................................................................................10 2.2. Timings of Analyses..............................................................................................10 3. Study Objectives ..............................................................................................................11 3.1. Primary Objective .................................................................................................11 3.2. Secondary Objectives...........................................................................................11 3.3. Brief Description ...................................................................................................11 3.4. Subject Selection..................................................................................................12 3.4.1. Inclusion Criteria .................................................................................................. 12 3.4.2. Exclusion Criteria ................................................................................................. 13 3.5. Determination of Sample Size...............................................................................14 3.6. Treatment Assignment & Blinding.........................................................................14 3.7. Administration of Study Medication.......................................................................15 3.8. Study Procedures and Flowchart ..........................................................................15 4. Endpoints .........................................................................................................................19 4.1. Primary Efficacy Endpoint.....................................................................................19 4.2. Secondary Efficacy Endpoints ..............................................................................19 4.3. Pharmacokinetic Endpoints...................................................................................19 4.4. Safety Endpoints...................................................................................................19 4.5. Exploratory Endpoints...........................................................................................19 5. Analysis Populations ........................................................................................................20 5.1. Intent-to-Treat (ITT) Population.............................................................................20 5.2. Safety Population..................................................................................................20 5.3. Modified Intent-to-Treat (MITT) Population ...........................................................20 5.4. PK Population.......................................................................................................20 5.5. Completer Population ...........................................................................................20 5.6. Per-Protocol (PP) Population................................................................................20 6. General Aspects for Statistical Analysis ...........................................................................21 SAP Version: Final v2.0 CCI , Effective Date 30-Apr-2018 Page of 6WDWLVWLFDO$QDO\VLV3ODQIRU,QWHUYHQWLRQDO6WXGLHV Sponsor: Karuna Pharmaceuticals, Inc.; Protocol No.: KAR-004 6.1. General Methods ..................................................................................................21 6.2. Key Definitions......................................................................................................21 6.2.1. First Dose Date .................................................................................................... 21 6.2.2. Last Dose Date .................................................................................................... 21 6.2.3. Study Day............................................................................................................. 21 6.2.4. Baseline and Change from Baseline ...................................................................21 6.3. Missing Data.........................................................................................................22 6.4. Visit Windows .......................................................................................................23 6.5. Pooling of Centers ................................................................................................23 CCI 7. Demographic, Other Baseline Characteristics and Medication .........................................24 7.1. Subject Disposition and Withdrawals ....................................................................24 7.2. Inclusion/Exclusion Criteria...................................................................................24 7.3. Protocol Deviations...............................................................................................24 7.4. Demographic and Other Baseline Characteristics.................................................25 7.5. Medical History .....................................................................................................25 7.6. Other Baseline Characteristics..............................................................................25 7.7. Prior and Concomitant Medication ........................................................................25 7.7.1. Prior Medication ................................................................................................... 25 7.7.2. Concomitant Medication ...................................................................................... 25 8. Efficacy Analyses .............................................................................................................26 8.1. Primary Efficacy Endpoint and Analysis................................................................26 8.1.1. Primary Analysis .................................................................................................. 26 CCI 8.1.3. Sensitivity Analyses of Primary Endpoint ............................................................28 CCI 8.2. Secondary Efficacy Endpoints and Analyses ........................................................30 8.2.1. Hierarchical test for efficacy evaluation ...............................................................30 8.2.2. Change from Baseline in PANSS Positive Score ................................................30 8.2.3. Change in CGI-S score........................................................................................ 31 8.2.4. Change from Baseline in PANSS Negative Score...............................................31 8.2.5. Change in PANSS Marder Factor Score .............................................................31 SAP Version: Final v2.0 CCI , Effective Date 30-Apr-2018 Page of 6WDWLVWLFDO$QDO\VLV3ODQIRU,QWHUYHQWLRQDO6WXGLHV Sponsor: Karuna Pharmaceuticals, Inc.; Protocol
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