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Study Protocol and Amendments As Applicable  Obtaining Signed Informed Consent  Investigator Reporting Requirements (E.G

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Study Protocol and Amendments As Applicable  Obtaining Signed Informed Consent  Investigator Reporting Requirements (E.G 2015N249732_02 CONFIDENTIAL The GlaxoSmithKline group of companies 201464 TITLE PAGE Division: Worldwide Development Information Type: Protocol Amendment Title: A multiple treatment session, open label phase 2 clinical study of GSK2398852 administered following and together with GSK2315698 in cohorts of patients with cardiac amyloidosis Compound Number: GSK2315698+GSK2398852 II Development Phase: Effective Date: [05-MAR-2018] Protocol Amendment Number: 02 Author (s): PPD PPD Revision Chronology GlaxoSmithKline Date Version Document Number 2015N249732_00 2016-MAY-09 Original 2015N249732_01 2017-APR-20 Amendment No. 1 Changes made to reflect regulatory input from the FDA. Other changes made to correct minor errors included in the original version. 2015N249732_02 2018-MAR-05 Amendment No. 2 Regulatory input from the FDA on clarifying requirements for recruitment. Define plasma SAP depletion target level of <3 mg/L. Inclusion criterion for LVmass updated for Groups 2 and 3 to reflect the AL patient population. Reflect regulatory safety update information for Gadolinium contrast agents. Dermatology review timings adjusted for grade 3 rash incidences. Other changes made for clarity and to correct minor typographical errors. Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1 PPD PPD 2015N249732_02 CONFIDENTIAL 201464 MEDICAL MONITOR/SPONSOR INFORMATION PAGE Medical Monitor/SAE Contact Information: Role Name Day Time Phone Number After-hours Fax Site Address and email address Phone/Cell/ Number Pager Number Primary PPD GlaxoSmithKline Medical Medicines Monitor Research & Development, Gunnels Wood Road, Stevenage SG1 2NY United Kingdom Secondary Medical Monitor SAE Medical contact monitor information as above Sponsor Legal Registered Address: GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate Company (or designee). If applicable, the details of the alternative Sponsor and contact person in the territory will be provided to the relevant regulatory authority as part of the clinical trial application. Regulatory Agency Identifying Number(s): EudraCT: 2016-000276-23, IND: 129568 3 2015N249732_02 CONFIDENTIAL 201464 INVESTIGATOR PROTOCOL AGREEMENT PAGE For protocol number: 201464 I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment. I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study. I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study. Investigator Name: Investigator Address: Investigator Phone Number: Investigator Signature Date 4 2015N249732_02 CONFIDENTIAL 201464 TABLE OF CONTENTS PAGE 1. PROTOCOL SYNOPSIS FOR STUDY 201464........................................................9 2. INTRODUCTION....................................................................................................15 2.1. Study Rationale ..........................................................................................15 2.2. Brief Background ........................................................................................15 2.3. Summary of First In Human (FIH) Findings.................................................16 2.4. Purpose of phase 2 Study...........................................................................17 2.4.1. Multimodality cardiac imaging ......................................................18 3. OBJECTIVE(S) AND ENDPOINT(S) ......................................................................19 4. STUDY DESIGN ....................................................................................................22 4.1. Overall Design ............................................................................................22 4.2. Treatment Groups and Duration .................................................................25 4.3. Number of Subjects ....................................................................................26 4.4. Justification of the study design ..................................................................26 4.4.1. Combining Anti-SAP Treatment with Chemotherapy....................27 4.4.1.1. Scheduling of Anti-SAP Treatment with Chemotherapy............................................................28 4.5. Justification of Dosing Regimen..................................................................29 4.5.1. GSK2315698 (CPHPC - Plasma SAP Depleter) ..........................29 4.5.2. GSK2398852 (anti-SAP mAb)......................................................30 4.5.3. Dosing schedule for GSK2315698 (CPHPC) + GSK2398852 (anti-SAP mAb)......................................................32 4.6. Benefit:Risk Assessment ............................................................................32 4.6.1. Risk Assessment .........................................................................33 4.6.1.1. Potential for Cardiotoxicity..........................................33 4.6.1.2. Summary of rashes ....................................................33 4.6.1.3. Potential for Circulating Immune Complex Formation ...................................................................34 4.6.1.4. Surveillance for Long-Term Toxicities.........................34 4.6.2. Risk Assessment Table ...............................................................35 4.6.3. Benefit Assessment .....................................................................42 4.6.4. Overall Benefit:Risk Conclusion...................................................42 5. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............43 5.1. Inclusion Criteria.........................................................................................43 5.2. Exclusion Criteria........................................................................................47 5.3. Screening/Baseline/Run-in Failures............................................................50 5.4. Withdrawal/Stopping Criteria.......................................................................50 5.4.1. Liver Chemistry Stopping Criteria ................................................51 5.4.1.1. Study Treatment Restart or Rechallenge....................51 5.4.2. Renal Function Stopping Criteria .................................................51 5.4.3. Platelet Stopping Criteria .............................................................52 5.4.4. Neutrophil Stopping Criteria.........................................................52 5.4.5. Cardiovascular Safety Stopping Criteria ......................................52 5.4.5.1. Individual subject cardiovascular stopping criteria ........................................................................52 5 2015N249732_02 CONFIDENTIAL 201464 5.4.6. QTc Stopping Criteria ..................................................................53 5.4.6.1. Individual Subject QTcF Stopping Criteria ..................53 5.4.7. Dermatological Toxicity Stopping Criteria.....................................53 5.4.7.1. Individual subject dermatological stopping criteria ........................................................................53 5.4.8. Haematological Stopping Criteria (Groups 2 & 3).........................53 5.4.8.1. Individual subject haematological stopping criteria ........................................................................53 5.4.9. Study Safety Stopping Criteria.....................................................54 5.5. Subject Withdrawal Procedures ..................................................................54 5.6. Replacement of Withdrawn Subjects ..........................................................54 5.7. Subject and Study Completion....................................................................54 6. STUDY TREATMENT ............................................................................................55 6.1. Investigational Product and Other Study Treatment....................................55 6.1.1. Anti-SAP treatment ......................................................................55 6.2. Planned Dose Adjustments- Subject Specific Dose Adjustment Criteria........................................................................................................56 6.2.1. CPHPC dosing regimen according to renal function ....................56 6.2.2. Dose-Level Reduction Schedule for anti-SAP mAb Due to Adverse Events............................................................................56 6.2.3. Dose-Interval Extension between Anti-SAP Treatment Sessions......................................................................................57 6.2.4. Dose Modifications for Skin Rashes.............................................57 6.3. Blinding.......................................................................................................58 6.4. Packaging and Labelling.............................................................................58 6.5. Preparation/Handling/Storage/Accountability ..............................................58 6.6. Compliance with Study Treatment Administration.......................................59 6.7. Treatment of Study Treatment Overdose....................................................59
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