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Study Title: RAIN (Renal AL Amyloid Involvement and NEOD001)

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Study Title: RAIN (Renal AL Amyloid Involvement and NEOD001) 1 Study Title: RAIN (Renal AL amyloid Involvement and NEOD001): A Multicenter Randomized Double-blind Phase 2b Study of NEOD001 in Previously Treated Subjects with Systemic Light-chain (AL) Amyloidosis and Persistent Renal Involvement Protocol Number: NEOD001-IST007 RAIN Investigational Product: NEOD001 US IND Number: 13383 Indication: Light Chain (AL) Amyloidosis Development Phase: Development Phase: Phase 2b Date of Original Protocol: 11 April 2017 Amendment 1: 13 April 2017 Amendment 2: 13 July 2017 Version Number: 2.0 NCT number: 03168906 Confidential The information contained in this document and all information provided to you related to NEOD001 is the confidential and proprietary information of Tufts Medical Center and Prothena Therapeutics Limited (Prothena). It is intended solely for the recipient clinical investigator(s) and must not be disclosed to any other party. This material may be used only for evaluating or conducting clinical investigations; any other proposed use requires written consent from Tufts and Prothena. 2 Participating Centers and Clinical Investigators Tufts Medical Center Boston, MA PI Cindy Varga, MD Co-I Lesley Inker, MD Co-I Grace Kao, MD Co-I Ronald Perrone, MD Memorial Sloan-Kettering Cancer Center New York, New York PI Heather Landau. MD Hospital of the University of Pennsylvania Philadelphia, PA PI Brendan Weiss, MD Karmanos Cancer Institute Wayne State University Detroit, MI PI Jeff Zonder, MD Vanderbilt University Medical Center Nashville, TN PI Stacey Goodman, MD Mayo Clinic (Rochester) Rochester, MN PI Morie Gertz, MD Co-I Nelson Leung, MD Co-I Angela Dispenzieri, MD Mayo Clinic (Arizona) Scottsdale, AZ PI Joseph Mikhael, MD Mayo Clinic (Florida) Jacksonville, FL PI Taimur Sher, MD University of California San Francisco San Francisco, CA PI Sandy Wong, MD 3 Ancillary Studies Collaborators: 1Amyloidosis Research Consortium (ARC), 2University of Michigan Principal Investigators Isabelle Lousada (ARC) Cindy Varga, MD (Tufts) Patient Reported Outcomes1 Isabelle Lousada Stacey Goodman, MD Michaela Liedtke, MD Heather Landau, MD Renal Pathology Studies1 Monika Pilichowska, MD Sami Nasr, MD Agnes B Fogo, MD Others to be named Renal Transcriptional Profiling Studies1,2 Isabelle Lousada Cindy Varga, MD Brendan Weiss, MD Nelson Leung, MD Angela Dispenzieri, MD Lesley Inker, MD Ronald Perrone, MD Monika Pilichowska, MD Sami Nasr, MD Agnes B Fogo, MD Mathias Kretzler, MD 4 SPONSOR PROTOCOL APPROVAL PAGE Protocol Title: RAIN (Renal AL amyloid Involvement and NEOD001): A Multicenter Randomized Double-blind Phase 2b Study of NEOD001 in Previously Treated Subjects with Systemic Light-chain (AL) Amyloidosis and Persistent Renal Involvement Protocol Number: NEOD001-201 Sponsor: Tufts Medical Center Protocol Number: NEOD001-IST007 RAIN Date of Original Protocol: 11 April 2017 Date of Amendment 1: 13 April 2017 Date of Amendment 2: 13 July 2017 Declaration of Sponsor This clinical study protocol was subjected to critical review. The information it contains is consistent with current knowledge of the risks and benefits of the study drug, as well as with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki and the guidelines on Good Clinical Practices applicable to this clinical study. This protocol has been approved by Tufts Medical Center. The following person is authorized on behalf of Tufts Medical Center to approve this protocol and the signature below documents this approval. ______________________________ ________________ Raymond Comenzo, MD Date Medical Monitor 5 Protocol version 2.0 dated 13 July 2017 I have read the foregoing protocol and agree to conduct this study in accordance with the current protocol. ______________________________________________________ Investigator Signature Date ______________________________________________________ Investigator Name (Print) Please sign, date, and return this form to your Study Monitor. Please retain a copy for your study files. __________________________________________________ Site Name and Number 6 TABLE OF CONTENTS 1 INTRODUCTION 21 1.1 Background 22 1.2 Study Rationale 22 1.3 Background on NEOD001 22 1.3.1 Clinical Safety and Tolerability 23 2 OBJECTIVES 24 3 STUDY PLAN 24 3.1 Study Design 24 3.2 Endpoints 25 3.2.1 Primary 25 3.2.2 Secondary 25 3.2.3 Ancillary Studies 25 3.3 Number of Sites and Subjects 26 3.4 Randomization and Blinding 26 3.4.1 Randomization 26 3.4.2 Emergency Unblinding 27 3.5 Medical Monitor 27 3.6 Estimated Study Duration 27 3.7 Definition of End of Study 28 4 SELECTION, DISCONTINUATION, AND WITHDRAWAL OF SUBJECTS 28 4.1 Inclusion Criteria 28 4.2 Exclusion Criteria 29 4.3 Early Treatment Discontinuation 29 4.4 Early Termination from the Study 30 4.5 Replacement of Subjects 30 4.6 Termination of the Clinical Study 31 4.7 Local Recruitment Methods 31 5 TREATMENT OF SUBJECTS 32 5.1 Study Drug 32 5.1.1 Formulation, Packaging, and Labeling 32 5.1.2 Accountability and Return of Study Supplies 32 5.2 Dosage, Preparation, and Administration 32 5.3 Dosage Adjustments 33 5.3.1 Withholding of Study Drug 33 5.3.2 Management of Suspected Infusion-Related/Hypersensitivity Adverse Events 33 5.3.3 Dose Reductions 34 5.4 Treatment Compliance 34 5.5 Prior and Concomitant Medication/Therapy 34 5.5.1 Allowed (Concomitant) 34 5.5.2 Prohibited (Concomitant) 34 6 STUDY PROCEDURES 34 6.1 Evaluations by Visit 34 6.1.1 Screening 34 6.1.2 Treatment Visit 36 6.1.2.1 Month 1 Day 1 36 6.1.2.2 Months 2 through 12 – day 1 (±5 Days) 37 6.2 End of Study/Early Treatment Discontinuation (EOS/ETD): 30 (±5) days AFTER Final Dose 38 6.2.1 Confirmatory EOS visit: 30 (+/- 5) days after the initial EOS visit 39 6.3 90-day Post-dose Pregnancy Test 40 7 6.4 Vital Status Follow-Up Phone Call 40 6.5 METHODS OF ASSESSMENT 40 6.5.1 Safety 40 6.5.1.1 Clinical Laboratory Evaluations 40 6.5.1.2 Vital Signs 40 6.5.1.3 Physical Examination 41 6.5.2 Efficacy 41 6.5.2.1 Primary: Renal Response 41 6.5.2.2 Secondary 41 7 ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING 41 7.1 Adverse Events—Definition 41 7.2 Adverse Events—Severity Rating 42 7.3 Adverse Events—Causality Rating 43 7.4 Serious Adverse Events and Unexpected Adverse events 44 7.4.1 Elective Procedures and Surgeries 45 7.4.2 Other Reportable Information 45 7.4.3 Disease Progression and Death 46 7.4.4 Serious Adverse Events—Reporting 46 7.4.5 Data Safety and Monitoring Board 47 8 STATISTICAL METHODS AND CONSIDERATIONS 47 8.1 Analysis Populations 47 8.2 Analysis of Study Population and Subject Characteristics 48 8.3 Analysis of Efficacy Endpoints 48 8.3.1 Primary Efficacy Analysis 48 8.3.2 Secondary Efficacy Analyses 48 8.3.3 Ancillary Studies Analyses (ARC) 48 8.4 Analysis of Safety Endpoints 49 8.5 Determination of Sample Size 49 8.6 Handling of Dropouts and Missing Data 50 9 DATA RECORDING, RETENTION, AND MONITORING 50 9.1 Case Report Forms 50 9.2 Availability and Retention of Records 50 9.3 Quality Control and Quality Assurance 51 9.4 Subject Confidentiality 51 10 Potential Risks Associated with NEOD001 51 10.1 Reproductive Risks 53 10.2 Risks from Taking Diphenhydramine or Acetaminophen 54 10.3 Venipucture Risks 54 10.4 Intravenous Risks 54 10.5 Biopsy Risk 54 10.6 Risk of ECG Procedure 55 10.7 Risk of Echocardiogram Procedure 55 11 Benefits 55 12 ETHICAL AND LEGAL ISSUES 55 12.1 Ethical Conduct of the Study 55 12.2 Regulatory Approval 55 12.3 Ethics Committee Approval 55 12.4 Communication Among Sites 56 12.5 Subject Informed Consent 56 12.6 Resources Available 57 12.7 Subject Compensation for Participating in the Study 58 12.8 Subject Compensation for Adverse Effects on Health 58 12.9 Protocol Amendments and Study Termination 58 8 12.10 Finance, Insurance, and Indemnity 58 12.11 Publication Policy 58 13 REFERENCES 59 14 APPENDICES 61 Appendix 1 For Stratification: Hematologic Response and Progression Criteria and Renal Staging Criteria 61 Appendix 2 Examples of Highly Effective Contraception Methods 62 Appendix 3 Revised International Myeloma Working Group (IMWG) Diagnostic Criteria for Multiple Myeloma 63 Appendix 4 Modified Organ Response and Progression Criteria 64 Appendix 5 Eastern Cooperative Oncology Group (ECOG) Performance Status 65 Appendix 6 New York Heart Association (NYHA) Functional Classification 66 Appendix 7 SF-36 67 Appendix 8 Renal Scoring 72 Appendix 9 Measuring GFR 75 Appendix 10 Renal Gene Expression Profiling 80 Appendix 11 Open Label Extension Table of Procedures, Eligibility Checklist and Consent Form 82 LIST OF TABLES Table 1 Schedule of Assessments 15 Table 2 Treatment-Emergent Adverse Events Reported for > 10% of Subjects in Study NEOD001 24 Table 3 Urine and Blood Samples for mGFR 76 Table 4 Schedule of Procedures for mGFR 79 Table 5 OLE Table of Assessments 82 LIST OF FIGURES Figure 1 RAIN Study Design 18 Figure 2 Proposed Mechanism of Action for NEOD001 23 9 RAIN PROTOCOL SYNOPSIS Title RAIN (Renal AL-amyloid Involvement and NEOD001): A Multicenter Randomized Double-blind Phase 2b Study of NEOD001 in Previously Treated Subjects with Systemic Light-chain (AL) Amyloidosis and Persistent Renal Involvement Phase 2b Planned Number of 9 centers in the USA Study Centers Objective The objective of this study is to determine if the investigational agent NEOD001, a monoclonal antibody that targets a light chain amyloid epitope, increases the frequency of confirmed renal responses (see Appendix 1) in previously treated patients with AL and renal involvement who have responded to prior treatment with a maintained complete, very good partial or partial hematologic response (CR, VGPR, PR) and do not need chemotherapy for their hematologic disease.
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