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A Phase 3 Randomized, Double-Blind SPIMM-301 Version 4.0 15 June 2018 Title: A Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects with Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension NCT: NCT03323749 Final Approval Date: 15 June 2018 Stealth BioTherapeutics Inc. CONFIDENTIAL 1 00900-4.00 SPIMM-301 Version 4.0 15 June 2018 CLINICAL TRIAL PROTOCOL A Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo- Controlled Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects with Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension Trial Phase: Phase 3 Trial Number: SPIMM-301 Document Version: Version 4.0 Final Approval Date: 15 June 2018 IND Number: 123,553 EudraCT Number: 2017-002447-15 Sponsor: Stealth BioTherapeutics Inc. 275 Grove Street, Suite 3-107 Newton, MA 02466 United States of America (USA) Sponsor Chief Clinical Jim Carr, Pharm.D. Development Officer: Chief Clinical Development Officer 275 Grove Street 3-107, Newton, MA 02466, USA [email protected] +1 617-762-2503 Sponsor Medical Monitor: Sandrin Bergheanu, M.D., Ph.D Medical Monitor 275 Grove Street 3-107, Newton, MA 02466, USA [email protected] +1 617-762-2595 +31 (0) 641 476 460 Confidentiality Statement The information contained in this document is confidential and is the property of Stealth BioTherapeutics Inc. No part of it may be transmitted, reproduced, published, or used by anyone without the written permission of Stealth BioTherapeutics Inc. Stealth BioTherapeutics Inc. CONFIDENTIAL 1 00900-4.00 SPIMM-301 Version 4.0 15 June 2018 PROTOCOL APPROVAL Protocol Title: A Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects with Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension Protocol Number: SPIMM-301 Protocol Date: 15 June 2018, Version 4.0 06/15/2018 Jim Carr, Pharm.D. Date Chief Clinical Development Officer Stealth BioTherapeutics Inc. Stealth BioTherapeutics Inc. CONFIDENTIAL 2 SPIMM-301 Version 4.0 15 June 2018 INVESTIGATOR’S AGREEMENT I have received and read the Investigator’s Brochure for elamipretide (MTP-131). I have read the SPIMM-301 protocol and agree to conduct the trial as outlined. I confirm that I will conduct the trial in accordance with ICH GCP guidelines. I will also ensure that sub-Investigator(s) and other relevant members of my staff have access to copies of this protocol, and the ICH GCP guidelines to enable them to work in accordance with the provisions of these documents. I agree to maintain the confidentiality of all information received or developed in connection with this protocol. Printed Name of Investigator Signature of Investigator Date (DD/MMM/YYYY) Stealth BioTherapeutics Inc. CONFIDENTIAL 3 SPIMM-301 Version 4.0 15 June 2018 1. SYNOPSIS Name of Sponsor/Company: Stealth BioTherapeutics Inc. Name of Investigational Combination Product: Elamipretide delivery system Name of Active Ingredient: Elamipretide (MTP-131) Title of Trial: A Phase 3 Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Daily Subcutaneous Injections of Elamipretide in Subjects with Primary Mitochondrial Myopathy Followed by an Open-Label Treatment Extension Trial site(s): Multicenter (North America and Europe); approximately 27 sites Phase of development: 3 Objectives: This trial is designed with 2 parts, SPIMM-301 (PART 1) and SPIMM-301 OLE (PART 2). The objectives of each part are consistent with the trial design. • PART 1 is a 24-week, randomized, double-blind, parallel-group, placebo-controlled assessment of the efficacy and safety of single daily subcutaneous (SC) doses of 40 mg elamipretide (vs placebo) administered with the elamipretide delivery system as a treatment for subjects with primary mitochondrial myopathy (PMM). • PART 2 is an up to 144-week, open-label assessment of the long-term safety and tolerability of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system in subjects with PMM. PART 1 objectives are: Primary • To evaluate the effect of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for 24 weeks on the: – Distance Walked on the 6-Minute Walk Test (6MWT) – Total Fatigue on the Primary Mitochondrial Myopathy Symptom Assessment© (PMMSA) Secondary • To evaluate the effect of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for 24 weeks as measured by changes in the: – Fatigue During Activities on the PMMSA – Neuro-QoL Short Form Fatigue – Most bothersome symptom on the PMMSA – Neuro-QoL Fatigue activities of daily living (specific items from the Neuro-QoL Item Bank). • To evaluate the safety and tolerability of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for 24 weeks Stealth BioTherapeutics Inc. CONFIDENTIAL 4 SPIMM-301 Version 4.0 15 June 2018 Exploratory • To evaluate the effect of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for 24 weeks as measured by changes in the: – Individual symptoms on the PMMSA – Alternate version of the PMMSA Total Fatigue Score – Individual items of the Neuro-QoL Fatigue – EQ-5D-5L – Patient Global Impression (PGI) Scales – Clinician Global Impression (CGI) Scales Pharmacokinetic (PK) • To evaluate the PK of elamipretide PART 2 objectives are: • To assess the long-term safety and tolerability of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system for up to 144 weeks Methodology: This randomized, double-blind, parallel-group, placebo-controlled trial will enroll approximately 202 subjects who have PMM. There are 2 parts to this trial. • PART 1 is a 24-week, randomized, double-blind, parallel-group, placebo-controlled assessment of the efficacy and safety of single daily SC doses of 40 mg elamipretide (vs placebo) administered with the elamipretide delivery system as a treatment for subjects with PMM. Subjects will be randomized (in a ratio of 1:1) to one of two groups: – 24 weeks of single daily SC doses of 40 mg elamipretide or – 24 weeks of single daily SC doses of placebo. • PART 2 is an up to 144-week, open-label assessment of the long-term safety and tolerability of single daily SC doses of 40 mg elamipretide administered with the elamipretide delivery system in subjects with PMM. Subjects who continue into PART 2 will receive treatment with 40 mg SC elamipretide administered with the elamipretide delivery system for up to 144 weeks. Thus, treatment during PART 2 will be as follows: – Subjects who are originally randomized to elamipretide during PART 1 (double-blind treatment) will continue receiving elamipretide during PART 2. – Subjects who are originally randomized to placebo during PART 1 (double-blind treatment) will switch to treatment with elamipretide during PART 2. Note that the duration of PART 2 treatment for each subject will be the shortest of the following: • 144 weeks • Regulatory approval and commercial availability of the elamipretide delivery system in the subject’s respective country Stealth BioTherapeutics Inc. CONFIDENTIAL 5 SPIMM-301 Version 4.0 15 June 2018 • Termination of the clinical development for elamipretide in subjects with PMM. PART 1 Screening Period: Screening will begin with the subject’s signature of the informed consent form (ICF) and will last a minimum of 7 days to a maximum of 28 days. Subjects not previously enrolled in SPIMM-300, however, may have a longer screening period for review by the Adjudication Committee to determine their eligibility for study enrollment. Subjects will undergo Screening procedures as described in the PART 1 Schedule of Assessments (Appendix 1) and will be trained and instructed to complete the PMMSA daily during the Screening Period, in an electronic or paper diary, in order to characterize their baseline disease status and to assess compliance. Subjects who complete Screening and continue to meet all trial requirements, including all Inclusion Criteria and none of the Exclusion Criteria, may be randomized (stratified by the subclassification of the genetic abnormality determined to be the primary cause of the subject’s PMM [DiMauro 2003] as determined by the Adjudication Committee) and enter the Treatment Period. Treatment Period: The Treatment Period will begin on the day of the Baseline Visit, which is defined as Day 1, and lasts for 24 weeks. Subjects (and caregivers if needed) will be trained on the procedure for administration of the elamipretide delivery system (the investigational medicinal product [IMP] [elamipretide or placebo], the elamipretide pen injector, and needle) and recording of the location (injection in the abdomen, rotating around the four abdominal quadrants, or other appropriate location [after Investigator consultation with the Sponsor]) and time (at approximately the same time each day [e.g., early morning, noon, or early afternoon]) of the IMP administration daily in the electronic or paper diary. An elamipretide delivery system training kit and checklist will be provided to the clinical site to assist in training. At the Baseline Visit, following completion of all Baseline procedures described in the PART 1 Schedule of Assessments, subjects or trained caregivers will administer IMP at the clinical site. On non-visit days, subjects (or trained caregivers) will administer the IMP daily during the Treatment Period. The subject will return to the clinical site for the Week 4, Week 12, and Week 24 Visits for assessments, to administer the IMP (subject or trained caregiver), and to return all used IMP supplies. During the Treatment Period, subjects will continue to follow all trial requirements, including recording the location and time of the IMP administration daily and completing the PMMSA daily. The Treatment Period will conclude with a visit to the clinical site at the Week 24 Visit when subjects will return all trial-related supplies.
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