A Trial to Evaluate Safety and Efficacy of Elamipretide Primary Mitochondrial Myopathy Followed by Open-Label Extension

Study Overview
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Brief Summary
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This is a multicenter phase 3 randomized, double-blind, parallel-group, placebo-controlled trial to evaluate the safety and efficacy of daily subcutaneous injections of elamipretide in subjects with primary mitochondrial myopathy. This will be followed by an open-label treatment extension.

Detailed Description
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Part 11 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 was 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.

Official Title
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A Phase 3 Randomized, 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

Conditions
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Primary Mitochondrial Myopathy

Intervention / Treatment
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* Combination Product: elamipretide
* Combination Product: placebo comparator
* Combination Product: elamipretide open label treatment


Participation Criteria
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Eligibility Criteria
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PART 1: Inclusion Criteria: Willing and able to provide a signed informed consent form prior to participation in any trial-related procedures Agrees to adhere to the trial requirements for the length of the trial, including the use of the elamipretide delivery system Subject is ≥ 16 and ≤ 80 years of age Diagnosed with PMM in the opinion of the investigator and confirmed by an Adjudication Committee Woman of childbearing potential must agree to use a highly effective method of birth control Exclusion Criteria: Subject has myopathic signs and or/symptoms due to a neuropathic process or gait problem that would interfere with the 6 minute walk test (6MWT), in the opinion of the Investigator Female who are pregnant, planning to become pregnant, or breastfeeding/lactating At Screening, the estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2 Subject has undergone an in-patient hospitalization within the 30 days prior to the Baseline Visit or has a planned hospitalization or a surgical procedure during the trial. Subject has clinically significant cardiac disease or prior interventional procedure and/or respiratory disease (medical history or current clinical findings) within 3 months of the Baseline Visit, in the opinion of the Investigator. Subject has QTc elongation (using the correction factor utilized at the clinical site) defined as a QTc >450 msec in male subjects and >480 msec in female subjects. ECG evidence of acute ischemia, atrial fibrillation, or active conduction system abnormalities with the exception of any of the following: First degree Atrioventricular bock (AV-block) Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type) Right bundle branch block Subject has severe vision impairment that, in the opinion of the Investigator, may interfere with their ability to complete all trial requirements Subject has a seizure disorder that, in the opinion of the Investigator, may interfere with their ability to complete all trial requirements. Active malignancy or any other cancer from which the subject has been disease-free for < 2 years. Subject has a solid organ transplant and/or is currently receiving treatment with therapy for immunosuppression, in the opinion of the Investigator. Subject has been previously diagnosed with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection. Subject has a history of a systemic eosinophilic illness and/or an eosinophil count >1,000 cells x10^6/L at the Screening Visit. Subject is currently participating or has participated in an interventional clinical trial (i.e.,investigational product or device, stem cell therapy, gene therapy) within 30 days of the Baseline Visit; or is currently enrolled in a non-interventional clinical trial (except for SPIMM-300) at the Baseline Visit which, in the opinion of the Investigator, may be potentially confounding with results of the current trial (e.g., exercise therapy trial). Subject has previously received elamipretide (MTP-131), for any reason. Subject has a history of active substance abuse during the year before the Baseline Visit, in the opinion of the Investigator. Subject has any prior or current medical condition that, in the judgment of the Investigator, would prevent the subject from safely participating in and/or completing all trial requirements. PART 2: Continuation Criteria: Subjects must continue to be able and willing to adhere to the trial requirements. Subject is appropriate to continue in Part 2 (i.e. subject was compliant in Part 1), in the opinion of the Investigator. Subject has not had a serious adverse event (SAE)/serious adverse device effect (SADE) attributed to the elamipretide delivery system. Subject has not permanently discontinued the elamipretide delivery system.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Elamipretide<br>40 mg (0.5mL) elamipretide subcutaneous (SC) daily | Combination Product: elamipretide<br>* 40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system<br>* Other names: MTP-131;|
| Placebo Comparator: Part 1: Placebo<br>Placebo SC daily | Combination Product: placebo comparator<br>* 40 mg of placebo administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system<br>* Other names: Placebo;|
| Experimental: Part 2: Elamipretide open label<br>Elamepretide 40 mg (0.5 mL) SC daily | Combination Product: elamipretide open label treatment<br>* 40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for up to 144 weeks using the elamipretide delivery system<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six-minute Walk Test (6MWT) | Change From Baseline in Distance Walked (meters) on the Six-Minute Walk Test by Visit | Baseline to 24 weeks | 
| Total Fatigue Score on the on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) | Change from Baseline in Total fatigue score on the on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) by visit. Each individual item score ranges from 1 (none) to 4 (severe). The total fatigue score ranges from 4-16. Lower values represent a better outcome. The total fatigue score is the sum of question 1 through question 4 on the Primary Mitochondrial Myopathy Symptom Assessment. | Baseline to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fatigue During Activities Score on the Primary Mitochondrial Disease Symptom Assessment (PMMSA). | Change from baseline in Fatigue During Activities. Fatigue During Activities is the sum of question 2 (tiredness during activities) and question 4 (muscle weakness during activities.) The four response options are: 1=Not at all, 2=Mild, 3=Moderate, and 4=Severe. Raw scores for each subject range from 2-8. A lower score means a better outcome, with less fatigue. A higher score means a worse outcome, with more fatigue. | Baseline to 24 weeks | 
| Neuro-QoL Fatigue Activities of Daily Living | Change From Baseline in Neuro-QoL Fatigue Activities of Daily Living by Visit. Each individual item score ranges from 1-5. Total raw score for the entire item bank ranges from 19-95. Raw scores will be calibrated using Item Response Theory Model. Lower values represent a better outcome. Individual items will be summed to calculate total scores. | Baseline to 24 weeks | 
| Change From Baseline in the Most Bothersome Symptom Score on the Primary Mitochondrial Myopathy Symptoms Assessment | The item score rangers from 1 (none) to 4 (severe). Lower values represent a better outcome. The most bothersome score is the average of the identified most bothersome symptom of the Primary Mitochondrial Myopathy Symptom Assessment by each subject. | Baseline to 24 weeks | 
| Neuro-QoL Fatigue Short Form Score | Change From Baseline in Neuro-QoL Fatigue - Short Form: Total T-Scores by Visit. The Neuro-QoL Fatigue Short Form is comprised of the sum of the first 8 questions of the Neuro-QoL Item Bank v1.0 - Fatigue. Each question is scored as following: 1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Always. The questions include: I felt exhausted, I felt that I had no energy, I felt fatigued, I was too tired to do my household chores, I was too tired to leave the house, I was frustrated by being too tired to do the things I wanted to do, I felt tired, and I had to limit my social activity because I was tired. T-scores are calculated from the short form scoring table provided by the instrument authors (Neuro-QoL User Manual, 2015). T-score distributions rescale raw scores into standardized scores with a mean of 50 and a standard deviation (SD) of 10. Change from baseline: Negative numbers mean less fatigue, better outcome, positive score means more fatigue, worse outcome. | 24 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PMD, Myopathy, Primary Mitochondrial Disease, MTP-131, elamipretide