Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)

Study Overview
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Brief Summary
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SPIMD-301 is a 48-week, randomized, double-blind, parallel-group, placebo-controlled trial to assess efficacy and safety of single daily subcutaneous (SC) administration of elamipretide as a treatment for subjects with primary mitochondrial myopathy associated with nuclear DNA mutations (nPMD).

Detailed Description
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This 48-week randomized, double-blind, parallel-group, placebo-controlled trial will enroll approximately 130 subjects, consisting of 90 subjects who have nPMD associated with pathogenic mutations of the mitochondrial replisome(replisome-related mutations) for primary analysis and an additional subset of up to 40 subjects who have nPMD associated with other non-replisome-related pathogenic mutations specific to the nuclear DNA. Efficacy and safety of single daily SC doses of elamipretide administered as a treatment for subjects who have primary mitochondrial myopathy associated with nPMD will be determined. Subjects will be randomized 1:1 to 60mg Elamipretide or matching placebo groups.

Official Title
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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 Disease Resulting From Pathogenic Nuclear DNA Mutations (nPMD) NuPower

Conditions
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Mitochondrial Myopathies, Mitochondrial Pathology, Mitochondrial DNA Mutation, Mitochondrial Diseases, Mitochondrial DNA Deletion, Mitochondrial DNA Depletion, Mitochondrial Metabolism Defect, Mitochondrial Complex I Deficiency

Intervention / Treatment
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* Drug: Elamipretide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A subject must meet all of the following inclusion criteria at the Screening and Baseline Visit (unless otherwise specified) to be eligible for inclusion in the SPIMD-301 trial: Willing and able to provide a signed informed consent form (ICF) prior to participation in any trial-related procedures. Agrees and is able to adhere to the trial requirements for the length of the trial, including administration of assigned treatment. Is ≥18 years and ≤ 70 years of age at the time of screening. Diagnosed with nPMD with a predominant clinical manifestation of myopathy, which must include progressive external ophthalmoplegia (PEO) and exercise intolerance and/or skeletal muscle weakness, with genetic confirmation of either: Nuclear DNA mutation of the mitochondrial replisome (replisome-related mutations), which include the following genes: POLG 1/2 TWINKLE (C10ORF2) TYMP DGUOK TK2 RRM2B RNASEH1 SSBP MGME1 DNA2 ANT1 (SLC25A4) SUCLG1 SUCLA2 MPV17 or Other pathogenic mutations specific to nuclear DNA. Women of childbearing potential must agree to use one of the following methods of birth control from the date they sign the ICF until 28 days after the last dose of IMP: Abstinence, when it is in line with the preferred and usual lifestyle of the subject. Subject agrees to use a highly effective method of contraception should they become sexually active. Relationships with male partners who have been surgically sterilized by vasectomy (the vasectomy procedure must have been conducted at least 60 days prior to the Screening Visit). Barrier method (e.g., condom or occlusive cap) with spermicidal foam/gel/film/cream AND either hormonal contraception (oral, implanted, or injectable) or an intrauterine device or system. Note: Non-childbearing potential is defined as surgical sterilization (e.g., bilateral oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as permanent cessation of menstruation for at least 12 consecutive months prior to the Screening Visit). Male subjects with female partners of childbearing potential must be willing to use a highly effective method of contraception from the date they sign the ICF until 28 days after the last dose of IMP. Exclusion Criteria: Is unable to perform the 6MWT, 3TUG, or 5XSST functional tests. The use of a gait assist device is allowed; however, use should remain consistent for the entire duration of the trial. Female subjects who are pregnant, planning to become pregnant, or breastfeeding/lactating. Walks < 150 meters or > 450 meters during the 6MWT (Screening Visit only). The estimated glomerular filtration rate (eGFR) is < 30 mL/min/1.73 m2, using the Modification of Diet in Renal Disease (MDRD) Study equation (Screening Visit only). Has undergone an in-patient hospitalization within 30 days prior to screening or has a planned hospitalization or a surgical procedure during the trial, unless, in the opinion of the Investigator, it is concluded that it will not impact the outcome measurements of the trial. Has clinically significant respiratory disease and/or cardiac disease that would interfere with trial assessments, in the opinion of the Investigator. Has had any prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening. Has history of or current severe neurologic impairment, severe epilepsy, severe ataxia, or severe neuropathy that may interfere with their ability to complete all trial requirements, in the opinion of the Investigator. Active malignancy or any other cancer from which the subject has been disease-free for < 2 years. Localized squamous or non-invasive basal cell skin carcinomas are allowed, if appropriately treated prior to screening. Has had a solid organ transplant. Has been previously diagnosed with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection. Has a history of a systemic eosinophilic illness and/or an eosinophil count >1,000 cells x106/L at the Screening Visit. 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 prior to current trial; or is currently enrolled in a non-interventional clinical trial that, in the opinion of the Investigator, may be potentially confounding to the results of the current trial (e.g., exercise therapy trial). Has received elamipretide (MTP-131) within the past one year of the Screening Visit. Has a history of active substance abuse during the year prior, in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Interventional Model Description: In this 48-week trial, subjects will be randomized (in a ratio of 1:1) to one of two groups: single daily subcutaneous doses of 60mg elamipretide, or, matching placebo, using a central randomization stratified by whether or not subjects have nPMD associated with replisome-related mutations. 130 subjects, consisting of 90 subjects with nPMD associated mutations of the mitochondrial replisome for primary analysis and an additional subset of up to 40 subjects who have nPMD associated with other non-replisome-related pathogenic mutations specific to nuclear DNA. Three periods: Screening (up to 28 days), Treatment (48 Weeks) and Follow-Up Period (4 weeks).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Elamipretide<br>0.75 mL of 80mg/mL solution of elamipretide for a single daily SC dose of 60mg elamipretide | Drug: Elamipretide<br>* 60 mg of elamipretide administered as once daily 0.75 mL subcutaneous injections for 48 weeks<br>* Other names: MTP-131;|
| Placebo Comparator: Placebo<br>0.75 mL of 80mg/mL solution of matching placebo for a single daily SC dose of 60mg | Drug: Placebo<br>* Placebo administered as once daily 0.75 mL subcutaneous injections for 48 weeks<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 (in meters) on the Six-Minute Walk Test by Visit | Baseline, Weeks 12, 24, 36, 48, 52 (End of Trial Visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5 times sit-to-stand test (5XSST) | Change from Baseline in Total time (in seconds) to complete the 5XSST. Participant is directed to stand up straight as quickly as possible 5 times, without stopping in between, keeping arms folded across the chest. An average time is calculated. | Baseline, Weeks 12, 24, 36, 48, 52 (End of Trial Visit) | 
| Triple Timed up-and-go test (3TUG) | Change from Baseline in Total time (in seconds) to complete the 3TUG. Participant is directed to stand up from chair, walk at normal pace to the line on the floor 3 meters away, turn, walk back to the chair at normal pace, sit down again; activity is timed, in seconds. Activity is repeated 3 times consecutively without rest and an average time is calculated. | Baseline, Weeks 12, 24, 36, 48, 52 (End of Trial Visit) | 
| Patient Global Impression of Severity (PGI-S) Scale | Change from Baseline for PGI of Severity (PGI-S) Scale. Patient-reported current health status by week and at end of treatment. PGI-S Scale is a categorical scale and asks the participant to rate the severity of your muscle weakness symptoms today as one of the following categories: None, Mild, Moderate, Severe, or Very Severe. None means better health status, and best outcome, Very severe means worse health status and worse outcome. | Baseline, Weeks 12, 24, 36, 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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primary mitochondrial myopathy (PMM), nuclear DNA mutations n(PMD), exercise intolerance, muscle weakness, mitochondrial dysfunction, POLG, TWINKLE, progressive external ophthalmoplegia, Elamipretide, mitochondrial replisome, replisome related mutations, MTP-131, primary mitochondrial disease (PMD)