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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Mitochondrial Diseases; Mitochondrial Myopathies; Mitochondrial Complex I Deficiency; Mitochondrial Pathology; Mitochondrial DNA Depletion; Mitochondrial DNA Mutation; Mitochondrial DNA Deletion; Mitochondrial Metabolism Defect
• Intervention / Treatment: Drug: Elamipretide; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Rekha Sathyanarayana; Phone Number: 617-762-2579; Email: rekha.sathyanarayana@stealthbt.com

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2065
      • Royal North Shore Hospital Neurology
  • Victoria
    • Parkdale, Victoria, Australia, 3162
      • Calvary Health Care Bethlehem
• Germany
  • Dresden, Germany
    • Universitaetsklinikum Carl Gustav Carus Dresden Neurologie
  • Tübingen, Germany
    • Univ of Tubingen, Hertie Institute for Clinical Brain Research
  • Bavaria
    • Munich, Bavaria, Germany, 80336
      • Department of Neurology, University Clinics Munich
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem Genomikai Medicina es Ritka Betegsegek
  • Pecs, Hungary, 7624
    • University of Pécs, Department of Neurology Klinikai Kozpont - neurologiai Klinika
• Italy
  • Bologna, Italy
    • IRCCS Institute of Neorological Sciences of Bologna Bellaria Hospital
  • Messina, Italy, 98125
    • Azienda Ospedaliero Universitaria Policlinico G. Martino
  • Milano, Italy, 20133
    • Istituto Nazionale Neurologico Carlo Besta
  • Pisa, Italy, 56126
    • Azienda Ospedaliero Universitario Pisana, Dipartimento Ambientale di Neuroscienze
  • Brescia
    • Gussago, Brescia, Italy, 25064
      • University of Brescia, NeMO Clinical Center for Neuromuscular Diseases
  • Lazio
    • Roma, Lazio, Italy, 00168
      • Istituto di Neurologia, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore
• Netherlands
  • Nijmegen, Netherlands, 6525
    • Radboud University Medical Center
• New Zealand
  • Auckland, New Zealand, 1023
    • University of Auckland - Auckland City Hospital, Neurology Department
• Norway
  • Bergen, Norway, 5021
    • Helse Bergen HF
• Spain
  • Barcelona, Spain, 8036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 8025
    • Hospital de la Sta Creu i Sant Pau
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Valencia, Spain, 46026
    • Hospital La Fe de Valencia
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • University of Cambridge, Department of Clinical Neurosciences
  • London, United Kingdom, WC1N 3BG
    • Queen Square Centre for Neuromuscular Diseases The National Hospital for Neurology and Neurosurgery
  • Newcastle, United Kingdom, NE77DN
    • Newcastle upon Tyne Hospitals Freeman Hospital
• United States
  • California
    • San Diego, California, United States, 92093
      • University of California, San Diego
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Rare Disease Research, LLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center College of Physician and Surgeon
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh School of Medicine Children's Hospital of Pittsburgh of UPMC Department of Genetics
  • Texas
    • Houston, Texas, United States, 77030
      • UT Health,Center for the Treatment of Pediatric Neurodegenerative Disease

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

1. Willing and able to provide a signed informed consent form (ICF) prior to participation in any trial-related procedures.
2. Agrees and is able to adhere to the trial requirements for the length of the trial, including administration of assigned treatment.
3. Is ≥18 years and ≤ 70 years of age at the time of screening.

4. 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:

   1. 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
   2. Other pathogenic mutations specific to nuclear DNA.

5. 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:

   1. 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.
   2. 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).
   3. 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).

6. 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:

1. 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.
2. Female subjects who are pregnant, planning to become pregnant, or breastfeeding/lactating.
3. Walks < 150 meters or > 450 meters during the 6MWT (Screening Visit only).
4. 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).
5. 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.
6. Has clinically significant respiratory disease and/or cardiac disease that would interfere with trial assessments, in the opinion of the Investigator.
7. Has had any prior interventional cardiac procedure (e.g., cardiac catheterization, angioplasty/percutaneous coronary intervention, balloon valvuloplasty, etc.) within 3 months prior to screening.
8. 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.
9. 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.
10. Has had a solid organ transplant.
11. Has been previously diagnosed with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection.
12. Has a history of a systemic eosinophilic illness and/or an eosinophil count >1,000 cells x106/L at the Screening Visit.
13. 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).
14. Has received elamipretide (MTP-131) within the past one year of the Screening Visit.
15. Has a history of active substance abuse during the year prior, in the opinion of the Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Elamipretide; 0.75 mL of 80mg/mL solution of elamipretide for a single daily SC dose of 60mg elamipretide	Drug: Elamipretide; 60 mg of elamipretide administered as once daily 0.75 mL subcutaneous injections for 48 weeks; Other Names: MTP-131
Placebo Comparator: Placebo; 0.75 mL of 80mg/mL solution of matching placebo for a single daily SC dose of 60mg	Drug: Placebo; Placebo administered as once daily 0.75 mL subcutaneous injections for 48 weeks

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Stealth BioTherapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2022
• Primary Completion (Estimated): September 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: December 8, 2021
• First Submitted That Met QC Criteria: December 8, 2021
• First Posted (Actual): December 17, 2021

Study Record Updates

• Last Update Posted (Estimated): December 12, 2023
• Last Update Submitted That Met QC Criteria: December 9, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: muscle weakness; MTP-131; exercise intolerance; mitochondrial dysfunction; POLG; primary mitochondrial myopathy (PMM); nuclear DNA mutations n(PMD); TWINKLE; progressive external ophthalmoplegia; Elamipretide; mitochondrial replisome; replisome related mutations; primary mitochondrial disease (PMD)
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Mitochondrial Diseases; Muscular Diseases; Mitochondrial Myopathies
• Other Study ID Numbers: SPIMD-301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No