Clinical trial NCT05162768: Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
Official 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 Disease Resulting From Pathogenic Nuclear DNA Mutations (nPMD) NuPower
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Mitochondrial Myopathies
Mitochondrial Pathology
Mitochondrial DNA Mutation
Mitochondrial Diseases
Mitochondrial DNA Deletion
Mitochondrial DNA Depletion
Mitochondrial Metabolism Defect
Mitochondrial Complex I Deficiency
Keywords: 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)
Lead sponsor: Stealth BioTherapeutics Inc.
Sponsor class: INDUSTRY
First posted: 2021-12-17
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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).
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Six-minute walk test (6MWT)
timeFrame: Baseline, Weeks 12, 24, 36, 48, 52 (End of Trial Visit)
Secondary outcomes:
measure: 5 times sit-to-stand test (5XSST)
timeFrame: Baseline, Weeks 12, 24, 36, 48, 52 (End of Trial Visit)
measure: Triple Timed up-and-go test (3TUG)
timeFrame: Baseline, Weeks 12, 24, 36, 48, 52 (End of Trial Visit)
measure: Patient Global Impression of Severity (PGI-S) Scale
timeFrame: Baseline, Weeks 12, 24, 36, 48
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: Atlanta
country: United States
facility: Rare Disease Research, LLC
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center College of Physician and Surgeon
state: New York
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh School of Medicine Children's Hospital of Pittsburgh of UPMC Department of Genetics
state: Pennsylvania
city: Houston
country: United States
facility: UT Health,Center for the Treatment of Pediatric Neurodegenerative Disease
state: Texas
city: Sydney
country: Australia
facility: Royal North Shore Hospital Neurology
state: New South Wales
city: Parkdale
country: Australia
facility: Calvary Health Care Bethlehem
state: Victoria
city: Munich
country: Germany
facility: Department of Neurology, University Clinics Munich
state: Bavaria
city: Dresden
country: Germany
facility: Universitaetsklinikum Carl Gustav Carus Dresden Neurologie
city: Tübingen
country: Germany
facility: Univ of Tubingen, Hertie Institute for Clinical Brain Research
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Genomikai Medicina es Ritka Betegsegek
city: Pecs
country: Hungary
facility: University of Pécs, Department of Neurology Klinikai Kozpont - neurologiai Klinika
city: Gussago
country: Italy
facility: University of Brescia, NeMO Clinical Center for Neuromuscular Diseases
state: Brescia
city: Roma
country: Italy
facility: Istituto di Neurologia, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore
state: Lazio
city: Bologna
country: Italy
facility: IRCCS Institute of Neorological Sciences of Bologna Bellaria Hospital
city: Messina
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico G. Martino
city: Milano
country: Italy
facility: Istituto Nazionale Neurologico Carlo Besta
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitario Pisana, Dipartimento Ambientale di Neuroscienze
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
city: Auckland
country: New Zealand
facility: University of Auckland - Auckland City Hospital, Neurology Department
city: Bergen
country: Norway
facility: Helse Bergen HF
city: Barcelona
country: Spain
facility: Hospital de la Sta Creu i Sant Pau
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Hospital la Fe de Valencia
city: Cambridge
country: United Kingdom
facility: University of Cambridge, Department of Clinical Neurosciences
city: London
country: United Kingdom
facility: Queen Square Centre for Neuromuscular Diseases The National Hospital for Neurology and Neurosurgery
city: Newcastle
country: United Kingdom
facility: Newcastle upon Tyne Hospitals Freeman Hospital
Study officials:
References: