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

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

Status

Terminated

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03323749

Acronym

MMPOWER-3

Enrollment

218

Registered

2017-10-27

Start date

2017-10-09

Completion date

2020-02-10

Last updated

2022-01-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Primary Mitochondrial Myopathy

Keywords

Myopathy, PMD, Primary Mitochondrial Disease, MTP-131, elamipretide

Brief summary

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

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.

Interventions

COMBINATION_PRODUCTelamipretide

40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system

COMBINATION_PRODUCTplacebo comparator

40 mg of placebo administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system

COMBINATION_PRODUCTelamipretide open label treatment

40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for up to 144 weeks using the elamipretide delivery system

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

16 Years to 80 Years

Healthy volunteers

Inclusion criteria

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: 1. First degree Atrioventricular bock (AV-block) 2. Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type) 3. 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.

Design outcomes

Primary

Measure	Time frame	Description
Six-minute Walk Test (6MWT)	Baseline to 24 weeks	Change From Baseline in Distance Walked (meters) on the Six-Minute Walk Test by Visit
Total Fatigue Score on the on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA)	Baseline to 24 weeks	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.

Secondary

Measure	Time frame	Description
Fatigue During Activities Score on the Primary Mitochondrial Disease Symptom Assessment (PMMSA).	Baseline to 24 weeks	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.
Neuro-QoL Fatigue Activities of Daily Living	Baseline to 24 weeks	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.
Change From Baseline in the Most Bothersome Symptom Score on the Primary Mitochondrial Myopathy Symptoms Assessment	Baseline to 24 weeks	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.
Neuro-QoL Fatigue Short Form Score	24 Weeks	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.

Countries

Canada, Denmark, Germany, Hungary, Italy, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Elamipretide Double-blind Period: 40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for 24 weeks using the elamipretide delivery system, then Open-label Period: 40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for up to 144 weeks using the elamipretide delivery system	109
Placebo Double-Blind Period: Placebo comparator: 40 mg of placebo administered as once daily 0.5 mL subcutaneous injections for 24 weeks, then Open-label Period: Elamipretide: 40 mg of elamipretide administered as once daily 0.5 mL subcutaneous injections for up to 144 weeks using the elamipretide delivery system	109
Total	218

Withdrawals & dropouts

Period	Reason	FG000	FG001
Double-blind Period	Adverse Event	3	1
Double-blind Period	Lost to Follow-up	4	5
Open-Label Period	Adverse Event	3	10
Open-Label Period	Termination of the Clinical Development of Elamipretide in Subjects with PMM	83	88
Open-Label Period	Withdrawal by Subject	7	5

Baseline characteristics

Characteristic	Elamipretide	Total	Placebo
Age, Customized Years, Double-blind	45.5 years STANDARD_DEVIATION 15.72	44.9 years STANDARD_DEVIATION 15.02	44.3 years STANDARD_DEVIATION 14.34
Age, Customized Years, Open-label	45.7 years STANDARD_DEVIATION 15.97	45.3 years STANDARD_DEVIATION 15.05	45.0 years STANDARD_DEVIATION 14.25
Ethnicity (NIH/OMB) Ethnicity Double-Blind Hispanic or Latino	11 Participants	21 Participants	10 Participants
Ethnicity (NIH/OMB) Ethnicity Double-Blind Not Hispanic or Latino	95 Participants	191 Participants	96 Participants
Ethnicity (NIH/OMB) Ethnicity Double-Blind Unknown or Not Reported	3 Participants	6 Participants	3 Participants
Ethnicity (NIH/OMB) Ethnicity Open-Label Hispanic or Latino	8 Participants	18 Participants	10 Participants
Ethnicity (NIH/OMB) Ethnicity Open-Label Not Hispanic or Latino	82 Participants	173 Participants	91 Participants
Ethnicity (NIH/OMB) Ethnicity Open-Label Unknown or Not Reported	3 Participants	5 Participants	2 Participants
Race (NIH/OMB) Double-blind Period American Indian or Alaska Native	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Double-blind Period Asian	2 Participants	7 Participants	5 Participants
Race (NIH/OMB) Double-blind Period Black or African American	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Double-blind Period More than one race	2 Participants	3 Participants	1 Participants
Race (NIH/OMB) Double-blind Period Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Double-blind Period Unknown or Not Reported	0 Participants	3 Participants	3 Participants
Race (NIH/OMB) Double-blind Period White	103 Participants	203 Participants	100 Participants
Race (NIH/OMB) Open-label period American Indian or Alaska Native	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Open-label period Asian	0 Participants	4 Participants	4 Participants
Race (NIH/OMB) Open-label period Black or African American	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Open-label period More than one race	2 Participants	3 Participants	1 Participants
Race (NIH/OMB) Open-label period Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Open-label period Unknown or Not Reported	0 Participants	3 Participants	3 Participants
Race (NIH/OMB) Open-label period White	89 Participants	184 Participants	95 Participants
Sex: Female, Male Double-Blind Sex Female	67 Participants	140 Participants	73 Participants
Sex: Female, Male Double-Blind Sex Male	42 Participants	78 Participants	36 Participants
Sex: Female, Male Open-Enrollment Sex Female	56 Participants	123 Participants	67 Participants
Sex: Female, Male Open-Enrollment Sex Male	37 Participants	73 Participants	36 Participants
Weight (kg) Double-blind	64.81 kg STANDARD_DEVIATION 20.287	66.02 kg STANDARD_DEVIATION 18.865	67.24 kg STANDARD_DEVIATION 17.336
Weight (kg) Open-label	65.66 kg STANDARD_DEVIATION 20.867	66.89 kg STANDARD_DEVIATION 19.033	68.01 kg STANDARD_DEVIATION 17.237

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 109	0 / 109	0 / 93	0 / 103
other Total, other adverse events	107 / 109	83 / 109	88 / 93	102 / 103
serious Total, serious adverse events	5 / 109	3 / 109	12 / 93	9 / 103