Skeletal Muscle Mitochondrial Dysfunction in the Elderly
Conditions
Keywords
Skeletal muscle dysfunction, MTP-131, Bendavia™, elamipretide
Brief summary
This was a Phase 2, randomized, double-blind, placebo-controlled study, enrolling 41 elderly subjects with previous evidence of mitochondrial dysfunction to evaluate whether the administration of MTP-131 (elamipretide) will change either hand skeletal muscle energetics or muscle performance in age-related skeletal muscle mitochondrial dysfunction.
Detailed description
This was a Phase 2, randomized, double-blind, placebo-controlled study, enrolling 41 elderly subjects with previous evidence of mitochondrial dysfunction to evaluate whether the administration of MTP-131 (elamipretide) will change either hand skeletal muscle energetics or muscle performance in age-related skeletal muscle mitochondrial dysfunction. Subjects were randomized 1:1 to receive either elamipretide at 0.25 mg/kg/hr intravenously at a rate of 60 mL/hr for 2 hours, or placebo (lyophilized excipients without elamipretide) intravenously at a rate of 60 mL/hr for 2 hours. Each treatment group went through three distinct periods: Screening (up to 28 days), Treatment (1day), and Observation (7 days).
Interventions
DRUGElamipretide
Elamipretide 0.25 mg/kg/hour administered as an intravenous infusion at the rate of 60 mL/hour for 2 hours
DRUGPlacebo
Placebo administered as intravenous infusion at a rate of 60 mL/hour for 2 hours
Sponsors
Stealth BioTherapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Are male and female adults aged ≥60 and ≤85 years 2. Female subjects must be post-menopausal 3. Have in vivo phosphorus-31 (31P) Magnetic Resonance Spectroscopy (MRS) and (Optical Spectra Scan (OPS) determined maximum adenosine triphosphate synthetic rate (ATPmax) \< 0.70 milliMol/second (mM/sec) 4. Have in vivo 31P MRS and OPS determined P/O (Phosphate/Oxygen ratio) \< 1.9 5. Are ambulatory and able to perform activities of daily living without assistance 6. Had sufficient venous access for study drug administration and clinical testing. 7. Could speak and read English fluently. 8. Provided informed consent.
Exclusion criteria
1. Had significant disease(s) or condition(s) which, in the opinion of the Investigator, may have put the subject at risk because of their participation in the study or may have influenced either the results of the study or the subject's ability to participate in the study. 2. Had a history of rhabdomyolysis. 3. Had been hospitalized within 3 months prior to Screening for major atherosclerotic events (e.g., myocardial infarction, target-vessel revascularization, coronary bypass surgery or stroke) or other major medical condition (as deemed by the Primary Investigator). 4. Had any metal implants that could not be removed from the body that in the opinion of the Investigator were a contra-indication for undergoing the MRS procedure or any other protocol-related procedure. 5. Had an implanted cardiac pacemaker or other implanted cardiac device. 6. Had a serum sodium level \<136 milliequivalents per litre (mEq/L) at Screening or Pre-infusion. 7. Had a hemoglobin level \<12 g/dL at Screening or Pre-infusion. 8. Had chronic, uncontrolled hypertension as judged by the Investigator (e.g., Baseline systolic blood pressure \[SBP\] \>140 mm Hg, diastolic blood pressure \[DBP\] \> 90 mm Hg) or a SBP \>150 mm Hg or DBP \>95 mm Hg at the time of Screening or Baseline (if the initial blood pressure \[BP\] reading was above these values, the reading may have been repeated one time within 20 minutes of the initial reading). 9. Had a body mass index (BMI) of \<16 or \>35 kg/m2. 10. Had a creatinine clearance \<45 mL/min as calculated by the Cockcroft Gault equation. 11. Had a 12-lead electrocardiogram (ECG) demonstrating severe bradycardia (heart rate \< 40 bpm) or average corrected QC interval (QTc) \>450 ms for males and \> 470 ms for females, and in the opinion of the Investigator was clinically significant. (If on the initial ECG, QTc exceeded 450 ms for males or 470 ms for females, the ECG was to be repeated 2 more times and the average of the 3 QTc values was to be used to determine the subject's eligibility). 12. Had a neurologic disorder that in the opinion of the Investigator was a contra-indication for enrollment into the study. 13. Had any symptoms consistent with or a current diagnosis of peripheral neuropathy, such as numbness, tingling, pain, or altered sensation of hands or feet. 14. Had an active, systemic autoimmune disease other than autoimmune thyroid disease (e.g., diabetes, lupus, rheumatoid arthritis) that currently required treatment or was likely to require treatment during the study. 15. Subject's right hand had a history of mobility impairment, fractures, arthritis, hand surgery, muscle disease or other injury that may interfere with any study procedure. 16. Had any symptoms consistent with or a current diagnosis of claustrophobia. 17. Had a history of cancer, unless subject had documentation of completed curative treatment. 18. Had a history of or risk factors (e.g., significant family history, concomitant medical condition) for deep vein thrombosis or pulmonary embolism. 19. Had a history of serious mental illness as judged by the Investigator. 20. Had a body temperature \> 37.5°C at the time of planned dosing. 21. Subjects who in the opinion of the Investigator abused alcohol or drugs. 22. Had donated or received blood or blood products within the past 30 days. 23. Investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family was defined as a spouse, parent, child, or sibling, whether biological or legally adopted. 24. Sponsor employees and/or their immediate families. Immediate family was defined as a spouse, parent, child, or sibling, whether biological or legally adopted. 25. Were currently enrolled in a clinical study involving an investigational product or non-approved use of a drug or device or concurrently enrolled in any other type of medical research judged to be scientifically or medically incompatible with this study. 26. Had participated, within the last 30 days, in a clinical study involving an investigational product. If the previous investigational product had a long half-life, 3 months or 5 half-lives (whichever was longer) should have passed. 27. Had previously been randomized into any study investigating elamipretide or been exposed to elamipretide for any reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in ATPmax (Maximal ATP Synthetic Rate) | From Baseline, Day 1 Hour 2 (2 hours after the start of infusion, or end of infusion) and Day 7 | Maximal ATP synthetic rate (phosphorylation capacity per unit muscle volume) as determined by a muscle fatigue test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Phosphate/Oxygen (P/O) Ratio | From Baseline, Day 1 Hour 2 (2 hours after the start of infusion, or end of infusion) and Day 7 | As a measure of mitochondrial hand skeletal muscle energetics, mitochondrial coupling, or Phosphate/Oxygen ratio (P/O) was assessed at Baseline, Day 1 Hour 2, and Day 7. |
| Mean Change From Baseline in Nicotine Adenine Dinucleotide (NAD) | From Baseline, Day 1 Hour 2 (2 hours after the start of infusion, or end of infusion) and Day 7 | — |
| Mean Change From Baseline in Muscle Force-Time-Integral (FTI) | From Baseline to Day 1 Hour 2, Day 3, and Day 7 | Muscle Force-Time-Integral was measured as mean change from baseline at Day 1 Hour 2, Day 3, and Day 7. |
Countries
United States
Participant flow
Pre-assignment details
2 subjects discontinued prematurely as per Investigator's discretion. These 2 subjects (Subject 001019 \[Elamipretide group\] and Subject 001063 \[Placebo group\]) were discontinued after randomization but prior to receiving study treatment; both were not treated due to their pre-infusion sodium levels meeting Exclusion Criteria 6.
Participants by arm
| Arm | Count |
|---|---|
| MTP-131 (Bendavia™) MTP-131 (Bendavia™) administered as an intravenous infusion of 0.25 mg/kg/hr at a rate of 60 mL/hr for 2 hours. | 19 |
| Placebo Placebo administered as intravenous infusion at a rate of 60 mL/hour for 2 hours | 20 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 |
Baseline characteristics
| Characteristic | MTP-131 (Bendavia™) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 67.9 years STANDARD_DEVIATION 3.35 | 69.0 years STANDARD_DEVIATION 3.96 | 68.5 years STANDARD_DEVIATION 3.67 |
| Body Mass index | 26.5 kg/m² STANDARD_DEVIATION 4.27 | 26.1 kg/m² STANDARD_DEVIATION 2.82 | 26.3 kg/m² STANDARD_DEVIATION 3.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 19 Participants | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 20 Participants | 38 Participants |
| Region of Enrollment United States | 19 participants | 20 participants | 39 participants |
| Sex: Female, Male Female | 11 Participants | 7 Participants | 18 Participants |
| Sex: Female, Male Male | 8 Participants | 13 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 20 |
| other Total, other adverse events | 3 / 19 | 2 / 20 |
| serious Total, serious adverse events | 0 / 19 | 0 / 20 |
Outcome results
Primary
Change From Baseline in ATPmax (Maximal ATP Synthetic Rate)
Maximal ATP synthetic rate (phosphorylation capacity per unit muscle volume) as determined by a muscle fatigue test.
Time frame: From Baseline, Day 1 Hour 2 (2 hours after the start of infusion, or end of infusion) and Day 7
Population: All participants for whom Maximal ATP synthetic rate was measured at baseline and Day 1 Hour 2, and Day 7
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MTP-131 (Bendavia™) | Change From Baseline in ATPmax (Maximal ATP Synthetic Rate) | Day 1 Hour 2 | 0.17 mM/sec | Standard Deviation 0.196 |
| MTP-131 (Bendavia™) | Change From Baseline in ATPmax (Maximal ATP Synthetic Rate) | Day 7 | 0.09 mM/sec | Standard Deviation 0.142 |
| Placebo | Change From Baseline in ATPmax (Maximal ATP Synthetic Rate) | Day 1 Hour 2 | 0.12 mM/sec | Standard Deviation 0.244 |
| Placebo | Change From Baseline in ATPmax (Maximal ATP Synthetic Rate) | Day 7 | 0.06 mM/sec | Standard Deviation 0.172 |
Secondary
Mean Change From Baseline in Muscle Force-Time-Integral (FTI)
Muscle Force-Time-Integral was measured as mean change from baseline at Day 1 Hour 2, Day 3, and Day 7.
Time frame: From Baseline to Day 1 Hour 2, Day 3, and Day 7
Population: All participants for whom Muscle Force-Time-Integral (FTI) was measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MTP-131 (Bendavia™) | Mean Change From Baseline in Muscle Force-Time-Integral (FTI) | Day 1 Hour 2 | 0.43 Newton/second | Standard Deviation 0.882 |
| MTP-131 (Bendavia™) | Mean Change From Baseline in Muscle Force-Time-Integral (FTI) | Day 3 | 0.46 Newton/second | Standard Deviation 1.036 |
| MTP-131 (Bendavia™) | Mean Change From Baseline in Muscle Force-Time-Integral (FTI) | Day 7 | 0.83 Newton/second | Standard Deviation 1.485 |
| Placebo | Mean Change From Baseline in Muscle Force-Time-Integral (FTI) | Day 1 Hour 2 | 0.10 Newton/second | Standard Deviation 0.728 |
| Placebo | Mean Change From Baseline in Muscle Force-Time-Integral (FTI) | Day 3 | 0.24 Newton/second | Standard Deviation 0.948 |
| Placebo | Mean Change From Baseline in Muscle Force-Time-Integral (FTI) | Day 7 | 0.44 Newton/second | Standard Deviation 1.114 |
Secondary
Mean Change From Baseline in Nicotine Adenine Dinucleotide (NAD)
Time frame: From Baseline, Day 1 Hour 2 (2 hours after the start of infusion, or end of infusion) and Day 7
Population: All participants for whom Nicotine Adenine Dinucleotide (NAD) was measured.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MTP-131 (Bendavia™) | Mean Change From Baseline in Nicotine Adenine Dinucleotide (NAD) | Day 1 Hour 2 | 0.04 millimolar | Standard Deviation 0.169 |
| MTP-131 (Bendavia™) | Mean Change From Baseline in Nicotine Adenine Dinucleotide (NAD) | Day 7 | 0.11 millimolar | Standard Deviation 0.215 |
| Placebo | Mean Change From Baseline in Nicotine Adenine Dinucleotide (NAD) | Day 7 | 0.09 millimolar | Standard Deviation 0.263 |
| Placebo | Mean Change From Baseline in Nicotine Adenine Dinucleotide (NAD) | Day 1 Hour 2 | 0.01 millimolar | Standard Deviation 0.213 |
Secondary
Mean Change From Baseline in Phosphate/Oxygen (P/O) Ratio
As a measure of mitochondrial hand skeletal muscle energetics, mitochondrial coupling, or Phosphate/Oxygen ratio (P/O) was assessed at Baseline, Day 1 Hour 2, and Day 7.
Time frame: From Baseline, Day 1 Hour 2 (2 hours after the start of infusion, or end of infusion) and Day 7
Population: All participants for whom Phosphate/Oxygen (P/O) ratio was measured at baseline and Day 1 Hour 2, and Day 7
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MTP-131 (Bendavia™) | Mean Change From Baseline in Phosphate/Oxygen (P/O) Ratio | Day 1 Hour 2 | 0.25 ratio of phosphate to oxygen | Standard Deviation 0.679 |
| MTP-131 (Bendavia™) | Mean Change From Baseline in Phosphate/Oxygen (P/O) Ratio | Day 7 | 0.32 ratio of phosphate to oxygen | Standard Deviation 0.473 |
| Placebo | Mean Change From Baseline in Phosphate/Oxygen (P/O) Ratio | Day 1 Hour 2 | 0.26 ratio of phosphate to oxygen | Standard Deviation 0.693 |
| Placebo | Mean Change From Baseline in Phosphate/Oxygen (P/O) Ratio | Day 7 | 0.51 ratio of phosphate to oxygen | Standard Deviation 0.788 |