Mitochondrial Myopathy
Conditions
Keywords
Mitochondrial Myopathy, Primary Mitochondrial Disease, Bendavia™, elamipretide
Brief summary
Phase 1/2, multi-center, randomized, double-blind, multiple ascending dose, placebo-controlled study that enrolled 36 subjects with mitochondrial myopathy associated with genetically confirmed mitochondrial disease to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of MTP-131 in this patient population.
Detailed description
This multi-center, randomized, double-blind, placebo-controlled study enrolled 36 subjects into 3 cohorts of 12 subjects each to evaluate treatment with 3 ascending doses of intravenous elamipretide (0.01, 0.10, and 0.25 mg/kg/hr infused for 2 hours). After each cohort, a Safety Monitoring Board (SMB) determined if dose escalation to the next higher dose of elamipretide was warranted. Each cohort went through 3 distinct periods: Screening, Treatment, and Follow-up. The Screening Period started with informed consent and may have lasted up to 40 days. During this period, screening procedures to determine subject eligibility for the study occurred, including confirmation of disease, which incorporated a committee review of the investigator-submitted diagnosis and genetic results. The Treatment Period began on Day 1 (Visit 2) and lasted for 5 days (until Day 5 \[Visit 6\]). Within each cohort, 9 subjects were randomized to active drug and 3 subjects were randomized to placebo on Day 1 and subjects received treatment once a day for 5 consecutive days. Safety, tolerability, and efficacy measures were performed at pre-specified times. The Follow-up Period began at the time of discharge on Day 5. Subjects returned to the study center for the Follow-up Visit on Day 7 (+1 day).
Interventions
DRUGelamipretide (low dose)
elamipretide (0.01 mg/kg/hr) administered as single day intravenous infusion over 2 hours for 5 days
DRUGelamipretide (intermediate dose)
elamipretide (0.10 mg/kg/hr) administered as single day intravenous infusion over 2 hours for 5 days
DRUGelamipretide (high dose)
elamipretide (0.25 mg/kg/hr) administered as single day intravenous infusion over 2 hours for 5 days
DRUGPlacebo
placebo (at each dose cohort) administered as single day intravenous infusion over 2 hours for 5 days
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
16 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of mitochondrial disease believed to impair the mitochondrial respiratory chain. * Eligibility requires prior genetic confirmation of mitochondrial disease. * Diagnosis of mitochondrial myopathy judged by the Investigators to be due to existing mitochondrial disease. * Must be able to complete a Screening Visit 6MWT. * Body mass index (BMI) score \>15.0 and \<35.0 kg/m2 at Screening Visit. * Women of childbearing potential must agree to use birth control as specified in the protocol from the date they sign the ICF until two months after the last dose of study drug.
Exclusion criteria
* 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 study requirements. * Had any exclusionary Newcastle Mitochondrial Disease Adult Scale (NMDAS) scores at Screening Visit. * Hospitalized (admitted as in-patient) within 1 month prior to the Baseline Visit. * A history of type 1 diabetes mellitus (T1DM). * Uncontrolled Type 1 (T1DM) or Type 2 diabetes mellitus (T2DM), in the opinion of the investigator. * A creatinine clearance \<45 mL/min as calculated by the Cockcroft Gault equation. * Requires pacemaker, defibrillator, or has undergone cardiac surgery within 2 years of Screening Visit. * QTc elongation defined as a QTc \>450 msec in male subjects and \>480 msec in female subjects. * Uncontrolled hypertension (\>160 mmHg systolic or \>100 mmHg diastolic) at Screening Visit. * History of rhabdomyolysis defined as an acute rise in the serum creatine phosphokinase (CPK) value that, in the opinion of the investigator, caused clinically significant symptoms. * Serum sodium more than 5 meq/L below the reference lower limit of normal at Screening Visit. * Participated in another interventional clinical trial within 3 months of the screening visit or is currently enrolled in a non-interventional clinical trial judged by the Investigator to be incompatible with the current trial. * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Distance Walked (Meters) on the 6-minute Walk Test (6MWT) | Assessed at Baseline, Day 5 (end-of-treatment visit) | Change in distance walked as measured by meters on the 6-minute walk test from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Maximum Oxygen Uptake (ml/kg/Min) | Baseline, Day 5 | Change in maximum oxygen uptake as measured by mL/kg/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Ventilatory Efficiency (VE/VCO2 Slope) | Baseline, Day 5 | Change in ventilatory efficiency as measured by the VE/VCO2 slope from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Aerobic Efficiency (ΔO2 Consumption/Δ Work Ratio) | Baseline, Day 5 | Change in aerobic efficiency as measured by ΔO2 consumption/Δ work ratio from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Oxygen Utilization (ΔVO2/ΔlogVE Ratio) | Baseline, Day 5 | Change in oxygen utilization as measured by ΔVO2/ΔlogVE ratio from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Pre-exercise Lactate Levels (mg/dL) | Baseline, Day 5 | Change in pre-exercise lactate levels as measured by mg/dL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Post-exercise Lactate Levels (mg/dL) | Baseline, Day 5 | Change in post-exercise lactate levels as measured by mg/dL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Peak Respiratory Exchange Ratio (VCO2/VO2) | Baseline, Day 5 | Change in peak respiratory exchange ratio as measured by VCO2/VO2 from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Peak Respiratory Rate (Breaths/Min) | Baseline, Day 5 | Change in peak respiratory rate as measured by breaths/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Peak Ventilation (L/Min) | Baseline, Day 5 | Change in peak ventilation as measured by L/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Peak Heart Rate (Beats/Min) | Baseline, Day 5 | Change in peak heart rate as measured by beats per minute from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Peak Oxygen Saturation (% O2-saturated Hemoglobin) | Baseline, Day 5 | Change in peak oxygen saturation as measured by percentage of O2-saturated hemoglobin from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Peak Systolic Blood Pressure (mmHg) | Baseline, Day 5 | Change in peak systolic blood pressure as measured by mmHg from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Peak Diastolic Blood Pressure (mmHg) | Baseline, Day 5 | Change in peak diastolic blood pressure as measured by mmHg from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Oxygen Uptake Kinetics (Mean Response Time as Measured by Seconds) | Baseline, Day 5 | Change in oxygen uptake kinetics (mean response time) as measured by seconds from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in VO2 Anaerobic Threshold (mL) | Baseline, Day 5 | Change in VO2 anaerobic threshold as measured by mL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Watts | Baseline, Day 5 | Change in watts from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Temperature (°C) | Baseline, Day 5 | Change in temperature as measured by units of Celsius from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in ECG-PR Interval (Msec) | Baseline, Day 5 | Change in PR interval as measured by ECG in milliseconds from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in ECG-QRS Complex (Msec) | Baseline, Day 5 | Change in QRS complex as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in ECG-QT Interval (Msec) | Baseline, Day 5 | Change in QT interval as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in ECG-QTc Interval (Msec) | Baseline, Day 5 | Change in QTc interval as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Number of Participants Who Had Suicide Ideation, Suicidal Behavior, or Non-suicidal Self-injurious Behavior Post-screening. | Days 1-5 and Day 7. | Number of participants with suicide ideation, suicidal behavior, or non-suicidal self-injurious behavior post-screening as measured on Days 1-5, and Day 7 on the Columbia Suicide Severity Rating Scale (CSSRS). A yes/no binary response is utilized in the following ten categories: 1 - Wish to be Dead; 2 - Non-specific Active Suicidal Thoughts; 3 - Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; 4 - Active Suicidal Ideation with Some Intent to Act, without Specific Plan; 5 - Active Suicidal Ideation with Specific Plan and Intent; 6 - Preparatory Acts or Behavior; 7 - Aborted Attempt; 8 - Interrupted Attempt; Category 9 - Actual Attempt (non-fatal); 10 - Completed Suicide. A yes/no binary response is also utilized in assessing self-injurious behavior without suicidal intent. A lower score means a better outcome whereas a higher score means a worse outcome. |
| Change in Creatine Phosphokinase (IU/L) | Baseline, Day 5 | Change in Creatine Phosphokinase as measured by IU/L from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Alanine Aminotransferase (ALT) (U/L) | Baseline, Day 5 | Change in Alanine aminotransferase (ALT) as measured by (U/L) from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Aspartate Aminotransferase (AST) (U/L) | Baseline, Day 5 | Change in aspartate aminotransferase (AST) as measured by U/L from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Eosinophils (10^9 Cells/L) | Baseline, Day 5 | Change in eosinophils as measured by (10\^9 cells/L) from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
| Change in Peak Borg Dyspnea | Baseline, Day 5 | Change in peak Borg dyspnea as measured by 0-10 with 0 meaning no breathlessness and 10 meaning maximal breathlessness from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit). |
Countries
United States
Participant flow
Recruitment details
Study Centers: Akron Children's Hospital; Massachusetts General Hospital; University of Pittsburgh School of Medicine; University of California, San Diego
Participants by arm
| Arm | Count |
|---|---|
| Low Dose MTP-131: MTP-131 (low dose) administered as single day intravenous infusion over 2 hours for 5 days | 9 |
| Intermediate Dose MTP-131: MTP-131 (intermediate dose) administered as single day intravenous infusion over 2 hours for 5 days | 9 |
| High Dose MTP-131: MTP-131 (high dose) administered as single day intravenous infusion over 2 hours for 5 days | 9 |
| Placebo Placebo: Placebo Comparator (at each dose cohort) administered as single day intravenous infusion over 2 hours for 5 days | 9 |
| Total | 36 |
Baseline characteristics
| Characteristic | Low Dose | Intermediate Dose | High Dose | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 40.8 years STANDARD_DEVIATION 11.32 | 45.0 years STANDARD_DEVIATION 14.09 | 42.3 years STANDARD_DEVIATION 16.84 | 41.9 years STANDARD_DEVIATION 15.83 | 42.5 years STANDARD_DEVIATION 14.12 |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 6 Participants | 9 Participants | 30 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 6 Participants |
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 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 7 / 9 | 7 / 9 | 5 / 9 | 5 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Change in Distance Walked (Meters) on the 6-minute Walk Test (6MWT)
Change in distance walked as measured by meters on the 6-minute walk test from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Assessed at Baseline, Day 5 (end-of-treatment visit)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Low Dose | Change in Distance Walked (Meters) on the 6-minute Walk Test (6MWT) | 13.5 meters |
| Intermediate Dose | Change in Distance Walked (Meters) on the 6-minute Walk Test (6MWT) | 36.5 meters |
| High Dose | Change in Distance Walked (Meters) on the 6-minute Walk Test (6MWT) | 64.5 meters |
| Placebo | Change in Distance Walked (Meters) on the 6-minute Walk Test (6MWT) | 20.4 meters |
Secondary
Change in Aerobic Efficiency (ΔO2 Consumption/Δ Work Ratio)
Change in aerobic efficiency as measured by ΔO2 consumption/Δ work ratio from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: All participants for whom aerobic efficiency measurements were recorded at Baseline and Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Aerobic Efficiency (ΔO2 Consumption/Δ Work Ratio) | -0.234 ΔO2 consumption/Δwork ratio | Standard Deviation 4.3414 |
| Intermediate Dose | Change in Aerobic Efficiency (ΔO2 Consumption/Δ Work Ratio) | 0.643 ΔO2 consumption/Δwork ratio | Standard Deviation 2.7507 |
| High Dose | Change in Aerobic Efficiency (ΔO2 Consumption/Δ Work Ratio) | -0.214 ΔO2 consumption/Δwork ratio | Standard Deviation 1.9727 |
| Placebo | Change in Aerobic Efficiency (ΔO2 Consumption/Δ Work Ratio) | 0.738 ΔO2 consumption/Δwork ratio | Standard Deviation 3.5959 |
Secondary
Change in Alanine Aminotransferase (ALT) (U/L)
Change in Alanine aminotransferase (ALT) as measured by (U/L) from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom Alanine aminotransferase was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Alanine Aminotransferase (ALT) (U/L) | 19.3 U/L | Standard Deviation 42.24 |
| Intermediate Dose | Change in Alanine Aminotransferase (ALT) (U/L) | -3.0 U/L | Standard Deviation 4.92 |
| High Dose | Change in Alanine Aminotransferase (ALT) (U/L) | -5.3 U/L | Standard Deviation 3.28 |
| Placebo | Change in Alanine Aminotransferase (ALT) (U/L) | 1.1 U/L | Standard Deviation 5.8 |
Secondary
Change in Aspartate Aminotransferase (AST) (U/L)
Change in aspartate aminotransferase (AST) as measured by U/L from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom aspartate aminotransferase was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Aspartate Aminotransferase (AST) (U/L) | 5.6 U/L | Standard Deviation 9.93 |
| Intermediate Dose | Change in Aspartate Aminotransferase (AST) (U/L) | -2.2 U/L | Standard Deviation 10.38 |
| High Dose | Change in Aspartate Aminotransferase (AST) (U/L) | -12.6 U/L | Standard Deviation 18.08 |
| Placebo | Change in Aspartate Aminotransferase (AST) (U/L) | -4.4 U/L | Standard Deviation 13.07 |
Secondary
Change in Creatine Phosphokinase (IU/L)
Change in Creatine Phosphokinase as measured by IU/L from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom creatine phosphokinase was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Creatine Phosphokinase (IU/L) | -24.8 IU/L | Standard Deviation 25.1 |
| Intermediate Dose | Change in Creatine Phosphokinase (IU/L) | -161.7 IU/L | Standard Deviation 176.49 |
| High Dose | Change in Creatine Phosphokinase (IU/L) | -101.2 IU/L | Standard Deviation 149.07 |
| Placebo | Change in Creatine Phosphokinase (IU/L) | -154.9 IU/L | Standard Deviation 232.99 |
Secondary
Change in ECG-PR Interval (Msec)
Change in PR interval as measured by ECG in milliseconds from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom PR interval was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in ECG-PR Interval (Msec) | -3.2 msec | Standard Deviation 7.77 |
| Intermediate Dose | Change in ECG-PR Interval (Msec) | 8.3 msec | Standard Deviation 7.05 |
| High Dose | Change in ECG-PR Interval (Msec) | 9.1 msec | Standard Deviation 9.55 |
| Placebo | Change in ECG-PR Interval (Msec) | -1.6 msec | Standard Deviation 15.61 |
Secondary
Change in ECG-QRS Complex (Msec)
Change in QRS complex as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom QRS complex was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in ECG-QRS Complex (Msec) | 1.2 msec | Standard Deviation 7.14 |
| Intermediate Dose | Change in ECG-QRS Complex (Msec) | 2.3 msec | Standard Deviation 6.56 |
| High Dose | Change in ECG-QRS Complex (Msec) | -2.2 msec | Standard Deviation 8.86 |
| Placebo | Change in ECG-QRS Complex (Msec) | 0.8 msec | Standard Deviation 5.78 |
Secondary
Change in ECG-QTc Interval (Msec)
Change in QTc interval as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom QTc interval was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in ECG-QTc Interval (Msec) | 3.4 msec | Standard Deviation 20.17 |
| Intermediate Dose | Change in ECG-QTc Interval (Msec) | 1.3 msec | Standard Deviation 20.24 |
| High Dose | Change in ECG-QTc Interval (Msec) | -23.2 msec | Standard Deviation 77.53 |
| Placebo | Change in ECG-QTc Interval (Msec) | 6.7 msec | Standard Deviation 17.28 |
Secondary
Change in ECG-QT Interval (Msec)
Change in QT interval as measured by ECG in msec from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom QT interval was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in ECG-QT Interval (Msec) | -6.0 msec | Standard Deviation 30.53 |
| Intermediate Dose | Change in ECG-QT Interval (Msec) | -4.8 msec | Standard Deviation 12.94 |
| High Dose | Change in ECG-QT Interval (Msec) | -16.7 msec | Standard Deviation 81.02 |
| Placebo | Change in ECG-QT Interval (Msec) | -1.3 msec | Standard Deviation 18.49 |
Secondary
Change in Eosinophils (10^9 Cells/L)
Change in eosinophils as measured by (10\^9 cells/L) from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom eosinophils was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Eosinophils (10^9 Cells/L) | 0.06 10^9 cells/L | Standard Deviation 0.073 |
| Intermediate Dose | Change in Eosinophils (10^9 Cells/L) | 0.08 10^9 cells/L | Standard Deviation 0.097 |
| High Dose | Change in Eosinophils (10^9 Cells/L) | -0.01 10^9 cells/L | Standard Deviation 0.064 |
| Placebo | Change in Eosinophils (10^9 Cells/L) | 0.04 10^9 cells/L | Standard Deviation 0.088 |
Secondary
Change in Maximum Oxygen Uptake (ml/kg/Min)
Change in maximum oxygen uptake as measured by mL/kg/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: All participants for whom maximum oxygen uptake was measured at baseline and Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Maximum Oxygen Uptake (ml/kg/Min) | 0.35 ml/kg/min | Standard Deviation 2.617 |
| Intermediate Dose | Change in Maximum Oxygen Uptake (ml/kg/Min) | 2.36 ml/kg/min | Standard Deviation 2.714 |
| High Dose | Change in Maximum Oxygen Uptake (ml/kg/Min) | 0.64 ml/kg/min | Standard Deviation 3.121 |
| Placebo | Change in Maximum Oxygen Uptake (ml/kg/Min) | 2.14 ml/kg/min | Standard Deviation 3.137 |
Secondary
Change in Oxygen Uptake Kinetics (Mean Response Time as Measured by Seconds)
Change in oxygen uptake kinetics (mean response time) as measured by seconds from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom oxygen uptake kinetics was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Oxygen Uptake Kinetics (Mean Response Time as Measured by Seconds) | 6.40 seconds | Standard Deviation 11.402 |
| Intermediate Dose | Change in Oxygen Uptake Kinetics (Mean Response Time as Measured by Seconds) | -2.49 seconds | Standard Deviation 26.83 |
| High Dose | Change in Oxygen Uptake Kinetics (Mean Response Time as Measured by Seconds) | -9.75 seconds | Standard Deviation 26.288 |
| Placebo | Change in Oxygen Uptake Kinetics (Mean Response Time as Measured by Seconds) | -7.47 seconds | Standard Deviation 14.357 |
Secondary
Change in Oxygen Utilization (ΔVO2/ΔlogVE Ratio)
Change in oxygen utilization as measured by ΔVO2/ΔlogVE ratio from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: All participants for whom oxygen utilization measurements were recorded at Baseline and Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Oxygen Utilization (ΔVO2/ΔlogVE Ratio) | -118.87 ΔVO2/ΔlogVE ratio | Standard Deviation 229.105 |
| Intermediate Dose | Change in Oxygen Utilization (ΔVO2/ΔlogVE Ratio) | 184.99 ΔVO2/ΔlogVE ratio | Standard Deviation 410.093 |
| High Dose | Change in Oxygen Utilization (ΔVO2/ΔlogVE Ratio) | 90.13 ΔVO2/ΔlogVE ratio | Standard Deviation 116.281 |
| Placebo | Change in Oxygen Utilization (ΔVO2/ΔlogVE Ratio) | 166.50 ΔVO2/ΔlogVE ratio | Standard Deviation 479.145 |
Secondary
Change in Peak Borg Dyspnea
Change in peak Borg dyspnea as measured by 0-10 with 0 meaning no breathlessness and 10 meaning maximal breathlessness from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom peak Borg dyspnea was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Peak Borg Dyspnea | -2.00 Units on a scale | Standard Deviation 2 |
| Intermediate Dose | Change in Peak Borg Dyspnea | -2.2 Units on a scale | Standard Deviation 2.23 |
| High Dose | Change in Peak Borg Dyspnea | -1.4 Units on a scale | Standard Deviation 1.3 |
| Placebo | Change in Peak Borg Dyspnea | -0.4 Units on a scale | Standard Deviation 1.7 |
Secondary
Change in Peak Diastolic Blood Pressure (mmHg)
Change in peak diastolic blood pressure as measured by mmHg from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom peak diastolic blood pressure was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Peak Diastolic Blood Pressure (mmHg) | 0.6 mmHg | Standard Deviation 12.67 |
| Intermediate Dose | Change in Peak Diastolic Blood Pressure (mmHg) | -1.4 mmHg | Standard Deviation 11.13 |
| High Dose | Change in Peak Diastolic Blood Pressure (mmHg) | -2.5 mmHg | Standard Deviation 9.07 |
| Placebo | Change in Peak Diastolic Blood Pressure (mmHg) | -6.6 mmHg | Standard Deviation 12.74 |
Secondary
Change in Peak Heart Rate (Beats/Min)
Change in peak heart rate as measured by beats per minute from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom peak heart rate was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Peak Heart Rate (Beats/Min) | 10.1 beats/min | Standard Deviation 11.15 |
| Intermediate Dose | Change in Peak Heart Rate (Beats/Min) | 16.7 beats/min | Standard Deviation 13.02 |
| High Dose | Change in Peak Heart Rate (Beats/Min) | 4.5 beats/min | Standard Deviation 9.58 |
| Placebo | Change in Peak Heart Rate (Beats/Min) | 3.8 beats/min | Standard Deviation 7.85 |
Secondary
Change in Peak Oxygen Saturation (% O2-saturated Hemoglobin)
Change in peak oxygen saturation as measured by percentage of O2-saturated hemoglobin from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom peak oxygen saturation was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Peak Oxygen Saturation (% O2-saturated Hemoglobin) | 0.0 percentage of O2-saturated hemoglobin | Standard Deviation 1.69 |
| Intermediate Dose | Change in Peak Oxygen Saturation (% O2-saturated Hemoglobin) | 0.1 percentage of O2-saturated hemoglobin | Standard Deviation 1.07 |
| High Dose | Change in Peak Oxygen Saturation (% O2-saturated Hemoglobin) | 0.6 percentage of O2-saturated hemoglobin | Standard Deviation 0.74 |
| Placebo | Change in Peak Oxygen Saturation (% O2-saturated Hemoglobin) | 0.3 percentage of O2-saturated hemoglobin | Standard Deviation 1.6 |
Secondary
Change in Peak Respiratory Exchange Ratio (VCO2/VO2)
Change in peak respiratory exchange ratio as measured by VCO2/VO2 from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom peak respiratory exchange ratio was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Peak Respiratory Exchange Ratio (VCO2/VO2) | 0.109 VCO2/VO2 ratio | Standard Deviation 0.0741 |
| Intermediate Dose | Change in Peak Respiratory Exchange Ratio (VCO2/VO2) | 0.114 VCO2/VO2 ratio | Standard Deviation 0.1803 |
| High Dose | Change in Peak Respiratory Exchange Ratio (VCO2/VO2) | 0.010 VCO2/VO2 ratio | Standard Deviation 0.0561 |
| Placebo | Change in Peak Respiratory Exchange Ratio (VCO2/VO2) | 0.133 VCO2/VO2 ratio | Standard Deviation 0.1297 |
Secondary
Change in Peak Respiratory Rate (Breaths/Min)
Change in peak respiratory rate as measured by breaths/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom peak respiratory rate was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Peak Respiratory Rate (Breaths/Min) | 1.4 breaths/min | Standard Deviation 6.54 |
| Intermediate Dose | Change in Peak Respiratory Rate (Breaths/Min) | -0.7 breaths/min | Standard Deviation 5.72 |
| High Dose | Change in Peak Respiratory Rate (Breaths/Min) | 0.9 breaths/min | Standard Deviation 6.24 |
| Placebo | Change in Peak Respiratory Rate (Breaths/Min) | 8.2 breaths/min | Standard Deviation 5.26 |
Secondary
Change in Peak Systolic Blood Pressure (mmHg)
Change in peak systolic blood pressure as measured by mmHg from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom peak systolic blood pressure was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Peak Systolic Blood Pressure (mmHg) | 16.7 mmHg | Standard Deviation 21 |
| Intermediate Dose | Change in Peak Systolic Blood Pressure (mmHg) | -1.5 mmHg | Standard Deviation 36.47 |
| High Dose | Change in Peak Systolic Blood Pressure (mmHg) | 16.0 mmHg | Standard Deviation 12.71 |
| Placebo | Change in Peak Systolic Blood Pressure (mmHg) | -2.7 mmHg | Standard Deviation 21.84 |
Secondary
Change in Peak Ventilation (L/Min)
Change in peak ventilation as measured by L/min from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom peak ventilation was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Peak Ventilation (L/Min) | 2.70 L/min | Standard Deviation 8.692 |
| Intermediate Dose | Change in Peak Ventilation (L/Min) | 8.87 L/min | Standard Deviation 7.975 |
| High Dose | Change in Peak Ventilation (L/Min) | 2.49 L/min | Standard Deviation 8.303 |
| Placebo | Change in Peak Ventilation (L/Min) | 8.47 L/min | Standard Deviation 8.564 |
Secondary
Change in Post-exercise Lactate Levels (mg/dL)
Change in post-exercise lactate levels as measured by mg/dL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom post- exercise lactate levels were measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Post-exercise Lactate Levels (mg/dL) | 6.9 mg/dL | Standard Deviation 11.87 |
| Intermediate Dose | Change in Post-exercise Lactate Levels (mg/dL) | 10.6 mg/dL | Standard Deviation 42.93 |
| High Dose | Change in Post-exercise Lactate Levels (mg/dL) | 4.3 mg/dL | Standard Deviation 22.1 |
| Placebo | Change in Post-exercise Lactate Levels (mg/dL) | 8.4 mg/dL | Standard Deviation 13.21 |
Secondary
Change in Pre-exercise Lactate Levels (mg/dL)
Change in pre-exercise lactate levels as measured by mg/dL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom pre-exercise lactate levels were measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Pre-exercise Lactate Levels (mg/dL) | 3.4 mg/dL | Standard Deviation 9 |
| Intermediate Dose | Change in Pre-exercise Lactate Levels (mg/dL) | 13.8 mg/dL | Standard Deviation 18.3 |
| High Dose | Change in Pre-exercise Lactate Levels (mg/dL) | 0.4 mg/dL | Standard Deviation 10.25 |
| Placebo | Change in Pre-exercise Lactate Levels (mg/dL) | 4.4 mg/dL | Standard Deviation 14.06 |
Secondary
Change in Temperature (°C)
Change in temperature as measured by units of Celsius from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom temperature was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Temperature (°C) | -0.3 °C | Standard Deviation 0.54 |
| Intermediate Dose | Change in Temperature (°C) | 0.2 °C | Standard Deviation 0.42 |
| High Dose | Change in Temperature (°C) | 0.1 °C | Standard Deviation 0.28 |
| Placebo | Change in Temperature (°C) | 0.0 °C | Standard Deviation 0.67 |
Secondary
Change in Ventilatory Efficiency (VE/VCO2 Slope)
Change in ventilatory efficiency as measured by the VE/VCO2 slope from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: All participants for whom VE/VCO2 slope measurements were recorded at Baseline and Day 5
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Ventilatory Efficiency (VE/VCO2 Slope) | 0.749 VE/VCO2 slope | Standard Deviation 2.9412 |
| Intermediate Dose | Change in Ventilatory Efficiency (VE/VCO2 Slope) | -0.671 VE/VCO2 slope | Standard Deviation 5.4024 |
| High Dose | Change in Ventilatory Efficiency (VE/VCO2 Slope) | -1.681 VE/VCO2 slope | Standard Deviation 3.2834 |
| Placebo | Change in Ventilatory Efficiency (VE/VCO2 Slope) | -1.375 VE/VCO2 slope | Standard Deviation 5.5801 |
Secondary
Change in VO2 Anaerobic Threshold (mL)
Change in VO2 anaerobic threshold as measured by mL from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom VO2 was measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in VO2 Anaerobic Threshold (mL) | 30.00 mL | Standard Deviation 83.93 |
| Intermediate Dose | Change in VO2 Anaerobic Threshold (mL) | 10.8 mL | Standard Deviation 80.35 |
| High Dose | Change in VO2 Anaerobic Threshold (mL) | 1.6 mL | Standard Deviation 42.17 |
| Placebo | Change in VO2 Anaerobic Threshold (mL) | 42.0 mL | Standard Deviation 51.89 |
Secondary
Change in Watts
Change in watts from baseline (last assessment prior to start of study) to Day 5 (end of treatment visit).
Time frame: Baseline, Day 5
Population: Participants for whom watts was measured
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Low Dose | Change in Watts | 9.6 watts | Standard Deviation 14.15 |
| Intermediate Dose | Change in Watts | 13.9 watts | Standard Deviation 12.48 |
| High Dose | Change in Watts | 5.4 watts | Standard Deviation 10.03 |
| Placebo | Change in Watts | 4.4 watts | Standard Deviation 11.87 |
Secondary
Number of Participants Who Had Suicide Ideation, Suicidal Behavior, or Non-suicidal Self-injurious Behavior Post-screening.
Number of participants with suicide ideation, suicidal behavior, or non-suicidal self-injurious behavior post-screening as measured on Days 1-5, and Day 7 on the Columbia Suicide Severity Rating Scale (CSSRS). A yes/no binary response is utilized in the following ten categories: 1 - Wish to be Dead; 2 - Non-specific Active Suicidal Thoughts; 3 - Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; 4 - Active Suicidal Ideation with Some Intent to Act, without Specific Plan; 5 - Active Suicidal Ideation with Specific Plan and Intent; 6 - Preparatory Acts or Behavior; 7 - Aborted Attempt; 8 - Interrupted Attempt; Category 9 - Actual Attempt (non-fatal); 10 - Completed Suicide. A yes/no binary response is also utilized in assessing self-injurious behavior without suicidal intent. A lower score means a better outcome whereas a higher score means a worse outcome.
Time frame: Days 1-5 and Day 7.
Population: Participants for whom CSSR was measured.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Dose | Number of Participants Who Had Suicide Ideation, Suicidal Behavior, or Non-suicidal Self-injurious Behavior Post-screening. | 0 Participants |
| Intermediate Dose | Number of Participants Who Had Suicide Ideation, Suicidal Behavior, or Non-suicidal Self-injurious Behavior Post-screening. | 0 Participants |
| High Dose | Number of Participants Who Had Suicide Ideation, Suicidal Behavior, or Non-suicidal Self-injurious Behavior Post-screening. | 0 Participants |
| Placebo | Number of Participants Who Had Suicide Ideation, Suicidal Behavior, or Non-suicidal Self-injurious Behavior Post-screening. | 0 Participants |