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This randomized, double-blind, placebo-controlled, crossover study screened 32 subjects with primary mitochondrial myopathy (PMM) to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of subcutaneous elamipretide in this patient population.
This randomized, double-blind, placebo-controlled, crossover study screened 32 subjects with primary mitochondrial myopathy (PMM) who had completed participation in the SPIMM-201 study where they had received 5 days of intravenous (IV) elamipretide (0.01, 0.10, or 0.25 mg/kg/hour infused for 2 hours) or placebo (randomized 3:1). The primary objective was to evaluate the effect of single daily subcutaneous (SC) doses of elamipretide administered for 4 weeks on the 6-minute walking distance (6MWD).
Subjects were randomized (1:1) to one of two sequence groups: 4-weeks of treatment with 40 mg elamipretide administered once daily SC in Treatment Period 1 followed by 4-weeks of treatment with placebo administered once daily SC in Treatment Period 2 (separated by a 4-week washout period), or vice versa. Each sequence group went through 5 distinct periods: Screening, Treatment Period 1, Washout, Treatment Period 2, and Follow-Up. Safety, tolerability, pharmacokinetics (PK), and efficacy of subcutaneous elamipretide in this patient population were analyzed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Elamipretide, Then Placebo | Experimental | Participants first received 40 mg of elamipretide once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received placebo administered once daily subcutaneously for 4 weeks. |
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| Placebo, Then Elamipretide | Placebo Comparator | Participants first received placebo once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received 40 mg of elamipretide once daily subcutaneously for 4 weeks. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Elamipretide | Drug | 4 weeks of treatment with 40 mg elamipretide administered once daily subcutaneously |
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| Measure | Description | Time Frame |
|---|---|---|
| Distance Walked on the 6-minute Walk Test (6MWT) by Visit | Distance in meters walked on the 6-minute walk test (6MWT) at end of treatment, where end of treatment means end of week 4 for Period 1 and end of week 12 for Period 2. | End of Week 4 and End of Week 12 |
| Measure | Description | Time Frame |
|---|---|---|
| Wrist Accelerometer Counts by Day | Wrist Accelerometer Counts by the last 7 days prior to the date of the end of treatment visit; End of treatment being end of Week 4 for Treatment Period 1 and end of Week 12 for Treatment Period 2. Subjects wore an activity monitor, or wrist accelerometer, on their wrist daily (from the Screening Visit to the End-of-Study/Early Discontinuation Visit). As a measure of physical activity and mobility, subjects wore an activity monitor, or wrist accelerometer, which measured mean vector magnitude of accelerations per daywith higher counts indicating a more active status. Raw acceleration data was converted into proprietary counts which was used to estimate physical activity. The data was transformed from 30 Hz data into 1 minute epoch data; this 1 minute epoch data were used for the analysis of as the vector magnitude of the wrist data. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jim Carr | Stealth BioTherapeutics | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California | San Diego | California | 92093 | United States | ||
| Massachusetts General Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36562873 | Derived | Gwaltney C, Stokes J, Aiudi A, Mazar I, Ollis S, Love E, Karaa A, Houts CR, Wirth RJ, Shields AL. Psychometric performance of the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) in a randomized, double-blind, placebo-controlled crossover study in subjects with mitochondrial disease. J Patient Rep Outcomes. 2022 Dec 23;6(1):129. doi: 10.1186/s41687-022-00534-y. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Elamipretide, Then Placebo | Participants first received 40 mg of elamipretide once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received placebo administered once daily subcutaneously for 4 weeks. Elamipretide: 40 mg elamipretide administered once daily subcutaneously |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| First Intervention (4 Weeks) |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 21, 2016 | Mar 16, 2020 |
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| Placebo | Drug | 4 weeks of treatment with placebo administered once daily subcutaneously |
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| Last 7 days prior to the date of end of treatment visit |
| Average Hip Accelerator Counts by Day | Average Hip Accelerator Counts by last 7 days predose, and prior to end of treatment; End of treatment being Week 4 for Treatment Period 1 and Week 12 for Treatment Period 2. As a measure of physical activity and mobility, subjects wore an activity monitor, or hip accelerometer, on their hip (or belt line) daily during waking hours (minimum of at least 7 consecutive days immediately prior to study drug administration in each Treatment Period [Predose; at Visit 2 for Treatment Period 1 and at Visit 4 for Treatment Period 2]), and at the end of each Treatment Period [at Visit 3 for Treatment Period 1 and Visit 5 for Treatment Period 2]), which measured average acceleration per day, with higher counts indicating a more active status. Raw acceleration data was converted into proprietary counts which was used to estimate physical activity. The data was transformed from 30 Hz data into 1 minute epoch data; this 1 minute epoch data was used for the analysis of mean vertical axis (Y) cou | Last 7 days prior to the date of end of treatment visit |
| Neuro-QoL Fatigue Short Form Score: Total T-Scores (Question 1-8) | Participants respond to the following statements of the Quality of Life in Neurological Disorders Fatigue Assessment (Neuro-QOL Fatigue Item Bank at end of treatment: 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; I had to limit my social activity because I was tired.Individual response options range from a score of 1 to 5, where 1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Always for end of treatment, where end of treatment period is end of week 4 for period 1, and end of week 12 for period 2. Raw scores are calculated as simple summed scores to an Item Response Theory Metric referred to as the T-score metric. Higher T-score means more fatigue, which means a worse outcome, with possible scores ranging from 29.5 to 74.1. Mean population T-score and standard deviation was reported. | End of Week 4 and End of Week 12 |
| Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue Score by Week | Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue score at end of treatment (sum of Q1 to Q4; tiredness/muscle weakness) is scored as follows: 1=Not at all, 2=Mild, 3=Moderate, and 4=Severe. Total score range is 4-16; lower score means less fatigue and better outcome, higher score means more fatigue and worse outcome. Participants rate the following: Tiredness at rest, Tiredness during activities, Muscle weakness at rest, Muscle weakness during activities, at the end of each treatment period, where end of treatment period is the weekly average of the last 7 days of week 4 for period 1 and the last 7 days of week 12 for period 2. | Last 7 days of Week 4 and Last 7 days of Week 12 |
| Triple Timed Up and Go (3TUG) Test by Visit | Participant performed 3TUG test after the 6MWT, and after at least 15 minutes rest prior to study drug administration in each Treatment Period (End of Week 4 for Period 1 and End of Week 12 for Period 2.) Participant was 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 was timed, in seconds. Activity is repeated 3 times consecutively without rest and an average time is calculated. | End of Week 4 and End of Week 12 |
| Patient Global Assessment [PGA] Score by Visit, Continuous | Patient-reported current health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2. PGA Scale is as follows: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher score means worse health status, means worse outcome. | End of Week 4 and End of Week 12 |
| Patient Global Assessment by Visit, Categorical | Patient-reported current health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2. PGA Scale is as follows: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher score means worse health status, means worse outcome. Excellent means excellent health, means better outcome; poor means poor health, means worse outcome. | End of Week 4 and End of Week 12 |
| Physician Global Assessment (PhGA) By Visit, Continuous | Physician Global Assessment (PhGA) Physician-reported overall health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2.: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher scores equal worse outcome. | End of Week 4 and End of Week 12 |
| Physician Global Assessment (PhGA) By Visit, Categorical | Physician Global Assessment (PhGA) Physician-reported overall health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2.: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher scores equal worse outcome. Excellent means excellent health, means better outcome; poor means poor health, means worse outcome. | End of Week 4 and End of Week 12 |
| Boston |
| Massachusetts |
| 02114 |
| United States |
| Akron Children's Hospital | Akron | Ohio | 44308 | United States |
| Children's Hospital of Pittsburg of UPMC | Pittsburgh | Pennsylvania | 15224 | United States |
| Placebo, Then Elamipretide |
Participants first received placebo once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received 40 mg of elamipretide once daily subcutaneously for 4 weeks. Placebo: 4 weeks of treatment with placebo administered once daily subcutaneously |
| COMPLETED |
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| NOT COMPLETED |
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| Washout (4 Weeks) |
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| Second Intervention (4 Weeks) |
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| ID | Title | Description |
|---|---|---|
| BG000 | Elamipretide, Then Placebo | Participants first received 40 mg of elamipretide once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received placebo administered once daily subcutaneously for 4 weeks. |
| BG001 | Placebo, Then Elamipretide | Participants first received placebo once daily subcutaneously for 4 weeks. After a washout period of 4 weeks, they then received 40 mg of elamipretide once daily subcutaneously for 4 weeks. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Distance Walked on the 6-minute Walk Test (6MWT) by Visit | Distance in meters walked on the 6-minute walk test (6MWT) at end of treatment, where end of treatment means end of week 4 for Period 1 and end of week 12 for Period 2. | All participants for whom the distance walked on the 6MWT was measured. | Posted | Mean | Standard Deviation | meters | End of Week 4 and End of Week 12 |
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| ||||||||||||||||||||||||||||
| Secondary | Wrist Accelerometer Counts by Day | Wrist Accelerometer Counts by the last 7 days prior to the date of the end of treatment visit; End of treatment being end of Week 4 for Treatment Period 1 and end of Week 12 for Treatment Period 2. Subjects wore an activity monitor, or wrist accelerometer, on their wrist daily (from the Screening Visit to the End-of-Study/Early Discontinuation Visit). As a measure of physical activity and mobility, subjects wore an activity monitor, or wrist accelerometer, which measured mean vector magnitude of accelerations per daywith higher counts indicating a more active status. Raw acceleration data was converted into proprietary counts which was used to estimate physical activity. The data was transformed from 30 Hz data into 1 minute epoch data; this 1 minute epoch data were used for the analysis of as the vector magnitude of the wrist data. | All participants for whom wrist accelerometer counts by day was measured. | Posted | Mean | Standard Deviation | counts by day | Last 7 days prior to the date of end of treatment visit |
| ||||||||||||||||||||||||||||||
| Secondary | Average Hip Accelerator Counts by Day | Average Hip Accelerator Counts by last 7 days predose, and prior to end of treatment; End of treatment being Week 4 for Treatment Period 1 and Week 12 for Treatment Period 2. As a measure of physical activity and mobility, subjects wore an activity monitor, or hip accelerometer, on their hip (or belt line) daily during waking hours (minimum of at least 7 consecutive days immediately prior to study drug administration in each Treatment Period [Predose; at Visit 2 for Treatment Period 1 and at Visit 4 for Treatment Period 2]), and at the end of each Treatment Period [at Visit 3 for Treatment Period 1 and Visit 5 for Treatment Period 2]), which measured average acceleration per day, with higher counts indicating a more active status. Raw acceleration data was converted into proprietary counts which was used to estimate physical activity. The data was transformed from 30 Hz data into 1 minute epoch data; this 1 minute epoch data was used for the analysis of mean vertical axis (Y) cou | All participants for whom hip accelerometer counts by day was measured. | Posted | Mean | Standard Deviation | counts by day | Last 7 days prior to the date of end of treatment visit |
| ||||||||||||||||||||||||||||||
| Secondary | Neuro-QoL Fatigue Short Form Score: Total T-Scores (Question 1-8) | Participants respond to the following statements of the Quality of Life in Neurological Disorders Fatigue Assessment (Neuro-QOL Fatigue Item Bank at end of treatment: 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; I had to limit my social activity because I was tired.Individual response options range from a score of 1 to 5, where 1=Never, 2=Rarely, 3=Sometimes, 4=Often, and 5=Always for end of treatment, where end of treatment period is end of week 4 for period 1, and end of week 12 for period 2. Raw scores are calculated as simple summed scores to an Item Response Theory Metric referred to as the T-score metric. Higher T-score means more fatigue, which means a worse outcome, with possible scores ranging from 29.5 to 74.1. Mean population T-score and standard deviation was reported. | All participants for whom Neuro-QoL Fatigue Short Form Score was measured. | Posted | Mean | Standard Deviation | T-score | End of Week 4 and End of Week 12 |
| ||||||||||||||||||||||||||||||
| Secondary | Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue Score by Week | Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue score at end of treatment (sum of Q1 to Q4; tiredness/muscle weakness) is scored as follows: 1=Not at all, 2=Mild, 3=Moderate, and 4=Severe. Total score range is 4-16; lower score means less fatigue and better outcome, higher score means more fatigue and worse outcome. Participants rate the following: Tiredness at rest, Tiredness during activities, Muscle weakness at rest, Muscle weakness during activities, at the end of each treatment period, where end of treatment period is the weekly average of the last 7 days of week 4 for period 1 and the last 7 days of week 12 for period 2. | All participants for whom PMMSA was measured at end of treatment. | Posted | Mean | Standard Deviation | score on a scale | Last 7 days of Week 4 and Last 7 days of Week 12 |
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| Secondary | Triple Timed Up and Go (3TUG) Test by Visit | Participant performed 3TUG test after the 6MWT, and after at least 15 minutes rest prior to study drug administration in each Treatment Period (End of Week 4 for Period 1 and End of Week 12 for Period 2.) Participant was 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 was timed, in seconds. Activity is repeated 3 times consecutively without rest and an average time is calculated. | All participants for whom the 3TUG test was measured. | Posted | Mean | Standard Deviation | seconds | End of Week 4 and End of Week 12 |
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| Secondary | Patient Global Assessment [PGA] Score by Visit, Continuous | Patient-reported current health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2. PGA Scale is as follows: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher score means worse health status, means worse outcome. | All participants for whom the Patient Global Assessment was measured. | Posted | Mean | Standard Deviation | score on a scale | End of Week 4 and End of Week 12 |
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| Secondary | Patient Global Assessment by Visit, Categorical | Patient-reported current health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2. PGA Scale is as follows: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher score means worse health status, means worse outcome. Excellent means excellent health, means better outcome; poor means poor health, means worse outcome. | All participants for whom the Patient Global Assessment was measured. | Posted | Count of Participants | Participants | End of Week 4 and End of Week 12 |
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| Secondary | Physician Global Assessment (PhGA) By Visit, Continuous | Physician Global Assessment (PhGA) Physician-reported overall health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2.: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher scores equal worse outcome. | All participants for whom the Physician Global Assessment was measured. | Posted | Mean | Standard Deviation | score on a scale | End of Week 4 and End of Week 12 |
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| Secondary | Physician Global Assessment (PhGA) By Visit, Categorical | Physician Global Assessment (PhGA) Physician-reported overall health status at end of treatment, where end of treatment means End of Week 4 for Period 1 and End of Week 12 for Period 2.: 1=Excellent, 2=Very good, 3=Good, 4=Fair, and 5=Poor. Higher scores equal worse outcome. Excellent means excellent health, means better outcome; poor means poor health, means worse outcome. | All participants for whom the Physician Global Assessment was measured. | Posted | Count of Participants | Participants | End of Week 4 and End of Week 12 |
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Participants were followed for a total of 14 weeks; they had a Treatment Period for 4 weeks, then had a Washout Period of 4 weeks, then another Treatment Period of 4 weeks, then a Follow Up Period of 2 weeks.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Elamipretide | Participants received 40 mg of elamipretide once daily subcutaneously for 4 weeks, either in the first 4 weeks of treatment, or in the last 4 weeks of treatment. | 0 | 30 | 0 | 30 | 30 | 30 |
| EG001 | Placebo | Participants received placebo once daily subcutaneously for 4 weeks, either in the first 4 weeks of treatment or the last 4 weeks of treatment. | 0 | 30 | 0 | 30 | 15 | 30 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Injection site erythema | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Injection site pruritus | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Injection site pain | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Injection site urticaria | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Injection site bruising | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Injection site irritation | General disorders | MedDRA (20.0) | Systematic Assessment |
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| Urinary Tract Infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Viral Upper Respiratory Tract Infection | Infections and infestations | MedDRA (20.0) | Systematic Assessment |
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| Abdominal Pain | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA (20.0) | Systematic Assessment |
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| Muscle Spasms | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (20.0) | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Dysarthria | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (20.0) | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA (20.0) | Systematic Assessment |
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The Investigator may not submit for publication or presentation the results of this study without first receiving written authorization from Stealth BioTherapeutics Inc. Stealth BioTherapeutics Inc., agrees that before it publishes any results of the study, it shall provide the Investigator with at least 30 days for review of the pre-publication manuscript prior to the submission of the manuscript to the publisher.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Rekha Sathyanarayana, Executive Director, Clinical Operations | Stealth BioTherapeutics Inc. | 617-762-2579 | Rekha.Sathyanarayana@stealthbt.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 21, 2017 | Mar 16, 2020 | SAP_001.pdf |
| ID | Term |
|---|---|
| D017240 | Mitochondrial Myopathies |
| ID | Term |
|---|---|
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D028361 | Mitochondrial Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| C506540 | arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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