daily subcutaneous injection for 12 weeks

Muscle strength as measured by handheld dynamometry (HHD) in Newtons, where end of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period. Handheld dynamometry assesses the average strength of the knee extensors of both legs.

Muscle strength as measured by handheld dynamometry (HHD) in Newtons. Handheld dynamometry assesses the average strength of the knee extensors of both legs. Change from baseline where Baseline= Part 1 Period 1 Pre-dose: the greater positive change, the better the outcome, the smaller positive change (or negative change) the number the worse the outcome.

Time (in seconds) to complete the Five Times Sit-To-Stand, where end of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period.

Change in baseline in time (in seconds), where Baseline= Part 1 Period 1 Pre-dose to complete the Five Times Sit-To-Stand by visit. More time means worse outcome, less time means better outcome.

SWAY application balance assessment consists of five stances each performed for 10 seconds and scores postural stability on a scale from 0-100 with higher scores indicating better postural stability from Pre-dose to Week 12 (end of treatment), where end of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period.

Change from Baseline: SWAY Application Balance Assessment,where Baseline= Part 1 Period 1 Pre-doseSWAY application balance assessment consists of five stances each performed for 10 seconds and scores postural stability on a scale from 0-100 with higher scores indicating better postural stability. An increase from baseline is a better outcome and a decrease in score is a worse outcome.

Patient-reported health status over the past week, by visit, where end of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period. Scores range from 0-40 for adolescents and 0-50 for adults. PGI Scale is as follows: 0=None, 1=Mild, 2=Moderate, 3=Severe, and 4=Very Severe. Higher score means worse health status, means worse outcome; lower score means better health status, means better outcome.

Part 2: Change from Baseline: Patient Global Impression Scales of Symptoms by Visit Patient-reported health status over the past week where Baseline= Part 1 Period 1 Pre-dose, administered at Week 12 for Period 1 and Period 2. Scores range from 0-40 for adolescents and 0-50 for adults. PGI Scale is as follows: 1=None, 2=Mild, 3=Moderate, 4=Severe, and 5=Very Severe. Change from baseline: Higher score means worse health status, means worse outcome; lower score means better health status, means better outcome.

Clinician Global Impression Scale by visit: Clinician-reported overall health status at end of treatment, administered at Week 12 for Period 1 and Period 2. Scores range from 0-6 for both adolescents and adults. PGI Scale is as follows: 1= Very much Better, 2= Moderately Better, 3= A Little Better, 4= No Change, and 5= A Little Worse 6= Very much Worse. Higher score means worse health status, means worse outcome; lower score means better health status, means better outcome. End of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period.

Change from Baseline: CGI Symptom Scale by visit where Baseline= Part 1 Period 1 Pre-dose. Clinician Global Impression Scale: Clinician-reported overall health status at end of treatment, administered at Week 12 for Period 1 and Period 2. Scores range from 0-6 for both adolescents and adults. PGI Scale is as follows: 1= Very much Better, 2= Moderately Better, 3= A Little Better, 4= No Change, and 5= A Little Worse 6= Very much Worse. Change from baseline: higher score means worse health status, means worse outcome; lower score means better health status, means better outcome.

Patients will be randomized to receive 12 weeks of placebo in one of the two treatment periods. All subjects will receive 12 weeks of placebo, 4 weeks of washout, and 12 weeks of elamipretide, and 4 weeks of follow up (for those not continuing to Part 2).

Placebo: daily subcutaneous injection for 12 weeks Elamipretide: 40 mg daily subcutaneous injection for 12 weeks

Total of all reporting groups

All participants for whom sex was measured.

All individuals for whom race was measured.

All participants for whom Body Mass Index was measured.

Subjects were randomized (in a ratio of 1:1) to one of two sequence groups:

• Sequence 1: 12 weeks of single daily SC doses of 40 mg elamipretide in Treatment Period 1 followed by 12 weeks of treatment with placebo in Treatment Period 2 (separated by a 4-week washout period).
• Sequence 2: 12 weeks of single daily SC doses of placebo in Treatment Period 1 followed by 12 weeks of treatment with 40 mg elamipretide in Treatment Period 2 (separated by a 4-weekwashout period).

Total Fatigue Score (Q1, Q2, and Q4) Based on the BarTH Syndrome Symptom Assessment (BTHS-SA) by visit at predose, Weeks 1, 4, 8, and 12 (end of treatment). The BTHS-SA is 3-question fatigue assessment using a 0 to 4-point scale for each question where no fatigue =0 and very severe fatigue =4, with scores from all 3 questions combined and averaged for all subjects; a lower score means better outcome, higher score means a worse outcome. Combined Min score=0, max score =12. Weekly values are based on the weekly average of the last 7 days before the site or visiting nurse visit for both periods. Results from each 12-week period were combined, where end of treatment for Period 1 =Visit 5 (week 12), and End of Period 2 = Visit 10 (week 12)

All participants for whom Total Fatigue Score was measured

Change from baseline for distance walked in meters during the 6-minute walk test (6MWT) by visit where Baseline= Part 1 Period 1 Pre-dose

All participants for whom distance walked in 6MWT was measured.

Change from Baseline (mean) in Total Fatigue Score (Q1, Q2, and Q4) Based on the BarTH Syndrome Symptom Assessment (BTHS-SA) by visit. The BTHS-SA is 3-question fatigue assessment using a 0-4 point scale for each question where no fatigue =0 and very severe fatigue =4, with scores from all 3 questions combined and averaged for all subjects by visit; a lower score means better outcome, higher score means a worse outcome. Change from baseline: an increase in scores would mean worse outcome, a decrease in scores means better outcome. Combined Min score=-12, max score =12. Weekly values are based on the weekly average of the last 7 days before the site or visiting nurse visit for both periods. Baseline= Period 1 Predose.

All participants for whom Total Fatigue Score was measured.

Muscle strength as measured by handheld dynamometry (HHD) in Newtons, where end of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period. Handheld dynamometry assesses the average strength of the knee extensors of both legs.

All participants for whom muscle strength as measured by handheld dynamometry was measured.

Muscle strength as measured by handheld dynamometry (HHD) in Newtons. Handheld dynamometry assesses the average strength of the knee extensors of both legs. Change from baseline where Baseline= Part 1 Period 1 Pre-dose: the greater positive change, the better the outcome, the smaller positive change (or negative change) the number the worse the outcome.

All participants for whom Muscle Strength by HHD (Newtons) was measured.

Time (in seconds) to complete the Five Times Sit-To-Stand, where end of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period.

All participants for whom 5XSST was measured.

Change in baseline in time (in seconds), where Baseline= Part 1 Period 1 Pre-dose to complete the Five Times Sit-To-Stand by visit. More time means worse outcome, less time means better outcome.

All participants for whom 5X Sit to Stand was measured.

SWAY application balance assessment consists of five stances each performed for 10 seconds and scores postural stability on a scale from 0-100 with higher scores indicating better postural stability from Pre-dose to Week 12 (end of treatment), where end of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period.

All participants for who SWAY application balance was measured.

Change from Baseline: SWAY Application Balance Assessment,where Baseline= Part 1 Period 1 Pre-doseSWAY application balance assessment consists of five stances each performed for 10 seconds and scores postural stability on a scale from 0-100 with higher scores indicating better postural stability. An increase from baseline is a better outcome and a decrease in score is a worse outcome.

All participants for whom SWAY Application Balance Assessment was measured.

Patient-reported health status over the past week, by visit, where end of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period. Scores range from 0-40 for adolescents and 0-50 for adults. PGI Scale is as follows: 0=None, 1=Mild, 2=Moderate, 3=Severe, and 4=Very Severe. Higher score means worse health status, means worse outcome; lower score means better health status, means better outcome.

All participants for whom Patient Global Impression Scales of Symptoms was measured.

Part 2: Change from Baseline: Patient Global Impression Scales of Symptoms by Visit Patient-reported health status over the past week where Baseline= Part 1 Period 1 Pre-dose, administered at Week 12 for Period 1 and Period 2. Scores range from 0-40 for adolescents and 0-50 for adults. PGI Scale is as follows: 1=None, 2=Mild, 3=Moderate, 4=Severe, and 5=Very Severe. Change from baseline: Higher score means worse health status, means worse outcome; lower score means better health status, means better outcome.

All participants for whom Patient Global Impression Scales of Symptoms was measured.

Clinician Global Impression Scale by visit: Clinician-reported overall health status at end of treatment, administered at Week 12 for Period 1 and Period 2. Scores range from 0-6 for both adolescents and adults. PGI Scale is as follows: 1= Very much Better, 2= Moderately Better, 3= A Little Better, 4= No Change, and 5= A Little Worse 6= Very much Worse. Higher score means worse health status, means worse outcome; lower score means better health status, means better outcome. End of treatment means end of Visit 5 (Week 12) for Period 1 and end of Visit 10 (Week 12) for Period 2. Results were pooled for each 12 week period.

All participants for whom Patient Global Impression Scales of Symptoms was measured.

Change from Baseline: CGI Symptom Scale by visit where Baseline= Part 1 Period 1 Pre-dose. Clinician Global Impression Scale: Clinician-reported overall health status at end of treatment, administered at Week 12 for Period 1 and Period 2. Scores range from 0-6 for both adolescents and adults. PGI Scale is as follows: 1= Very much Better, 2= Moderately Better, 3= A Little Better, 4= No Change, and 5= A Little Worse 6= Very much Worse. Change from baseline: higher score means worse health status, means worse outcome; lower score means better health status, means better outcome.

All participants for whom Patient Global Impression Scales of Symptoms was measured.

Part 2: Participants from Part 1 who received 12 weeks of placebo first, then elamipretide for the last 12 weeks of treatment, then proceeded to Part 2 OLE and received up to 192 weeks of daily subcutaneous injections of 40mg elamipretide.

Participants who received Elamipretide either in the first or last 12 weeks of treatment.

Participants who received Placebo either in the first or last 12 weeks of treatment.