Trial Outcomes & Findings for Antioxidant Therapy in RYR1-Related Congenital Myopathy (NCT NCT02362425)

Results Overview

Urine will be assayed for 15-isoprostane-F2, which is formed when arachidonic acid reacts with reactive oxygen species(ROS). A validated gas chromatography(GC)-mass spectrometer (MS) method will be used to quantify 15-isoprostane-F2

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

63 participants

Primary outcome timeframe

12 months

Results posted on

2019-12-24

Participant Flow

Participant milestones

Participant milestones
Measure	RYR1-RM Volunteers Subjects with RYR1-RM entered into the Natural History Phase of the study.	Healthy Volunteers Healthy volunteers entered into the study for a one-visit assessment; no treatment given.	RYR1-RM Volunteers: N-acetylcysteine (NAC) RYR1-RM subjects who were eventually randomized to NAC 900 mg tablets	RYR1-RM Volunteers: Placebo RYR1-RM subjects who were eventually randomized to Placebo 900 mg tablets without active NAC
Phase 1 (up to 6 Months) STARTED	53	10	0	0
Phase 1 (up to 6 Months) COMPLETED	37	10	0	0
Phase 1 (up to 6 Months) NOT COMPLETED	16	0	0	0
Phase 2 (up to 6 Months, Randomized) STARTED	0	0	16	17
Phase 2 (up to 6 Months, Randomized) COMPLETED	0	0	15	14
Phase 2 (up to 6 Months, Randomized) NOT COMPLETED	0	0	1	3

Reasons for withdrawal

Reasons for withdrawal
Measure	RYR1-RM Volunteers Subjects with RYR1-RM entered into the Natural History Phase of the study.	RYR1-RM Volunteers: N-acetylcysteine (NAC) RYR1-RM subjects who were eventually randomized to NAC 900 mg tablets	RYR1-RM Volunteers: Placebo RYR1-RM subjects who were eventually randomized to Placebo 900 mg tablets without active NAC
Phase 1 (up to 6 Months) Withdrawal by Subject	2	0	0
Phase 1 (up to 6 Months) Medicinal contraindication	1	0	0
Phase 1 (up to 6 Months) Screening failure	1	0	0
Phase 1 (up to 6 Months) Confirmatory genetic testing negative	3	0	0
Phase 1 (up to 6 Months) Study closure	9	0	0
Phase 2 (up to 6 Months, Randomized) Adverse Event	0	0	2
Phase 2 (up to 6 Months, Randomized) Withdrawal by Subject	0	0	1
Phase 2 (up to 6 Months, Randomized) Discontinued study drug due to procedure	0	1	0

Baseline Characteristics

Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	RYR1-RM Volunteers n=53 Participants All participants with RYR1-RM enrolled into the natural history period of the trial.	Healthy Volunteers n=10 Participants Healthy volunteers were evaluated to determine normal values of biomarkers, muscle ultrasound, and near infrared spectroscopy in this rare disease, in order to develop a comparison between healthy and RYR1-RM individuals.	RYR1-RM Volunteers: N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on participant weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	RYR1-RM Volunteers :Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC	Total n=96 Participants Total of all reporting groups
Age, Continuous Phase 1: Natural History Period	29.2 years STANDARD_DEVIATION 17.5 • n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	44.8 years STANDARD_DEVIATION 13.2 • n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	31.7 years STANDARD_DEVIATION 17.9 • n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Age, Continuous Phase 2: Randomized Period	—	—	28.1 years STANDARD_DEVIATION 17.4 • n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	26.7 years STANDARD_DEVIATION 18.5 • n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	27.4 years STANDARD_DEVIATION 17.7 • n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Sex: Female, Male Phase 1: Natural History Period · Female	29 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	7 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	36 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Sex: Female, Male Phase 1: Natural History Period · Male	24 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	3 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	27 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Sex: Female, Male Phase 2: Randomized Period · Female	—	—	9 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	10 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	19 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Sex: Female, Male Phase 2: Randomized Period · Male	—	—	7 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	7 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	14 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 1: Natural History Period · American Indian or Alaska Native	0 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	0 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 1: Natural History Period · Asian	0 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	0 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 1: Natural History Period · Native Hawaiian or Other Pacific Islander	0 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	0 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 1: Natural History Period · Black or African American	6 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	2 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	8 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 1: Natural History Period · White	47 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	8 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	55 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 1: Natural History Period · More than one race	0 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	0 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 1: Natural History Period · Unknown or Not Reported	0 Participants n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	0 Participants n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 2: Randomized Period · American Indian or Alaska Native	—	—	0 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 2: Randomized Period · Asian	—	—	0 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 2: Randomized Period · Native Hawaiian or Other Pacific Islander	—	—	0 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 2: Randomized Period · Black or African American	—	—	1 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	1 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 2: Randomized Period · White	—	—	15 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	17 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	32 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 2: Randomized Period · More than one race	—	—	0 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Race (NIH/OMB) Phase 2: Randomized Period · Unknown or Not Reported	—	—	0 Participants n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	0 Participants n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Region of Enrollment United States	53 Participants n=53 Participants • This measure of Region of Enrollment is presented for subjects enrolled in the Natural History phase of the study as well as the Healthy Volunteers.	10 Participants n=10 Participants • This measure of Region of Enrollment is presented for subjects enrolled in the Natural History phase of the study as well as the Healthy Volunteers.	16 participants n=16 Participants • This measure of Region of Enrollment is presented for the subjects in the randomized period of the study, ie, randomized population.	17 participants n=17 Participants • This measure of Region of Enrollment is presented for the subjects in the randomized period of the study, ie, randomized population.	33 participants n=33 Participants • This measure of Region of Enrollment is presented for the subjects in the randomized period of the study, ie, randomized population.
Body Mass Index BMI(kg/m^2) Phase 1: Natural History Period	22.1 kg/m^2 STANDARD_DEVIATION 8.7 • n=53 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	32.1 kg/m^2 STANDARD_DEVIATION 6.1 • n=10 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	—	—	24.4 kg/m^2 STANDARD_DEVIATION 8.7 • n=63 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Body Mass Index BMI(kg/m^2) Phase 2: Randomized Period	—	—	22.8 kg/m^2 STANDARD_DEVIATION 8.2 • n=16 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	21.5 kg/m^2 STANDARD_DEVIATION 6.5 • n=17 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.	21.9 kg/m^2 STANDARD_DEVIATION 7.5 • n=33 Participants • Baseline measures are provided for the 53 RYR1-RM participants and the 10 healthy volunteers in the natural history phase, and for the 33 subjects who continued on into the randomized phase.
Mode of Inheritance, dominant/de novo Phase 1: Natural History Period	40 Participants n=53 Participants • Mode of Inheritance is not applicable to healthy volunteer participants and therefore was not collected. Baseline measures are provided for each of the other two parts of the study: natural history and randomized. Of the 53 participants in the natural history period, 33 continued on into the randomized phase.	—	—	—	40 Participants n=53 Participants • Mode of Inheritance is not applicable to healthy volunteer participants and therefore was not collected. Baseline measures are provided for each of the other two parts of the study: natural history and randomized. Of the 53 participants in the natural history period, 33 continued on into the randomized phase.
Mode of Inheritance, dominant/de novo Phase 2: Randomized Period	—	—	12 Participants n=16 Participants • Mode of Inheritance is not applicable to healthy volunteer participants and therefore was not collected. Baseline measures are provided for each of the other two parts of the study: natural history and randomized. Of the 53 participants in the natural history period, 33 continued on into the randomized phase.	13 Participants n=17 Participants • Mode of Inheritance is not applicable to healthy volunteer participants and therefore was not collected. Baseline measures are provided for each of the other two parts of the study: natural history and randomized. Of the 53 participants in the natural history period, 33 continued on into the randomized phase.	25 Participants n=33 Participants • Mode of Inheritance is not applicable to healthy volunteer participants and therefore was not collected. Baseline measures are provided for each of the other two parts of the study: natural history and randomized. Of the 53 participants in the natural history period, 33 continued on into the randomized phase.

PRIMARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers post-baseline (months 6 and 12), thus they are not included in the analysis.

Urine will be assayed for 15-isoprostane-F2, which is formed when arachidonic acid reacts with reactive oxygen species(ROS). A validated gas chromatography(GC)-mass spectrometer (MS) method will be used to quantify 15-isoprostane-F2

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Urine 15-F2t Isoprostane Concentration	2.7 ng/mg Cr Interval 1.7 to 3.7	2.6 ng/mg Cr Interval 1.5 to 3.6

PRIMARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Meters walked in 6 minutes will be recorded; distances in meters will be recorded at each minute interval; speed will be calculated.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Six Minute Walk Test (6MWT)	495.8 meters Interval 475.8 to 515.9	471.9 meters Interval 451.1 to 492.7

SECONDARY outcome

Timeframe: 12 months

Population: This analysis was performed only on participants in the randomized population who volunteered to have the muscle biopsy performed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity \[H2DCFDA (H2-DCF, DCF)\].

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=6 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=4 Participants Placebo 900 mg tablets identical but did not contain NAC
DCF-fluorescence Intensity (AU)	1.9 AU Interval 0.7 to 3.1	3.4 AU Interval 1.7 to 5.1

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants completed the following timed function tests: supine to stand, ascend four steps, descend four steps, and walk/run 10 meters. For time taken to ascend four steps, the subject was asked to ascend four steps whilst being timed.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Time to Ascend Steps (Seconds)	3.2 seconds Interval 2.9 to 3.5	3.3 seconds Interval 3.0 to 3.6

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants completed the following timed function tests: supine to stand, ascend four steps, descend four steps, and walk/run 10 meters. For time taken to descend four steps, the subject was asked to descend four steps whilst being timed.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Descend Steps	1.9 seconds Interval 1.5 to 2.3	2.4 seconds Interval 2.1 to 2.8

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants completed the following timed function tests: supine to stand, ascend four steps, descend four steps, and walk/run 10 meters. For walk/run 10 meters, participants were timed as they walked/ran a marked 10-meter course as quickly as possible.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Walk/Run 10 Meters	5.2 seconds Interval 4.3 to 6.1	5.9 seconds Interval 5.0 to 6.9

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants completed the following timed function tests: supine to stand, ascend four steps, descend four steps, and walk/run 10 meters. For time taken to transition from supine to standing, participants were asked to lay supine and then the time taken to move from supine to standing was recorded.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Supine to Stand	7.4 seconds Interval 6.6 to 8.1	8.4 seconds Interval 7.7 to 9.2

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Motor Function Measure, MFM-32 is a well-established scale of motor function in congenital muscle disease. The D1 domains measure standard and transfers, and consist of 13 items. Generic Values for each domain are: 0 = cannot perform the task, 1 = initiated the task, 2 - performs the movement incompletely, or completely but imperfectly, 3 = performs the task fully and 'normally'. Total score is the sum of all the domains for D1 divided by the maximum score possible and multiplied by 100. Min=0, Max = 100. Lower numbers on the scale represent a worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Motor Function Measure-32 (MFM-32) Domain 1 (D1)	74.9 % of maximum score Interval 72.1 to 77.6	71.5 % of maximum score Interval 68.6 to 74.3

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Motor Function Measure, MFM-32 is a well-established scale of motor function in congenital muscle disease. The D2 domains measure axial and proximal motor function and consists of 12 items. Generic Values for each domain are: 0 = cannot perform the task, 1 = initiated the task, 2 - performs the movement incompletely, or completely but imperfectly, 3 = performs the task fully and 'normally'. The total score is the sum of all the MFM-32 domains for D2, divided by maximum score possible and multiplied by 100. Min = 0, Max = 100. Lower numbers on the scale represent a worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Motor Function Measure-32 (MFM-32) Domain 2 (D2)	97.0 % of maximum score Interval 95.9 to 98.1	96.7 % of maximum score Interval 95.5 to 97.9

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Motor Function Measure, MFM-32 is a well-established scale of motor function in congenital muscle disease. The D3 domains measure distal motor function and consist of 7 items. Generic Values for each domain are: 0 = cannot perform the task, 1 = initiated the task, 2 - performs the movement incompletely, or completely but imperfectly, 3 = performs the task fully and 'normally'. The total score is the sum of all the MFM-32 domains for D3, divided by maximum score possible and multiplied by 100. Min = 0, Max = 100. Lower numbers on the scale represent a worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Motor Function Measure-32 (MFM-32) Domain 3 (D3)	95.5 % of maximum score Interval 93.9 to 97.1	96.7 % of maximum score Interval 95.0 to 98.3

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Motor Function Measure, MFM-32 is a well-established scale of motor function in congenital muscle disease. Generic Values for each domain are: 0 = cannot perform the task, 1 = initiated the task, 2 - performs the movement incompletely, or completely but imperfectly, 3 = performs the task fully and 'normally'. The total score is the sum of all the MFM-32 domains, divided by maximum score possible (96) and multiplied by 100. Min = 0, Max = 100. Lower numbers on the scale represent a worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Motor Function Measure-32 (MFM-32) Total Score	84.1 % of maximum score Interval 82.8 to 85.4	83.0 % of maximum score Interval 81.7 to 84.3

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Grip and pinch strength were determined using Myotools dynamometry. The myogrip hand held dynamometer was used to assess grip strength. Higher scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Hand Grip Strength	17.8 kg Interval 16.1 to 19.5	17.9 kg Interval 16.1 to 19.7

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Grip and pinch strength were determined using Myotools dynamometry. The myopinch pinch gauge was used to measure finger strength. Higher scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=15 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Hand Pinch Strength	4.7 kg Interval 4.0 to 5.5	4.9 kg Interval 4.2 to 5.7

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Lower-body isometric strength testing was used to determine peak torque during flexion and extension. Participant's blood pressure was assessed, to rule-out hypertension (\>140/90), prior to starting the test. Participants were then asked to push against a stationary arm and remained at the same joint angle for the duration of each test. Two short trials were completed to establish maximal force for each participant. This was followed by a long trial of flexion and extension to capture rate of fatigue to 50% after reaching their pre-determined maximal force. In the interest of safety, participants with hypertension and/or a history of knee injury did not perform the test.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=14 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=12 Participants Placebo 900 mg tablets identical but did not contain NAC
Peak Torque Flexion	24.7 nM Interval 23.0 to 26.3	22.6 nM Interval 20.8 to 24.3

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Lower-body isometric strength testing was used to determine peak torque during flexion and extension. Participant's blood pressure was assessed, to rule-out hypertension (\>140/90), prior to starting the test. Participants were then asked to push against a stationary arm and remained at the same joint angle for the duration of each test. Two short trials were completed to establish maximal force for each participant. This was followed by a long trial of flexion and extension to capture rate of fatigue to 50% after reaching their pre-determined maximal force. In the interest of safety, participants with hypertension and/or a history of knee injury did not perform the test.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=14 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=12 Participants Placebo 900 mg tablets identical but did not contain NAC
Peak Torque Extension	24.7 nM Interval 23.0 to 26.3	38.8 nM Interval 35.3 to 42.2

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the PROMIS (patient-reported outcomes measurement information system) through the NIH online, self-administered Clinical Trials Survey System. PROMIS scores are normed to 100 meaning that the raw score is converted to a scale where 50 is the mean and the standard deviation is 10. Scores less than 50 indicate less fatigue compared to the average and scores over 50 indicate more fatigue than the average. Lower scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=9 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=7 Participants Placebo 900 mg tablets identical but did not contain NAC
Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue	49.5 t score Interval 43.9 to 55.1	55.0 t score Interval 49.5 to 60.6

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the NeuroQoL questionnaire through the NIH online, self-administered Clinical Trials Survey System. The NeuroQoL scores were normed to 100, meaning that the raw score is converted to a scale where 50 is the mean and the standard deviation is 10. Scores less than 50 indicate less fatigue compared to the average and scores over 50 indicate more fatigue than the average. Lower scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=9 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=7 Participants Placebo 900 mg tablets identical but did not contain NAC
Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue	45.1 t score Interval 40.0 to 50.3	51.5 t score Interval 46.3 to 56.6

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the PROMIS questionnaire through the NIH online, self-administered Clinical Trials Survey System. PROMIS scores were normed to 100 meaning that the raw scores were converted to a scale where 50 is the mean and the standard deviation is 10. Scores less than 50 indicate less fatigue compared to the average and scores over 50 indicate more fatigue than the average. Lower scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=2 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=5 Participants Placebo 900 mg tablets identical but did not contain NAC
Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue	34.8 t score Interval 18.5 to 88.2	51.1 t score Interval 30.9 to 71.3

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the NeuroQoL questionnaire through the NIH online, self-administered Clinical Trials Survey System. NeuroQoL scores were normed to 100 meaning that the raw score is converted to a scale where 50 is the mean and the standard deviation is 10. Scores less than 50 indicate less fatigue compared to the average and scores over 50 indicate more fatigue than the average. Lower scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=2 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=5 Participants Placebo 900 mg tablets identical but did not contain NAC
Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue	43.1 t score Interval 0.7 to 85.5	53.1 t score Interval 40.4 to 65.9

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=14 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=12 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score	11.6 scores on a scale Interval 9.7 to 13.5	13.7 scores on a scale Interval 11.7 to 15.8

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=14 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=12 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score	11.5 scores on a scale Interval 9.3 to 13.6	11.9 scores on a scale Interval 9.7 to 14.2

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=14 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=12 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score	9.2 scores on a scale Interval 7.2 to 11.2	8.7 scores on a scale Interval 6.6 to 10.8

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=14 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=12 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score	7.8 scores on a scale Interval 6.2 to 9.4	7.4 scores on a scale Interval 5.7 to 9.1

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=14 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=12 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score	8.8 scores on a scale Interval 6.7 to 10.9	8.6 scores on a scale Interval 6.4 to 10.8

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the FACIT-f questionnaire through the NIH online, self-administered Clinical Trials Survey System. Minimum value = 0, maximum value = 160. Higher scores represent a better outcome/ better QOL.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=9 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=7 Participants Placebo 900 mg tablets identical but did not contain NAC
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score	76.1 scores on a scale Interval 67.7 to 84.5	73.6 scores on a scale Interval 64.1 to 83.2

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the FACIT-F questionnaire through the NIH online, self-administered Clinical Trials Survey System. The Trial Outcome Index (TOI) is the sum of the physical well-being, functional well-being and 'additional concerns' subscales. The minimum value = 0, and maximum value = 52. Scores under 30 is considered to be severe fatigue. Higher scores represent a better outcome/QOL.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=9 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=7 Participants Placebo 900 mg tablets identical but did not contain NAC
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index	37.6 scores on a scale Interval 32.3 to 42.8	37.0 scores on a scale Interval 31.0 to 42.9

SECONDARY outcome

Timeframe: 12 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Pediatric participants (\< 18 years) were asked to complete the Peds-FACIT-F questionnaire through the NIH online, self-administered Clinical Trials Survey System.Minimum value = 0, maximum value = 52. Higher scores represent a better outcome/ better QOL.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=6 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=6 Participants Placebo 900 mg tablets identical but did not contain NAC
Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score	29.8 scores on a scale Interval 12.0 to 47.6	42.3 scores on a scale Interval 30.4 to 54.3

SECONDARY outcome

Timeframe: Baseline

GSH:GSSG ratio analyzed only at baseline to offer comparison of RYR1-RM affected individuals to the general population.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=38 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=10 Participants Placebo 900 mg tablets identical but did not contain NAC
Blood Glutathione Reduced (GSH):Oxidized (GSSG) Ratio	10.8 ratio Standard Deviation 7.2	0.54 ratio Standard Deviation 1.18

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers post baseline, thus they are not included in this analysis..

Urine will be assayed for 15-isoprostane-F2, which is formed when arachidonic acid reacts with reactive oxygen species(ROS). A validated gas chromatography(GC)-mass spectrometer (MS) method will be used to quantify 15-isoprostane-F2

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=16 Participants Placebo 900 mg tablets identical but did not contain NAC
Urine 15-F2t Isoprostane Concentration Pre-Intervention	3.6 ng/mg Cr Standard Deviation 2.2	3.1 ng/mg Cr Standard Deviation 1.9

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Meters walked in 6 minutes will be recorded; distances in meters will be recorded at each minute interval; speed will be calculated.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Six Minute Walk Test (6MWT) Pre-Intervention	519.1 meters Standard Deviation 119.0	453.8 meters Standard Deviation 128.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: This analysis was performed only on participants in the randomized population who volunteered to have the muscle biopsy performed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity \[H2DCFDA (H2-DCF, DCF)\].

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=7 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=5 Participants Placebo 900 mg tablets identical but did not contain NAC
DCF-fluorescence Intensity (AU) Pre-Intervention	1.7 AU Standard Deviation 0.9	2.0 AU Standard Deviation 1.6

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants completed the following timed function tests: supine to stand, ascend four steps, descend four steps, and walk/run 10 meters. For time taken to ascend four steps, the subject was asked to ascend four steps whilst being timed.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Time to Ascend Steps (Seconds) Pre-Intervention	2.9 seconds Standard Deviation 1.5	3.4 seconds Standard Deviation 1.8

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants completed the following timed function tests: supine to stand, ascend four steps, descend four steps, and walk/run 10 meters. For time taken to descend four steps, the subject was asked to descend four steps whilst being timed.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Descend Steps Pre-Intervention	2.2 seconds Standard Deviation 1.0	2.3 seconds Standard Deviation 1.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants completed the following timed function tests: supine to stand, ascend four steps, descend four steps, and walk/run 10 meters. For walk/run 10 meters, participants were timed as they walked/ran a marked 10-meter course as quickly as possible.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=15 Participants Placebo 900 mg tablets identical but did not contain NAC
Walk/Run 10 Meters Pre-Intervention	5.0 seconds Standard Deviation 2.2	4.6 seconds Standard Deviation 1.7

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants completed the following timed function tests: supine to stand, ascend four steps, descend four steps, and walk/run 10 meters. For time taken to transition from supine to standing, participants were asked to lay supine and then the time taken to move from supine to standing was recorded.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=15 Participants Placebo 900 mg tablets identical but did not contain NAC
Supine to Stand Pre-Intervention	6.9 seconds Standard Deviation 5.5	6.7 seconds Standard Deviation 5.4

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Motor Function Measure, MFM-32 is a well-established scale of motor function in congenital muscle disease. The D1 domains measure standard and transfers, and consist of 13 items. Generic Values for each domain are: 0 = cannot perform the task, 1 = initiated the task, 2 - performs the movement incompletely, or completely but imperfectly, 3 = performs the task fully and 'normally'. Total score is the sum of all the domains for D1 divided by the maximum score possible and multiplied by 100. Min=0, Max = 100. Lower numbers on the scale represent a worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Motor Function Measure-32 (MFM-32) Domain 1 (D1) Pre-Intervention	75.8 % of maximum score Standard Deviation 16.6	71.6 % of maximum score Standard Deviation 21.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis..

Motor Function Measure, MFM-32 is a well-established scale of motor function in congenital muscle disease. The D2 domains measure axial and proximal motor function and consists of 12 items. Generic Values for each domain are: 0 = cannot perform the task, 1 = initiated the task, 2 - performs the movement incompletely, or completely but imperfectly, 3 = performs the task fully and 'normally'. The total score is the sum of all the MFM-32 domains for D2, divided by maximum score possible and multiplied by 100. Min = 0, Max = 100. Lower numbers on the scale represent a worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Motor Function Measure-32 (MFM-32) Domain 2 (D2) Pre-Intervention	96.0 % of maximum score Standard Deviation 4.8	96.6 % of maximum score Standard Deviation 7.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Motor Function Measure, MFM-32 is a well-established scale of motor function in congenital muscle disease. The D3 domains measure distal motor function and consist of 7 items. Generic Values for each domain are: 0 = cannot perform the task, 1 = initiated the task, 2 - performs the movement incompletely, or completely but imperfectly, 3 = performs the task fully and 'normally'. The total score is the sum of all the MFM-32 domains for D3, divided by maximum score possible and multiplied by 100. Min = 0, Max = 100. Lower numbers on the scale represent a worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Motor Function Measure-32 (MFM-32) Domain 3 (D3) Pre-Intervention	96.7 % of maximum score Standard Deviation 3.8	95.2 % of maximum score Standard Deviation 5.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Motor Function Measure, MFM-32 is a well-established scale of motor function in congenital muscle disease. Generic Values for each domain are: 0 = cannot perform the task, 1 = initiated the task, 2 - performs the movement incompletely, or completely but imperfectly, 3 = performs the task fully and 'normally'. The total score is the sum of all the MFM-32 domains, divided by maximum score possible (96) and multiplied by 100. Min = 0, Max = 100. Lower numbers on the scale represent a worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Motor Function Measure-32 (MFM-32) Total Score Pre-Intervention	84.4 % of maximum score Standard Deviation 7.6	82.7 % of maximum score Standard Deviation 9.8

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Grip and pinch strength were determined using Myotools dynamometry. The myogrip hand held dynamometer was used to assess grip strength. Higher scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Hand Grip Strength Pre-Intervention	20.5 kg Standard Deviation 14.0	17.5 kg Standard Deviation 11.0

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Grip and pinch strength were determined using Myotools dynamometry. The myopinch pinch gauge was used to measure finger strength. Higher scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=17 Participants Placebo 900 mg tablets identical but did not contain NAC
Hand Pinch Strength Pre-Intervention	6.5 kg Standard Deviation 5.0	5.1 kg Standard Deviation 2.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Lower-body isometric strength testing was used to determine peak torque during flexion and extension. Participant's blood pressure was assessed, to rule-out hypertension (\>140/90), prior to starting the test. Participants were then asked to push against a stationary arm and remained at the same joint angle for the duration of each test. Two short trials were completed to establish maximal force for each participant. This was followed by a long trial of flexion and extension to capture rate of fatigue to 50% after reaching their pre-determined maximal force. In the interest of safety, participants with hypertension and/or a history of knee injury did not perform the test.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Peak Torque Flexion Pre-Intervention	31.9 nM Standard Deviation 22.0	25.2 nM Standard Deviation 21.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Lower-body isometric strength testing was used to determine peak torque during flexion and extension. Participant's blood pressure was assessed, to rule-out hypertension (\>140/90), prior to starting the test. Participants were then asked to push against a stationary arm and remained at the same joint angle for the duration of each test. Two short trials were completed to establish maximal force for each participant. This was followed by a long trial of flexion and extension to capture rate of fatigue to 50% after reaching their pre-determined maximal force. In the interest of safety, participants with hypertension and/or a history of knee injury did not perform the test.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=16 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=14 Participants Placebo 900 mg tablets identical but did not contain NAC
Peak Torque Extension Pre-Intervention	56.9 nM Standard Deviation 42.9	41.6 nM Standard Deviation 45.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the PROMIS (patient-reported outcomes measurement information system) through the NIH online, self-administered Clinical Trials Survey System. PROMIS scores are normed to 100 meaning that the raw score is converted to a scale where 50 is the mean and the standard deviation is 10. Scores less than 50 indicate less fatigue compared to the average and scores over 50 indicate more fatigue than the average. Lower scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=7 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=10 Participants Placebo 900 mg tablets identical but did not contain NAC
Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue Pre-Intervention	59.2 t score Standard Deviation 11.8	58.5 t score Standard Deviation 11.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the NeuroQoL questionnaire through the NIH online, self-administered Clinical Trials Survey System. The NeuroQoL scores were normed to 100, meaning that the raw score is converted to a scale where 50 is the mean and the standard deviation is 10. Scores less than 50 indicate less fatigue compared to the average and scores over 50 indicate more fatigue than the average. Lower scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=7 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=10 Participants Placebo 900 mg tablets identical but did not contain NAC
Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention	53.25 t score Standard Deviation 8.5	51.9 t score Standard Deviation 7.4

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the PROMIS questionnaire through the NIH online, self-administered Clinical Trials Survey System. PROMIS scores were normed to 100 meaning that the raw scores were converted to a scale where 50 is the mean and the standard deviation is 10. Scores less than 50 indicate less fatigue compared to the average and scores over 50 indicate more fatigue than the average. Lower scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=4 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=4 Participants Placebo 900 mg tablets identical but did not contain NAC
Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Pre-Intervention	42.6 t score Standard Deviation 8.4	57.3 t score Standard Deviation 7.7

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the NeuroQoL questionnaire through the NIH online, self-administered Clinical Trials Survey System. NeuroQoL scores were normed to 100 meaning that the raw score is converted to a scale where 50 is the mean and the standard deviation is 10. Scores less than 50 indicate less fatigue compared to the average and scores over 50 indicate more fatigue than the average. Lower scores represent better outcomes.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=4 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=5 Participants Placebo 900 mg tablets identical but did not contain NAC
Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention	45.9 t score Standard Deviation 6.4	52.8 t score Standard Deviation 2.8

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=13 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=15 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score Pre-Intervention	12.9 scores on a scale Standard Deviation 4.2	14.3 scores on a scale Standard Deviation 3.8

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=13 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=15 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score Pre-Intervention	12.1 scores on a scale Standard Deviation 5.6	13.0 scores on a scale Standard Deviation 3.9

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=13 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=15 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score Pre-Intervention	9.5 scores on a scale Standard Deviation 4.7	11.3 scores on a scale Standard Deviation 3.2

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=13 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=15 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score Pre-Intervention	7.9 scores on a scale Standard Deviation 3.1	9.1 scores on a scale Standard Deviation 3.5

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the MFI-20 questionnaire through the NIH online, self-administered Clinical Trials Survey System. The MFI consists of 5 subscales: general fatigue, physical fatigue, mental fatigue, reduced activity, and reduced motivation. Values range from 4-20 for each scale. Higher scores represent increased fatigue/ worse outcome.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=13 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=15 Participants Placebo 900 mg tablets identical but did not contain NAC
Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score Pre-Intervention	8.8 scores on a scale Standard Deviation 4.8	9.7 scores on a scale Standard Deviation 4.4

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the FACIT-f questionnaire through the NIH online, self-administered Clinical Trials Survey System. Minimum value = 0, maximum value = 160. Higher scores represent a better outcome/ better QOL.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=9 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=10 Participants Placebo 900 mg tablets identical but did not contain NAC
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention	69.2 scores on a scale Standard Deviation 16.9	71.3 scores on a scale Standard Deviation 20.9

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Participants were asked to complete the FACIT-F questionnaire through the NIH online, self-administered Clinical Trials Survey System. The Trial Outcome Index (TOI) is the sum of the physical well-being, functional well-being and 'additional concerns' subscales. The minimum value = 0, and maximum value = 52. Scores under 30 is considered to be severe fatigue. Higher scores represent a better outcome/QOL.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=9 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=10 Participants Placebo 900 mg tablets identical but did not contain NAC
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index Pre-Intervention	33.8 scores on a scale Standard Deviation 11.4	34.3 scores on a scale Standard Deviation 10.3

OTHER_PRE_SPECIFIED outcome

Timeframe: 6 months

Population: Outcome measures are reported for participants who were randomized and continued into the randomized, double-blind period of the trial. Missing data was not imputed. This measure was not collected for Healthy Volunteers, thus they are not included in this analysis.

Pediatric participants (\< 18 years) were asked to complete the Peds-FACIT-F questionnaire through the NIH online, self-administered Clinical Trials Survey System.Minimum value = 0, maximum value = 52. Higher scores represent a better outcome/ better QOL.

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=5 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=4 Participants Placebo 900 mg tablets identical but did not contain NAC
Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention	43.2 scores on a scale Standard Deviation 7.7	37.0 scores on a scale Standard Deviation 8.4

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline

Population: Healthy volunteers who participated in a one-visit assessment and RYR1-RM Volunteers measured at Baseline.

Urine will be assayed for 15-isoprostane-F2, which is formed when arachidonic acid reacts with reactive oxygen species(ROS). A validated gas chromatography(GC)-mass spectrometer (MS) method will be used to quantify 15-isoprostane-F2

Outcome measures

Outcome measures
Measure	N-acetylcysteine (NAC) n=49 Participants N-acetylcysteine (NAC) 900 mg tablets; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	Placebo n=10 Participants Placebo 900 mg tablets identical but did not contain NAC
Urine 15-F2t Isoprostane Concentration at Baseline	3.17 ng/mg Cr Standard Deviation 1.48	1.36 ng/mg Cr Standard Deviation 0.48

Adverse Events

RYR1-RM Volunteers

Serious events: 1 serious events

Other events: 36 other events

Deaths: 0 deaths

RYR1-RM Volunteers: N-acetylcysteine (NAC)

Serious events: 4 serious events

Other events: 16 other events

Deaths: 0 deaths

RYR1-RM Volunteers :Placebo

Serious events: 5 serious events

Other events: 17 other events

Deaths: 0 deaths

Healthy Volunteers

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	RYR1-RM Volunteers n=53 participants at risk All participants with RYR1-RM enrolled into the natural history period of the trial	RYR1-RM Volunteers: N-acetylcysteine (NAC) n=16 participants at risk N-acetylcysteine (NAC) 900 mg tablets for 6 months; week 1 up to 1800 mg/day; Week 2- through end of study based on subject weight: \< 50 kg subjects up to 2700 mg/day, \>50 kg subjects 2700 mg/day	RYR1-RM Volunteers :Placebo n=17 participants at risk Placebo 900 mg tablets for 6 months; identical but did not contain NAC	Healthy Volunteers n=10 participants at risk Healthy volunteers were evaluated at a one-visit assessment at baseline to determine normal values of biomarkers, muscle ultrasound, and near infrared spectroscopy in order to develop a comparison between healthy and RYR1-RM individuals
Congenital, familial and genetic disorders Intestinal Malrotation	1.9% 1/53 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	6.2% 1/16 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/17 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/10 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events
Gastrointestinal disorders Diarrhoea	0.00% 0/53 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/16 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	5.9% 1/17 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/10 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/53 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/16 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	5.9% 1/17 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/10 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events
Reproductive system and breast disorders Uterine Leiomyoma	0.00% 0/53 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/16 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	5.9% 1/17 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/10 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events
Reproductive system and breast disorders Ovarian Cyst	0.00% 0/53 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	6.2% 1/16 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/17 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/10 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/53 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/16 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	5.9% 1/17 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/10 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events
Respiratory, thoracic and mediastinal disorders Chest Discomfort	0.00% 0/53 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	6.2% 1/16 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/17 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/10 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events
Vascular disorders Hypotension	0.00% 0/53 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	6.2% 1/16 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	5.9% 1/17 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events	0.00% 0/10 • Adverse events (AE) were collected from start of study drug through the end of the study at 12 months. AEs were analyzed for the natural history period and the treatment period separately. (Institutional Review Board) IRB determination was used for the classification of adverse events

Other adverse events

Additional Information

Katherine Meileur Chief, Neuromuscular Symptoms Unit

National Institute of Nursing

Phone: 301-435-1503

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place