Healthy volunteers who had physical exam, study biomarker, Near Infrared Spectroscopy (NIRS) testing and muscle ultrasound only, in one visit.

All participants with RYR1-RM enrolled into the natural history period of the trial.

RYR1-RM Volunteers

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.

Healthy Volunteers

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: N-acetylcysteine (NAC)

Placebo 900 mg tablets identical but did not contain NAC

RYR1-RM Volunteers :Placebo

Total

Sex: Female, Male

Race (NIH/OMB)

Region of Enrollment

Body Mass Index BMI(kg/m^2)

Mode of Inheritance is not applicable to healthy volunteer participants and therefore was not collected.

Mode of Inheritance, dominant/de novo

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

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

N-acetylcysteine (NAC)

Placebo

Urine 15-F2t Isoprostane Concentration

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

Six Minute Walk Test (6MWT)

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

DCF-fluorescence Intensity (AU)

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.

Time to Ascend Steps (Seconds)

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.

Descend Steps

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.

Walk/Run 10 Meters

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.

Supine to Stand

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.

Motor Function Measure-32 (MFM-32) Domain 1 (D1)

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.

Motor Function Measure-32 (MFM-32) Domain 2 (D2)

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.

Motor Function Measure-32 (MFM-32) Domain 3 (D3)

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.

Motor Function Measure-32 (MFM-32) Total Score

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.

Hand Grip Strength

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

Hand Pinch Strength

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.

Peak Torque Flexion

Peak Torque Extension

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.

Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue

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.

Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue

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.

Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue

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.

Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue

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.

Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score

Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score

Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score

Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score

Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score

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.

Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score

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.

Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index

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.

Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score

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

Healthy volunteers who participated in a one-visit assessment.

Healthy Volunteer

Blood Glutathione Reduced (GSH):Oxidized (GSSG) Ratio

Urine 15-F2t Isoprostane Concentration Pre-Intervention

Six Minute Walk Test (6MWT) Pre-Intervention

DCF-fluorescence Intensity (AU) Pre-Intervention

Time to Ascend Steps (Seconds) Pre-Intervention

Descend Steps Pre-Intervention

Walk/Run 10 Meters Pre-Intervention

Supine to Stand Pre-Intervention

Motor Function Measure-32 (MFM-32) Domain 1 (D1) Pre-Intervention

Motor Function Measure-32 (MFM-32) Domain 2 (D2) Pre-Intervention

Motor Function Measure-32 (MFM-32) Domain 3 (D3) Pre-Intervention

Motor Function Measure-32 (MFM-32) Total Score Pre-Intervention

Hand Grip Strength Pre-Intervention

Hand Pinch Strength Pre-Intervention

Peak Torque Flexion Pre-Intervention

Peak Torque Extension Pre-Intervention

Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue Pre-Intervention

Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention

Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Pre-Intervention

Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention

Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score Pre-Intervention

Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score Pre-Intervention

Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score Pre-Intervention

Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score Pre-Intervention

Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score Pre-Intervention

Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention

Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index Pre-Intervention

Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention

Healthy volunteers entered into the study for a one-visit assessment; no treatment given.

Urine 15-F2t Isoprostane Concentration at Baseline

Subjects with RYR1-RM entered into the Natural History Phase of the study.

RYR1-RM subjects who were eventually randomized to NAC 900 mg tablets

RYR1-RM subjects who were eventually randomized to Placebo 900 mg tablets without active NAC

RYR1-RM Volunteers: Placebo

Phase 1 (up to 6 Months)

Phase 2 (up to 6 Months, Randomized)

Katherine Meileur Chief, Neuromuscular Symptoms Unit

All participants with RYR1-RM enrolled into the natural history period of the trial

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

Placebo 900 mg tablets for 6 months; identical but did not contain NAC

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

Neuromuscular Disease

N-acetylcysteine

National Institutes of Health Clinical Center, 9000 Rockville Pike

Antioxidant Therapy in RYR1-Related Congenital Myopathy

National Institute of Nursing Research (NINR)

Patients with heart failure (FEVG ≥ 50%)

Patients with heart failure (FEVG ≤ 35%),

Heart Failure

Exercise training,

Muscle biopsy

physiologie clinique, hopital Arnaud de Villeneuve, 371 avenue du Doyen G;Giraud

Impact of Heart Failure on Calcium Homeostasis and Mitochondrial Function in Human Skeletal Muscle

Evaluation of Calcium Homeostasis and Mitochondrial Function in Skeletal Muscle in Subjects With Heart Failure

University Hospital, Montpellier

Institut National de la Santé Et de la Recherche Médicale, France

Ministry of Health, France

National Cancer Institute, France

Institut de Recherches Internationales Servier

Younger subjects (ages 20-35) were administered placebo sildenafil orally daily for 1 week.

Younger subjects (ages 20 -35) were administered sildenafil daily (25 mg/day) orally for 1 week.

Older subjects (ages 60-80) were administered placebo sildenafil orally daily for 1 week.

Older subjects (ages 60 - 80) were administered sildenafil daily (25 mg/day) orally for 1 week.

Placebo Sildenafil Young

Sildenafil Young

Placebo Sildenafil Older

Sildenafil Older

Age, Customized

Muscle fatigue was tested before and after 1 week of placebo/sildenafil (25mg/day) treatment.
Subjects were asked to perform maximum effort isokinetic knee extensions until force production reached 50% of their MVC (maximum voluntary contraction). Data was collected as number of successful repetitions completed between start and 50% MVC.
Data is presented as percent change in repetitions (1 week of treatment / baseline).

Change in Muscle Fatigue After 1 Week of Placebo or Sildenafil

Skeletal muscle protein synthesis, measured as the fractional synthesis rate (the percent of the total synthesized per unit time) after 1 week of either Placebo or Sildenafil (25 mg/day). Example: if FSR = 0.06 hr-1 it means that 6% of proteins in a given sample were synthesized in the last hour or proteins is synthesized at 6% per hour. A higher rate means that more synthesis is occurring.

Protein Synthesis Rate After 1 Week of Sildenafil or Placebo

Sildenafil Placebo Young

Sildenafil Placebo Older

Overall Study

Melinda Sheffield-Moore

Fatigue

Aging

Placebo sildenafil

Sildenafil

University of Texas Medical Branch

Role of Skeletal Muscle Nitric Oxide Production in Age-related Fatigue and Fatigability

The University of Texas Medical Branch, Galveston

Matched with patients on age and physical activity

ryanodine/umor

Antioxidant Therapy in RYR1-Related Congenital Myopathy

Impact of Heart Failure on Calcium Homeostasis and Mitochondrial Function in Human Skeletal Muscle

Role of Skeletal Muscle Nitric Oxide Production in Age-related Fatigue and Fatigability

Impact of Heart Failure on Calcium Homeostasis and Mitochondrial Function in Human Skeletal Muscle

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