Antioxidant Therapy in RYR1-Related Congenital Myopathy

Neuromuscular Disease Clinical Trial

— RYR1  

Official title:

Antioxidant Therapy in RYR1-Related Congenital Myopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02362425
• Other study ID #: 150072
• Secondary ID: 15-NR-0072
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: February 12, 2015
• Est. completion date: May 30, 2018

Study information

• Verified date: October 5, 2019
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

• Ryanodine receptor type 1-related myopathies (RYR1-RM) are the most common non-dystrophic muscle diseases that people are born with in the U.S. They affect development, muscles, and walking. Researchers want to test a new drug to help people with these diseases.

Objectives:

• To see if the drug N-acetylcysteine decreases muscle damage in people with RYR1-RM. To see if it improves their exercise tolerance.

Eligibility:

• People age 7 and older with a confirmed genetic diagnosis of RYR1 or a clinical diagnosis of RYR1 and a family member with a confirmed genetic diagnosis.

Design:

• Participants will be screened with a checklist of criteria. Adult participants may have a muscle biopsy. A needle will remove a tiny piece of muscle in the lower leg.

• Study visits will take several days.

• Visit 1:

• Medical history

• Physical exam

• Blood, urine, and saliva tests

• Questions about symptoms and quality of life

• Heart, lung, and walking tests

• Muscle Oxygenation Capacity Test. A blood pressure cuff around the thigh will be tightened for up to 10 minutes.

• Biodex testing, stretching the leg against resistance

• Muscle ultrasounds. A probe will be moved over the skin.

• Participants may be photographed or videotaped during procedures.

• They may have a muscle biopsy.

• Six months later, visit 2 will repeat visit 1. Participants will start taking the study drug dissolved in water or placebo three times a day for 6 months.

• Participants will stay at NIH for 2 days after starting the study drug.

• Participants will be contacted by phone during the study to monitor side effects

• Six months after starting the study drug, study visit 3 will repeat some or all of visit 1.

Description:

Although genetic disorders of muscle that present at birth are rare, RYR1-related myopathies comprise the most common non-dystrophic congenital myopathy in the United States, with a prevalence of approximately 1/90,000 people (Amburgey et al, 2011). Causative mutations in the ryanodine receptor gene of skeletal muscle, RYR1, have been found in several myopathy subtypes, including central core disease and centronuclear myopathy. These mutations result in defective excitation-contraction coupling and increased mitochondrial oxidative stress. Most patients present in childhood with delayed motor milestones, extremity muscle weakness, impaired ambulation, joint contractures, progressive scoliosis, and in some cases eye movement paralysis, respiratory failure, or susceptibility to malignant hyperthermia, an allelic condition. Despite these important morbidities and the risk of early mortality, no treatments exist to date.

RYR1 encodes a homotetrameric transmembrane ion channel, RyR1, which resides on the terminal sarcoplasmic reticulum in close proximity to the T-tubule. By releasing calcium from the sarcoplasmic reticulum into the cytosol in response to muscle fiber stimulation by the motor neuron at the neuromuscular junction, it mediates excitation-contraction coupling and functions as a regulator of cellular calcium concentrations and redox homeostasis. Dowling et al. (2012) recently elucidated the latter mechanism in zebrafish and patient myotubes, showing that RYR1 mutations result in increased oxidative stress and that this is rescued in both models by treatment with N-acetylcysteine (NAC), a known anti-oxidant. NAC functions as a precursor of glutathione, an endogenous antioxidant that becomes deficient during oxidative stress. This was substantiated by a cystic fibrosis clinical trial in which low glutathione levels in neutrophils undergoing oxidative stress significantly increased with NAC administration.

Dowling et al. (2012) found significant changes post NAC treatment including increased travel distance (endurance) in zebrafish and complete protection from cell death induced by experimentally increasing oxidative stress in myotubes. Thus NAC was a successful treatment in both ex vivo and in vivo model systems. Based on these results, we plan to perform a randomized, double-blinded, placebo controlled clinical trial of NAC in a subgroup of RYR1-related myopathy patients as the first pathophysiologically based treatment for this devastating disorder.

The objectives of the study are to determine if NAC reduces oxidative stress, fatigability, and fatigue in a study population of patients with RYR1-RM. The study population includes both males and females 7 years of age and older. The study design has two phases. The first 6-month phase will be used to validate the selected outcome measures in RYR1 congenital myopathy. The second 6-month phase is a randomized, double-blinded, placebo controlled drug intervention trial. The primary outcome measures are blood glutathione for oxidative stress and six minute walk test for fatigability. Healthy volunteers will be 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: May 30, 2018
• Est. primary completion date: May 30, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 7 Years and older

Eligibility

• EXCLUSION CRITERIA - PATIENTS:

• Adults who cannot provide their own consent and pediatric participants who do not have a parent able to provide consent.

• Patients with a history of liver disease (Liver Function Tests will be collected at baseline and

at each study visit as a precautionary measure). Liver disease is defined as moderate to severe hepatic impairment based on the following:

• Alanine Aminotransferase (ALT) greater than or equal to 8x upper limit of normal (ULN) with total bilirubin 2x ULN (plus >35% direct bilirubin) and/or International normalized ratio (INR) >1.5 or

• Gamma-glutamyl transferase (GGT) > 2-3x ULN with bilirubin 2x ULN (plus >35% direct bilirubin) and/or INR

• Patients with a history of peptic ulcers, gag reflex depression, and esophageal varices. Patients with gastrostomy tubes may be considered for participation, in the case of gag reflex depression or other swallowing or feeding difficulties.

• Patients who have a severe pulmonary dysfunction (FEV1< 40% predicted) or evidence of pulmonary exacerbation. Pulmonary exacerbations refer to an acute worsening of respiratory symptoms that result from a decline in lung function. Participants may present with increased coughing, increased dyspnea, increased haemoptysis, increased fatigue, decreased pulmonary function by a min of 10%, or a change in sputum color.

• Pregnant and breastfeeding women.

• Consumption of antioxidants [including NAC, GSH, melatonin, Immunocal (Immunotac

Research, Vandreuil-Dorion, QC, Canada), Nacystelyn (Galephar, Brussels)] in the 4 weeks before recruitment.

-Daily use of acetaminophen (including Percocet, Vicodin, Oxycodone, Excedrin, and other

acetaminophen-containing drugs), nitroglycerine, or carbamazepine during the past 7 days.

• Current use of Angiotensin-converting enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs).

• Patients who have ever used Beta2-adrenergic agonist tablets, for the purpose of increasing muscle mass (such as albuterol tablets).

• For the muscle biopsy procedure only (second and third visits, if applicable):

Patients who have taken Aspirin, Ibuprofen, Advil, Motrin, or Aleve within the 3 days prior to the muscle biopsy procedure, and/or patients who have taken Plavix, fresh garlic, gingko, or ginseng 5 days prior to the muscle biopsy.

• Participation in trials for other therapeutic investigational drugs simultaneously or 4 weeks before recruitment.

• Other clinically significant medical disease that, in the judgment of the investigators, would expose the patient to undue risk of harm or prevent the patient from completing the study. Examples include anemia (defined as Hgb < 8 gm/dl), an inability to walk safely without assistance for at least 6 minutes, and/or an inability to consume at least 6 ounces of fluid, 3 times a day, either orally or via G-tube. Patients with comorbidities (i.e. cancer, epilepsy) will be carefully assessed to determine if their comorbidity could lead to confounding or safety issues, should their participation continue.

EXCLUSION CRITERIA - HEALTHY VOLUNTEERS:

• Diagnosis of RYR1-related myopathy or other neurological disorder (by neurological exam, genetic testing, or muscle biopsy

• Complaints of fatigue or weakness

• Consumption of antioxidants [including NAC, GSH, melatonin, Immunocal (Immunotac

• Research, Vandreuil-Dorion, QC, Canada), Nacystelyn (Galephar, Brussels)] in the 4 weeks before recruitment.

• Use of Beta2-adrenergic agonists.

Related Conditions & MeSH terms

• Muscular Diseases
• Neuromuscular Disease
• Neuromuscular Diseases

Intervention

Drug:
• N-acetylcysteine

• Placebo

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Nursing Research (NINR)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Urine 15-F2t Isoprostane Concentration Pre-Intervention	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	6 months
Other	Six Minute Walk Test (6MWT) Pre-Intervention	Meters walked in 6 minutes will be recorded; distances in meters will be recorded at each minute interval; speed will be calculated.	6 months
Other	DCF-fluorescence Intensity (AU) Pre-Intervention	Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity [H2DCFDA (H2-DCF, DCF)].	6 months
Other	Time to Ascend Steps (Seconds) Pre-Intervention	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.	6 months
Other	Descend Steps Pre-Intervention	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.	6 months
Other	Walk/Run 10 Meters Pre-Intervention	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.	6 months
Other	Supine to Stand Pre-Intervention	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.	6 months
Other	Motor Function Measure-32 (MFM-32) Domain 1 (D1) Pre-Intervention	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.	6 months
Other	Motor Function Measure-32 (MFM-32) Domain 2 (D2) Pre-Intervention	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.	6 months
Other	Motor Function Measure-32 (MFM-32) Domain 3 (D3) Pre-Intervention	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.	6 months
Other	Motor Function Measure-32 (MFM-32) Total Score Pre-Intervention	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.	6 months
Other	Hand Grip Strength Pre-Intervention	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.	6 months
Other	Hand Pinch Strength Pre-Intervention	Grip and pinch strength were determined using Myotools dynamometry. The myopinch pinch gauge was used to measure finger strength. Higher scores represent better outcomes.	6 months
Other	Peak Torque Flexion Pre-Intervention	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.	6 months
Other	Peak Torque Extension Pre-Intervention	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.	6 months
Other	Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue Pre-Intervention	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.	6 months
Other	Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention	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.	6 months
Other	Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Pre-Intervention	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.	6 months
Other	Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention	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.	6 months
Other	Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score Pre-Intervention	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.	6 months
Other	Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score Pre-Intervention	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.	6 months
Other	Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score Pre-Intervention	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.	6 months
Other	Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score Pre-Intervention	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.	6 months
Other	Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score Pre-Intervention	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.	6 months
Other	Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention	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.	6 months
Other	Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index Pre-Intervention	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.	6 months
Other	Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention	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.	6 months
Other	Urine 15-F2t Isoprostane Concentration 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	Baseline
Primary	Urine 15-F2t Isoprostane Concentration	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	12 months
Primary	Six Minute Walk Test (6MWT)	Meters walked in 6 minutes will be recorded; distances in meters will be recorded at each minute interval; speed will be calculated.	12 months
Secondary	DCF-fluorescence Intensity (AU)	Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity [H2DCFDA (H2-DCF, DCF)].	12 months
Secondary	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 ascend four steps, the subject was asked to ascend four steps whilst being timed.	12 months
Secondary	Descend Steps	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.	12 months
Secondary	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 walk/run 10 meters, participants were timed as they walked/ran a marked 10-meter course as quickly as possible.	12 months
Secondary	Supine to Stand	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.	12 months
Secondary	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 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.	12 months
Secondary	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 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.	12 months
Secondary	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. 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.	12 months
Secondary	Motor Function Measure-32 (MFM-32) Total Score	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.	12 months
Secondary	Hand Grip Strength	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.	12 months
Secondary	Hand Pinch 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.	12 months
Secondary	Peak Torque Flexion	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.	12 months
Secondary	Peak Torque Extension	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.	12 months
Secondary	Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue	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.	12 months
Secondary	Adult Quality of Life in Neurological Disorders (NeuroQoL) 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.	12 months
Secondary	Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) 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.	12 months
Secondary	Pediatric Quality of Life in Neurological Disorders (NeuroQoL) 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.	12 months
Secondary	Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score	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.	12 months
Secondary	Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score	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.	12 months
Secondary	Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score	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.	12 months
Secondary	Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score	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.	12 months
Secondary	Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score	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.	12 months
Secondary	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. Minimum value = 0, maximum value = 160. Higher scores represent a better outcome/ better QOL.	12 months
Secondary	Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index	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.	12 months
Secondary	Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score	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.	12 months
Secondary	Blood Glutathione Reduced (GSH):Oxidized (GSSG) Ratio	GSH:GSSG ratio analyzed only at baseline to offer comparison of RYR1-RM affected individuals to the general population.	Baseline

External Links

•   NIH Clinical Center Detailed Web Page