Neuromuscular Disease
Conditions
Keywords
Neuromuscular Disease, Clinical Trial, Ryanodine Receptor Type 1, Myopathy
Brief 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.
Detailed 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.
Interventions
DRUGN-acetylcysteine
DRUGPlacebo
Sponsors
National Institute of Nursing Research (NINR)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
7 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
*
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Urine 15-F2t Isoprostane Concentration | 12 months | 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 |
| Six Minute Walk Test (6MWT) | 12 months | Meters walked in 6 minutes will be recorded; distances in meters will be recorded at each minute interval; speed will be calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score | 12 months | 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. |
| DCF-fluorescence Intensity (AU) | 12 months | Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity \[H2DCFDA (H2-DCF, DCF)\]. |
| Time to Ascend Steps (Seconds) | 12 months | 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. |
| Descend Steps | 12 months | 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. |
| Walk/Run 10 Meters | 12 months | 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. |
| Supine to Stand | 12 months | 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. |
| Motor Function Measure-32 (MFM-32) Domain 1 (D1) | 12 months | 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 2 (D2) | 12 months | 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 3 (D3) | 12 months | 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) Total Score | 12 months | 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. |
| Hand Grip Strength | 12 months | 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 Pinch Strength | 12 months | Grip and pinch strength were determined using Myotools dynamometry. The myopinch pinch gauge was used to measure finger strength. Higher scores represent better outcomes. |
| Peak Torque Flexion | 12 months | 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 Extension | 12 months | 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. |
| Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue | 12 months | 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 Quality of Life in Neurological Disorders (NeuroQoL) Fatigue | 12 months | 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. |
| Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue | 12 months | 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 Quality of Life in Neurological Disorders (NeuroQoL) Fatigue | 12 months | 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. |
| Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score | 12 months | 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) Physical Fatigue Score | 12 months | 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) Reduced Activity Score | 12 months | 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) Mental Fatigue Score | 12 months | 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. |
| Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score | 12 months | 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) Trial Outcome Index | 12 months | 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. |
| Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score | 12 months | 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. |
| Blood Glutathione Reduced (GSH):Oxidized (GSSG) Ratio | Baseline | GSH:GSSG ratio analyzed only at baseline to offer comparison of RYR1-RM affected individuals to the general population. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Six Minute Walk Test (6MWT) Pre-Intervention | 6 months | Meters walked in 6 minutes will be recorded; distances in meters will be recorded at each minute interval; speed will be calculated. |
| DCF-fluorescence Intensity (AU) Pre-Intervention | 6 months | Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity \[H2DCFDA (H2-DCF, DCF)\]. |
| Urine 15-F2t Isoprostane Concentration Pre-Intervention | 6 months | 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 |
| Time to Ascend Steps (Seconds) Pre-Intervention | 6 months | 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. |
| Descend Steps Pre-Intervention | 6 months | 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. |
| Walk/Run 10 Meters Pre-Intervention | 6 months | 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. |
| Supine to Stand Pre-Intervention | 6 months | 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. |
| Motor Function Measure-32 (MFM-32) Domain 1 (D1) Pre-Intervention | 6 months | 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 2 (D2) Pre-Intervention | 6 months | 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 3 (D3) Pre-Intervention | 6 months | 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) Total Score Pre-Intervention | 6 months | 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. |
| Hand Grip Strength Pre-Intervention | 6 months | 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 Pinch Strength Pre-Intervention | 6 months | Grip and pinch strength were determined using Myotools dynamometry. The myopinch pinch gauge was used to measure finger strength. Higher scores represent better outcomes. |
| Peak Torque Flexion Pre-Intervention | 6 months | 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 Extension Pre-Intervention | 6 months | 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. |
| Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue Pre-Intervention | 6 months | 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 Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention | 6 months | 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. |
| Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Pre-Intervention | 6 months | 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 Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention | 6 months | 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. |
| Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score Pre-Intervention | 6 months | 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) Physical Fatigue Score Pre-Intervention | 6 months | 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) Reduced Activity Score Pre-Intervention | 6 months | 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) Reduced Motivation Score Pre-Intervention | 6 months | 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) Mental Fatigue Score Pre-Intervention | 6 months | 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. |
| Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention | 6 months | 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) Trial Outcome Index Pre-Intervention | 6 months | 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. |
| Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention | 6 months | 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. |
| Urine 15-F2t Isoprostane Concentration at Baseline | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RYR1-RM Volunteers All participants with RYR1-RM enrolled into the natural history period of the trial. | 53 |
| Healthy 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. | 10 |
| RYR1-RM Volunteers: N-acetylcysteine (NAC) 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 | 16 |
| RYR1-RM Volunteers :Placebo Placebo 900 mg tablets identical but did not contain NAC | 17 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase 1 (up to 6 Months) | Confirmatory genetic testing negative | 3 | 0 | 0 | 0 |
| Phase 1 (up to 6 Months) | Medicinal contraindication | 1 | 0 | 0 | 0 |
| Phase 1 (up to 6 Months) | Screening failure | 1 | 0 | 0 | 0 |
| Phase 1 (up to 6 Months) | Study closure | 9 | 0 | 0 | 0 |
| Phase 1 (up to 6 Months) | Withdrawal by Subject | 2 | 0 | 0 | 0 |
| Phase 2 (up to 6 Months, Randomized) | Adverse Event | 0 | 0 | 0 | 2 |
| Phase 2 (up to 6 Months, Randomized) | Discontinued study drug due to procedure | 0 | 0 | 1 | 0 |
| Phase 2 (up to 6 Months, Randomized) | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Healthy Volunteers | RYR1-RM Volunteers | Total | RYR1-RM Volunteers: N-acetylcysteine (NAC) | RYR1-RM Volunteers :Placebo |
|---|---|---|---|---|---|
| Age, Continuous Phase 1: Natural History Period | 44.8 years STANDARD_DEVIATION 13.2 | 29.2 years STANDARD_DEVIATION 17.5 | 31.7 years STANDARD_DEVIATION 17.9 | — | — |
| Age, Continuous Phase 2: Randomized Period | — | — | 27.4 years STANDARD_DEVIATION 17.7 | 28.1 years STANDARD_DEVIATION 17.4 | 26.7 years STANDARD_DEVIATION 18.5 |
| Body Mass Index BMI(kg/m^2) Phase 1: Natural History Period | 32.1 kg/m^2 STANDARD_DEVIATION 6.1 | 22.1 kg/m^2 STANDARD_DEVIATION 8.7 | 24.4 kg/m^2 STANDARD_DEVIATION 8.7 | — | — |
| Body Mass Index BMI(kg/m^2) Phase 2: Randomized Period | — | — | 21.9 kg/m^2 STANDARD_DEVIATION 7.5 | 22.8 kg/m^2 STANDARD_DEVIATION 8.2 | 21.5 kg/m^2 STANDARD_DEVIATION 6.5 |
| Mode of Inheritance, dominant/de novo Phase 1: Natural History Period | — | 40 Participants | 40 Participants | — | — |
| Mode of Inheritance, dominant/de novo Phase 2: Randomized Period | — | — | 25 Participants | 12 Participants | 13 Participants |
| Race (NIH/OMB) Phase 1: Natural History Period American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Phase 1: Natural History Period Asian | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Phase 1: Natural History Period Black or African American | 2 Participants | 6 Participants | 8 Participants | — | — |
| Race (NIH/OMB) Phase 1: Natural History Period More than one race | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Phase 1: Natural History Period Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Phase 1: Natural History Period Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | — | — |
| Race (NIH/OMB) Phase 1: Natural History Period White | 8 Participants | 47 Participants | 55 Participants | — | — |
| Race (NIH/OMB) Phase 2: Randomized Period American Indian or Alaska Native | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2: Randomized Period Asian | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2: Randomized Period Black or African American | — | — | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2: Randomized Period More than one race | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2: Randomized Period Native Hawaiian or Other Pacific Islander | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2: Randomized Period Unknown or Not Reported | — | — | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2: Randomized Period White | — | — | 32 Participants | 15 Participants | 17 Participants |
| Region of Enrollment United States | 10 Participants | 53 Participants | 63 Participants | 16 participants | 17 participants |
| Sex: Female, Male Phase 1: Natural History Period Female | 7 Participants | 29 Participants | 36 Participants | — | — |
| Sex: Female, Male Phase 1: Natural History Period Male | 3 Participants | 24 Participants | 27 Participants | — | — |
| Sex: Female, Male Phase 2: Randomized Period Female | — | — | 19 Participants | 9 Participants | 10 Participants |
| Sex: Female, Male Phase 2: Randomized Period Male | — | — | 14 Participants | 7 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 16 | 0 / 17 | 0 / 10 |
| other Total, other adverse events | 36 / 53 | 16 / 16 | 17 / 17 | 5 / 10 |
| serious Total, serious adverse events | 1 / 53 | 4 / 16 | 5 / 17 | 0 / 10 |
Outcome results
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Six Minute Walk Test (6MWT) | 495.8 meters |
| Placebo | Six Minute Walk Test (6MWT) | 471.9 meters |
Comparison: In RYR1-RM myopathy patients, there will be no statistically significant difference in 6MWT (six minute walk test) total distance between NAC and placebo groups at month 12, after controlling for established a priori confounders.p-value: 0.1195% CI: [-5.5, 53.4]Regression, Linear
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
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Urine 15-F2t Isoprostane Concentration | 2.7 ng/mg Cr |
| Placebo | Urine 15-F2t Isoprostane Concentration | 2.6 ng/mg Cr |
Comparison: Null Hypothesis: In RYR1-RM myopathy patients, there will be no statistically significant difference in corrected 15-F2t-isoprostane concentration and/or corrected 15=f2t-Isop:PGR2alpha ratio between NAC and placebo groups at month 12, after controlling for established a priori confounders.p-value: 0.8895% CI: [-1.4, 1.6]Regression, Linear
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue | 49.5 t score |
| Placebo | Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue | 55.0 t score |
p-value: 0.1595% CI: [-13.4, 2.4]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue | 45.1 t score |
| Placebo | Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue | 51.5 t score |
p-value: 0.0895% CI: [-13.7, 1]t-test, 2 sided
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.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Blood Glutathione Reduced (GSH):Oxidized (GSSG) Ratio | 10.8 ratio | Standard Deviation 7.2 |
| Placebo | Blood Glutathione Reduced (GSH):Oxidized (GSSG) Ratio | 0.54 ratio | Standard Deviation 1.18 |
Secondary
DCF-fluorescence Intensity (AU)
Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity \[H2DCFDA (H2-DCF, DCF)\].
Time frame: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | DCF-fluorescence Intensity (AU) | 1.9 AU |
| Placebo | DCF-fluorescence Intensity (AU) | 3.4 AU |
p-value: 0.1495% CI: [-3.6, 0.7]Regression, Linear
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Descend Steps | 1.9 seconds |
| Placebo | Descend Steps | 2.4 seconds |
p-value: 0.0595% CI: [-1.1, 0]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score | 76.1 scores on a scale |
| Placebo | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score | 73.6 scores on a scale |
p-value: 0.6195% CI: [-10.3, 15.2]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index | 37.6 scores on a scale |
| Placebo | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index | 37.0 scores on a scale |
p-value: 0.8795% CI: [-7.4, 8.5]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Hand Grip Strength | 17.8 kg |
| Placebo | Hand Grip Strength | 17.9 kg |
p-value: 0.9395% CI: [-2.6, 2.4]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Hand Pinch Strength | 4.7 kg |
| Placebo | Hand Pinch Strength | 4.9 kg |
p-value: 0.6695% CI: [-1.3, 0.8]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Motor Function Measure-32 (MFM-32) Domain 1 (D1) | 74.9 % of maximum score |
| Placebo | Motor Function Measure-32 (MFM-32) Domain 1 (D1) | 71.5 % of maximum score |
p-value: 0.0995% CI: [-0.6, 7.3]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Motor Function Measure-32 (MFM-32) Domain 2 (D2) | 97.0 % of maximum score |
| Placebo | Motor Function Measure-32 (MFM-32) Domain 2 (D2) | 96.7 % of maximum score |
p-value: 0.6995% CI: [-1.3, 2]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Motor Function Measure-32 (MFM-32) Domain 3 (D3) | 95.5 % of maximum score |
| Placebo | Motor Function Measure-32 (MFM-32) Domain 3 (D3) | 96.7 % of maximum score |
p-value: 0.3195% CI: [-3.5, 1.1]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Motor Function Measure-32 (MFM-32) Total Score | 84.1 % of maximum score |
| Placebo | Motor Function Measure-32 (MFM-32) Total Score | 83.0 % of maximum score |
p-value: 0.2295% CI: [-0.8, 3]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score | 11.6 scores on a scale |
| Placebo | Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score | 13.7 scores on a scale |
p-value: 0.1295% CI: [-5, 0.6]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score | 8.8 scores on a scale |
| Placebo | Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score | 8.6 scores on a scale |
p-value: 0.8895% CI: [-2.8, 3.3]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score | 11.5 scores on a scale |
| Placebo | Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score | 11.9 scores on a scale |
p-value: 0.7695% CI: [-3.6, 2.7]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score | 9.2 scores on a scale |
| Placebo | Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score | 8.7 scores on a scale |
p-value: 0.7295% CI: [-2.5, 3.5]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score | 7.8 scores on a scale |
| Placebo | Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score | 7.4 scores on a scale |
p-value: 0.795% CI: [-1.8, 2.7]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Peak Torque Extension | 24.7 nM |
| Placebo | Peak Torque Extension | 38.8 nM |
p-value: 0.0995% CI: [-0.7, 9]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Peak Torque Flexion | 24.7 nM |
| Placebo | Peak Torque Flexion | 22.6 nM |
p-value: 0.0995% CI: [-0.4, 4.6]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score | 29.8 scores on a scale |
| Placebo | Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score | 42.3 scores on a scale |
p-value: 0.2895% CI: [-38.9, 13.9]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue | 34.8 t score |
| Placebo | Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue | 51.1 t score |
p-value: 0.3995% CI: [-80.1, 47.5]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue | 43.1 t score |
| Placebo | Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue | 53.1 t score |
p-value: 0.5795% CI: [-59.5, 39.5]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Supine to Stand | 7.4 seconds |
| Placebo | Supine to Stand | 8.4 seconds |
p-value: 0.0595% CI: [-2.1, 0]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Time to Ascend Steps (Seconds) | 3.2 seconds |
| Placebo | Time to Ascend Steps (Seconds) | 3.3 seconds |
p-value: 0.6295% CI: [-0.5, 0.3]t-test, 2 sided
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Walk/Run 10 Meters | 5.2 seconds |
| Placebo | Walk/Run 10 Meters | 5.9 seconds |
p-value: 0.2595% CI: [-2.1, 0.6]t-test, 2 sided
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue Pre-Intervention | 59.2 t score | Standard Deviation 11.8 |
| Placebo | Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue Pre-Intervention | 58.5 t score | Standard Deviation 11.3 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention | 53.25 t score | Standard Deviation 8.5 |
| Placebo | Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention | 51.9 t score | Standard Deviation 7.4 |
Other Pre-specified
DCF-fluorescence Intensity (AU) Pre-Intervention
Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity \[H2DCFDA (H2-DCF, DCF)\].
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | DCF-fluorescence Intensity (AU) Pre-Intervention | 1.7 AU | Standard Deviation 0.9 |
| Placebo | DCF-fluorescence Intensity (AU) Pre-Intervention | 2.0 AU | Standard Deviation 1.6 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Descend Steps Pre-Intervention | 2.2 seconds | Standard Deviation 1 |
| Placebo | Descend Steps Pre-Intervention | 2.3 seconds | Standard Deviation 1 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention | 69.2 scores on a scale | Standard Deviation 16.9 |
| Placebo | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention | 71.3 scores on a scale | Standard Deviation 20.9 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (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 |
| Placebo | Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index Pre-Intervention | 34.3 scores on a scale | Standard Deviation 10.3 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Hand Grip Strength Pre-Intervention | 20.5 kg | Standard Deviation 14 |
| Placebo | Hand Grip Strength Pre-Intervention | 17.5 kg | Standard Deviation 11 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Hand Pinch Strength Pre-Intervention | 6.5 kg | Standard Deviation 5 |
| Placebo | Hand Pinch Strength Pre-Intervention | 5.1 kg | Standard Deviation 2.3 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Motor Function Measure-32 (MFM-32) Domain 1 (D1) Pre-Intervention | 75.8 % of maximum score | Standard Deviation 16.6 |
| Placebo | Motor Function Measure-32 (MFM-32) Domain 1 (D1) Pre-Intervention | 71.6 % of maximum score | Standard Deviation 21.2 |
Other Pre-specified
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.
Time frame: 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..
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Motor Function Measure-32 (MFM-32) Domain 2 (D2) Pre-Intervention | 96.0 % of maximum score | Standard Deviation 4.8 |
| Placebo | Motor Function Measure-32 (MFM-32) Domain 2 (D2) Pre-Intervention | 96.6 % of maximum score | Standard Deviation 7.3 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Motor Function Measure-32 (MFM-32) Domain 3 (D3) Pre-Intervention | 96.7 % of maximum score | Standard Deviation 3.8 |
| Placebo | Motor Function Measure-32 (MFM-32) Domain 3 (D3) Pre-Intervention | 95.2 % of maximum score | Standard Deviation 5.3 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Motor Function Measure-32 (MFM-32) Total Score Pre-Intervention | 84.4 % of maximum score | Standard Deviation 7.6 |
| Placebo | Motor Function Measure-32 (MFM-32) Total Score Pre-Intervention | 82.7 % of maximum score | Standard Deviation 9.8 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score Pre-Intervention | 12.9 scores on a scale | Standard Deviation 4.2 |
| Placebo | Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score Pre-Intervention | 14.3 scores on a scale | Standard Deviation 3.8 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score Pre-Intervention | 8.8 scores on a scale | Standard Deviation 4.8 |
| Placebo | Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score Pre-Intervention | 9.7 scores on a scale | Standard Deviation 4.4 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score Pre-Intervention | 12.1 scores on a scale | Standard Deviation 5.6 |
| Placebo | Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score Pre-Intervention | 13.0 scores on a scale | Standard Deviation 3.9 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score Pre-Intervention | 9.5 scores on a scale | Standard Deviation 4.7 |
| Placebo | Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score Pre-Intervention | 11.3 scores on a scale | Standard Deviation 3.2 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score Pre-Intervention | 7.9 scores on a scale | Standard Deviation 3.1 |
| Placebo | Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score Pre-Intervention | 9.1 scores on a scale | Standard Deviation 3.5 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Peak Torque Extension Pre-Intervention | 56.9 nM | Standard Deviation 42.9 |
| Placebo | Peak Torque Extension Pre-Intervention | 41.6 nM | Standard Deviation 45.5 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Peak Torque Flexion Pre-Intervention | 31.9 nM | Standard Deviation 22 |
| Placebo | Peak Torque Flexion Pre-Intervention | 25.2 nM | Standard Deviation 21.3 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (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 |
| Placebo | Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention | 37.0 scores on a scale | Standard Deviation 8.4 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Pre-Intervention | 42.6 t score | Standard Deviation 8.4 |
| Placebo | Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Pre-Intervention | 57.3 t score | Standard Deviation 7.7 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention | 45.9 t score | Standard Deviation 6.4 |
| Placebo | Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention | 52.8 t score | Standard Deviation 2.8 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Six Minute Walk Test (6MWT) Pre-Intervention | 519.1 meters | Standard Deviation 119 |
| Placebo | Six Minute Walk Test (6MWT) Pre-Intervention | 453.8 meters | Standard Deviation 128.5 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Supine to Stand Pre-Intervention | 6.9 seconds | Standard Deviation 5.5 |
| Placebo | Supine to Stand Pre-Intervention | 6.7 seconds | Standard Deviation 5.4 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Time to Ascend Steps (Seconds) Pre-Intervention | 2.9 seconds | Standard Deviation 1.5 |
| Placebo | Time to Ascend Steps (Seconds) Pre-Intervention | 3.4 seconds | Standard Deviation 1.8 |
Other Pre-specified
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
Time frame: Baseline
Population: Healthy volunteers who participated in a one-visit assessment and RYR1-RM Volunteers measured at Baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Urine 15-F2t Isoprostane Concentration at Baseline | 3.17 ng/mg Cr | Standard Deviation 1.48 |
| Placebo | Urine 15-F2t Isoprostane Concentration at Baseline | 1.36 ng/mg Cr | Standard Deviation 0.48 |
Other Pre-specified
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
Time frame: 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..
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Urine 15-F2t Isoprostane Concentration Pre-Intervention | 3.6 ng/mg Cr | Standard Deviation 2.2 |
| Placebo | Urine 15-F2t Isoprostane Concentration Pre-Intervention | 3.1 ng/mg Cr | Standard Deviation 1.9 |
Other Pre-specified
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine (NAC) | Walk/Run 10 Meters Pre-Intervention | 5.0 seconds | Standard Deviation 2.2 |
| Placebo | Walk/Run 10 Meters Pre-Intervention | 4.6 seconds | Standard Deviation 1.7 |