Back to resultsAntioxidant Therapy in RYR1-Related Congenital Myopathy (RYR1)
Primary Purpose
Neuromuscular Disease
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
N-acetylcysteine
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Neuromuscular Disease focused on measuring Neuromuscular Disease, Clinical Trial, Ryanodine Receptor Type 1, Myopathy
Eligibility 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.
EXCLUSION CRITERIA - HEALTHY VOLUNTEERS:
- Diagnosis of RYR1-related myopathy or other neurological disorder (by neurological exam, genetic testing, or muscle biopsy
- Complaints of fatigue or weakness
- Consumption of antioxidants [including NAC, GSH, melatonin, Immunocal (Immunotac
- Research, Vandreuil-Dorion, QC, Canada), Nacystelyn (Galephar, Brussels)] in the 4 weeks before recruitment.
- Use of Beta2-adrenergic agonists.
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Placebo Comparator
No Intervention
Arm Label
RYR1-RM Patients Administered N-acetylcysteine
RYR1-RM Patients Administered Placebo
Healthy Volunteers
Arm Description
N-acetylcysteine
Placebo
Healthy volunteers who had physical exam, study biomarker, Near Infrared Spectroscopy (NIRS) testing and muscle ultrasound only, in one visit.
Outcomes
Primary Outcome Measures
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
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.
Secondary Outcome Measures
DCF-fluorescence Intensity (AU)
Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity [H2DCFDA (H2-DCF, DCF)].
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
NCT ID
NCT02362425
First Posted
February 12, 2015
Last Updated
December 9, 2019
Sponsor
National Institute of Nursing Research (NINR)
1. Study Identification
Unique Protocol Identification Number
NCT02362425
Brief Title
Antioxidant Therapy in RYR1-Related Congenital Myopathy
Acronym
RYR1
Official Title
Antioxidant Therapy in RYR1-Related Congenital Myopathy
Study Type
Interventional
2. Study Status
Record Verification Date
October 5, 2019
Overall Recruitment Status
Completed
Study Start Date
February 12, 2015 (undefined)
Primary Completion Date
May 30, 2018 (Actual)
Study Completion Date
May 30, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Nursing Research (NINR)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuromuscular Disease
Keywords
Neuromuscular Disease, Clinical Trial, Ryanodine Receptor Type 1, Myopathy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
63 (Actual)
8. Arms, Groups, and Interventions
Arm Title
RYR1-RM Patients Administered N-acetylcysteine
Arm Type
Active Comparator
Arm Description
N-acetylcysteine
Arm Title
RYR1-RM Patients Administered Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo
Arm Title
Healthy Volunteers
Arm Type
No Intervention
Arm Description
Healthy volunteers who had physical exam, study biomarker, Near Infrared Spectroscopy (NIRS) testing and muscle ultrasound only, in one visit.
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Urine 15-F2t Isoprostane Concentration
Description
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
Title
Six Minute Walk Test (6MWT)
Description
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
Secondary Outcome Measure Information:
Title
DCF-fluorescence Intensity (AU)
Description
Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity [H2DCFDA (H2-DCF, DCF)].
Time Frame
12 months
Title
Time to Ascend Steps (Seconds)
Description
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
Title
Descend Steps
Description
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
Title
Walk/Run 10 Meters
Description
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
Title
Supine to Stand
Description
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
Title
Motor Function Measure-32 (MFM-32) Domain 1 (D1)
Description
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
Title
Motor Function Measure-32 (MFM-32) Domain 2 (D2)
Description
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
Title
Motor Function Measure-32 (MFM-32) Domain 3 (D3)
Description
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
Title
Motor Function Measure-32 (MFM-32) Total Score
Description
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
Title
Hand Grip Strength
Description
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
Title
Hand Pinch Strength
Description
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
Title
Peak Torque Flexion
Description
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
Title
Peak Torque Extension
Description
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
Title
Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue
Description
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
Title
Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue
Description
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
Title
Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue
Description
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
Title
Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue
Description
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
Title
Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score
Description
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
Title
Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score
Description
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
Title
Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score
Description
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
Title
Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score
Description
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
Title
Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score
Description
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
Title
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score
Description
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
Title
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index
Description
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
Title
Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score
Description
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
Title
Blood Glutathione Reduced (GSH):Oxidized (GSSG) Ratio
Description
GSH:GSSG ratio analyzed only at baseline to offer comparison of RYR1-RM affected individuals to the general population.
Time Frame
Baseline
Other Pre-specified Outcome Measures:
Title
Urine 15-F2t Isoprostane Concentration Pre-Intervention
Description
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
Title
Six Minute Walk Test (6MWT) Pre-Intervention
Description
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
Title
DCF-fluorescence Intensity (AU) Pre-Intervention
Description
Dichlorodihydrofluorescein (DCFH) will be used on participate muscle biopsies to analyze intracellular oxidant activity [H2DCFDA (H2-DCF, DCF)].
Time Frame
6 months
Title
Time to Ascend Steps (Seconds) Pre-Intervention
Description
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
Title
Descend Steps Pre-Intervention
Description
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
Title
Walk/Run 10 Meters Pre-Intervention
Description
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
Title
Supine to Stand Pre-Intervention
Description
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
Title
Motor Function Measure-32 (MFM-32) Domain 1 (D1) Pre-Intervention
Description
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
Title
Motor Function Measure-32 (MFM-32) Domain 2 (D2) Pre-Intervention
Description
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
Title
Motor Function Measure-32 (MFM-32) Domain 3 (D3) Pre-Intervention
Description
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
Title
Motor Function Measure-32 (MFM-32) Total Score Pre-Intervention
Description
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
Title
Hand Grip Strength Pre-Intervention
Description
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
Title
Hand Pinch Strength Pre-Intervention
Description
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
Title
Peak Torque Flexion Pre-Intervention
Description
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
Title
Peak Torque Extension Pre-Intervention
Description
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
Title
Adult Patient-Reported Outcomes Measurement Information System (PROMIS) - Fatigue Pre-Intervention
Description
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
Title
Adult Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention
Description
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
Title
Pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Pre-Intervention
Description
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
Title
Pediatric Quality of Life in Neurological Disorders (NeuroQoL) Fatigue Pre-Intervention
Description
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
Title
Multidimensional Fatigue Inventory - 20 (MFI-20) General Fatigue Score Pre-Intervention
Description
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
Title
Multidimensional Fatigue Inventory-20 (MFI-20) Physical Fatigue Score Pre-Intervention
Description
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
Title
Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Activity Score Pre-Intervention
Description
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
Title
Multidimensional Fatigue Inventory-20 (MFI-20) Reduced Motivation Score Pre-Intervention
Description
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
Title
Multidimensional Fatigue Inventory-20 (MFI-20) Mental Fatigue Score Pre-Intervention
Description
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
Title
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention
Description
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
Title
Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Trial Outcome Index Pre-Intervention
Description
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
Title
Pediatric Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) Total Score Pre-Intervention
Description
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
Title
Urine 15-F2t Isoprostane Concentration at Baseline
Description
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
7 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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.
EXCLUSION CRITERIA - HEALTHY VOLUNTEERS:
Diagnosis of RYR1-related myopathy or other neurological disorder (by neurological exam, genetic testing, or muscle biopsy
Complaints of fatigue or weakness
Consumption of antioxidants [including NAC, GSH, melatonin, Immunocal (Immunotac
Research, Vandreuil-Dorion, QC, Canada), Nacystelyn (Galephar, Brussels)] in the 4 weeks before recruitment.
Use of Beta2-adrenergic agonists.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Suzanne J Wingate, C.R.N.P.
Organizational Affiliation
National Institute of Nursing Research (NINR)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
35698232
Citation
Greer LK, Meilleur KG, Harvey BK, Wires ES. Identification of ER/SR resident proteins as biomarkers for ER/SR calcium depletion in skeletal muscle cells. Orphanet J Rare Dis. 2022 Jun 13;17(1):225. doi: 10.1186/s13023-022-02368-9.
Results Reference
derived
PubMed Identifier
31941795
Citation
Todd JJ, Lawal TA, Witherspoon JW, Chrismer IC, Razaqyar MS, Punjabi M, Elliott JS, Tounkara F, Kuo A, Shelton MO, Allen C, Cosgrove MM, Linton M, Michael D, Jain MS, Waite M, Drinkard B, Wakim PG, Dowling JJ, Bonnemann CG, Emile-Backer M, Meilleur KG. Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies. Neurology. 2020 Mar 31;94(13):e1434-e1444. doi: 10.1212/WNL.0000000000008872. Epub 2020 Jan 15.
Results Reference
derived
PubMed Identifier
29970108
Citation
Witherspoon JW, Vasavada RP, Waite MR, Shelton M, Chrismer IC, Wakim PG, Jain MS, Bonnemann CG, Meilleur KG. 6-minute walk test as a measure of disease progression and fatigability in a cohort of individuals with RYR1-related myopathies. Orphanet J Rare Dis. 2018 Jul 3;13(1):105. doi: 10.1186/s13023-018-0848-9.
Results Reference
derived
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2015-NR-0072.html
Description
NIH Clinical Center Detailed Web Page
Learn more about this trial
Antioxidant Therapy in RYR1-Related Congenital Myopathy
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