Antioxidant Therapy in RYR1-Related Congenital Myopathy

NCT02362425 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 15007215-NR-0072
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

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.

Conditions

Neuromuscular Disease

Keywords

Neuromuscular Disease; Clinical Trial; Ryanodine Receptor Type 1; Myopathy

Outcome Measures

Primary Outcomes (2)

• Urine 15-F2t Isoprostane Concentration

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

  12 months

• Six Minute Walk Test (6MWT)

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

  12 months

Secondary Outcomes (26)

• DCF-fluorescence Intensity (AU)

  12 months

• Time to Ascend Steps (Seconds)

  12 months

• Descend Steps

  12 months

• Walk/Run 10 Meters

  12 months

• Supine to Stand

  12 months

Other Outcomes (28)

• Urine 15-F2t Isoprostane Concentration Pre-Intervention

  6 months

• Six Minute Walk Test (6MWT) Pre-Intervention

  6 months

• DCF-fluorescence Intensity (AU) Pre-Intervention

  6 months

Study Arms (3)

RYR1-RM Patients Administered N-acetylcysteine

ACTIVE COMPARATOR

N-acetylcysteine

Drug: N-acetylcysteine

RYR1-RM Patients Administered Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Healthy Volunteers

NO INTERVENTION

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

Interventions

N-acetylcysteine DRUG

RYR1-RM Patients Administered N-acetylcysteine

Placebo DRUG

RYR1-RM Patients Administered Placebo

Eligibility Criteria

• Age: 7 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Nursing Research (NINR): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Chin LMK, Todd JJ, Chrismer IC, Witherspoon JW, Jain M, Waite M, Meilleur KG, Drinkard B, Lawal TA. Exercise capacity in RYR1-related myopathies. Orphanet J Rare Dis. 2025 Sep 24;20(1):485. doi: 10.1186/s13023-025-04013-7.

  PMID: 40993798 DERIVED

• 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.

  PMID: 35698232 DERIVED

• 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.

  PMID: 31941795 DERIVED

• 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.

  PMID: 29970108 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neuromuscular Diseases; Muscular Diseases

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Nervous System Diseases; Musculoskeletal Diseases

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Katherine Meileur Chief, Neuromuscular Symptoms Unit
• Organization: National Institute of Nursing

meilleurk@mail.nih.gov

301-435-1503

Study Officials

• Suzanne J Wingate, C.R.N.P.

  National Institute of Nursing Research (NINR)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2015
• First Posted: February 13, 2015
• Study Start: February 12, 2015
• Primary Completion: May 30, 2018
• Study Completion: May 30, 2018
• Last Updated: December 24, 2019
• Results First Posted: December 24, 2019

Record last verified: 2019-10-05

Locations

US (1)