A Natural History Study of RYR1-Related Disorders

A Single-Center Prospective Natural History Study of RYR1-Related Disorders

Background:

Congenital myopathies (CM) are genetic disorders that can cause decreased muscle tone and muscle weakness. Most CMs in the United States are related to the ryanodine receptor 1 (RYR1) gene. Researchers need more natural history data to learn about these CMs in children and adults.

Objective:

To learn more about the signs, symptoms, and course of RYR1-related disorders.

Eligibility:

People aged 7 years and older with an RYR1-related disorder.

Design:

Ambulatory participants will come to the Clinical Center and non-ambulatory participants will visit via telehealth.

Visits will be once a year for 3 or 5 years. Clinical Center visits will take 2 to 3 days.

All participants will undergo tests including:

Photos and videos. These will be taken to document the participant s condition.

Blood and urine tests.

Activity Tracker. Participants will wear a device to record their activity.

Questionnaires. Participants will answer questions about their health, pain, fatigue, stress, quality of life, and other topics.

Participants who visit the Clinical Center will also undergo:

Tests of heart and lung function.

Motor skills and strength tests. Participants will walk, climb stairs, kneel, crawl, stand up, and perform other movements to test their strength and abilities. They will squeeze and pinch a handheld device to test their grip.

Imaging scans.

Skin biopsy. Adult participants may opt to have a sample of skin taken (one time only).

Eye exam

Study Overview

• Status: Not yet recruiting
• Conditions: Ryanodine Receptor 1-Related Myopathy; Ryanodine Receptor 1 Related Disorders

Detailed Description

STUDY DESCRIPTION:

This prospective natural history study seeks to characterize the clinical manifestations and course of Ryanodine Receptor 1 -related disorders (RYR1-RD). RYR1-RD include a wide range of rare congenital and adult-onset neuromuscular phenotypes that are typically slowly progressive. The study is observational and comprises a primary data collection phase (Years 1-3) and extended follow-up phase (Years 4-5). During each phase, there will be one visit per year. The study will enhance the foundational knowledge of RYR1-RD and support clinical trial readiness.

OBJECTIVE:

Primary Objective:

Characterize phenotype and disease course over a three-year period

Secondary Objectives:

Characterize phenotype and disease course over an extended (2-year) period (total 5 years)

Exploratory Objectives:

1. Investigate potential biomarkers of disease status and progression
2. Explore clinical meaningfulness thresholds for research assessments

3. Extract common data elements from existing medical records (realworld evidence)

   ENDPOINTS:

   Primary Endpoints:

   Change from baseline to Year 3 in:

   Motor function and performance

   • Motor Function Measure (MFM) sub-domains (percent of maximum score)
   • Six-minute walk test (meters travelled with percent predicted)
   • Timed functional tests (ascend four stairs, descend four stairs, supine to stand) (seconds)
   • Grip and pinch strength (kg and percent predicted)
   • Accelerometry (wearable sensor)
   • Quantitative muscle assessment
   • Brooke and Vignos assessment

   Pulmonary function

   • Forced vital capacity (percent reference norm)
   • Forced expiratory volume at 1 second (percent reference norm)
   • Slow vital capacity (Liters)
   • Maximal voluntary ventilation (Liters)
   • Maximum inspiratory pressure (MIP)
   • Maximum expiratory pressure (MEP)

   Patient-reported outcomes

   • PROMIS-57 Profile v2.1 (subscale and overall t-scores); adults - depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and satisfaction with participation in social roles
   • PROMIS Ped-25 Profile v2.0 (subscale and overall t-scores); 8 - 17 y
   • PROMIS Parent Proxy CAT v2.0 - Fatigue, physical stress experiences, positive affect and wellbeing, psychological stress experiences, anxiety/fear, physical function, pain; 5-7 y
   • NeuroQoL Upper and lower limb function
   • Physical Activity Questionnaire for Children (PAQ-C); 8 - 13 y
   • Physical Activity Questionnaire for Adolescents (PAQ-A); 14 - 17 y
   • International physical activity questionnaire (IPAQ); adults
   • Falls questionnaire; adults

   Ophthalmology

   • Marginal reflex distance (Ptosis)
   • Binocular horizontal visual field test
   • Optical Coherence Tomography
   • Goldmann Perimetry Degrees: lateral rectus, superior rectus, inferior oblique, medial rectus, superior oblique, inferior rectus

   Medical data review

   • Demographics
   • Developmental history
   • Medical history
   • Social determinants of health (environmental conditions such as economic stability, health care and education access and quality, neighborhood and built environment, and social and community context.
   • Full physical exam
   • Review of genetic diagnostic report/results
   • Prior medical records

   Adverse and disease-related events

   Serious (21CFR312.32) adverse events:

   • Narrative description (clinician)
   • Causality assessment (related or unrelated to disease)
   • CTCAE system organ class
   • CTCAE lower-level term

   Exploratory Endpoints:

   Biomarkers

   Including but not limited to:

   • Plasma NAD plus, NADH
   • Plasma GSH, GSSG
   • Plasma cytokines
   • Serum creatine phosphokinase
   • Urine and plasma 15-F2t isoprostane
   • Urine 8OHdG
   • Near infrared spectroscopy (muscle tissue oxygenation)
   • Dixon MRI of lower extremity
   • Optional skin punch biopsy (fibroblast culture)
   • Muscle ultrasound
   • Electrical impedance myography (EIM)

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: Irene C Chrismer, R.N.; Phone Number: (240) 591-8884; Email: irene.chrismer@nih.gov
• Study Contact Backup: Name: Tokunbor A Lawal, Ph.D.; Phone Number: (301) 594-6484; Email: lawalt@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center
      • Contact: NIH Clinical Center Office of Patient Recruitment (OPR); Phone Number: TTY dial 711 (800) 411-1222; Email: ccopr@nih.gov
      • Contact: Irene Chrismer; Phone Number: 240-591-8884; Email: irene.chrismer@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

A total of 150 clinically stable adults and children (7 years of age or older) with genetically confirmed RYR1-RD.

Description

• INCLUSION CRITERIA (CENTRALIZED ARM)

  1. Stated willingness to comply with all study procedures, availability for the duration of the study, and submission of medical records to research team prior to screening.
  2. Male or female, aged >=7 years of age.
  3. Genetically confirmed RYR1-related disorder, evidenced by pathogenic or likely pathogenic variants identified by CLIA testing (whole genome, exome, targeted, partial or full RYR1 sequencing) OR variant of uncertain significance with supporting clinical phenotype.
  4. Agreement to adhere to Lifestyle Considerations throughout study duration.
  5. Ability of subject to communicate their understanding of the purpose of the study, and willingness to provide assent and/or to sign a written informed consent document.
  6. Resides in the United States.

INCLUSION CRITERIA (DE-CENTRALIZED ARM)

1. Stated willingness to comply with all study procedures, availability for the duration of the study, and submission of medical records to research team prior to screening.
2. Male or female, aged > 7 years of age.
3. Genetically confirmed RYR1-related disorder, evidenced by pathogenic or likely pathogenic variants identified by CLIA testing (whole genome, exome, targeted, partial or full RYR1 sequencing) OR variant of uncertain significance with supporting clinical phenotype.
4. Ability of subject to communicate their understanding of the purpose of the study, and willingness to provide assent and/or sign a written informed consent document.
5. Resides in the United States

EXCLUSION CRITERIA (CENTRALIZED ARM)

1. Participation in an IND, IDE, or equivalent clinical study in the past six months
2. Severe disability or mobility issues (inability to walk 10 meters with or without assistance)
3. Requires mechanical ventilation or tracheotomy
4. Other neuromuscular diseases resulting in muscle weakness
5. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study (e.g. active infection) or safety of the subject.

EXCLUSION CRITERIA (DE-CENTRALIZED ARM)

1. Participation in an IND, IDE, or equivalent clinical study in the past six months
2. Other neuromuscular diseases resulting in muscle weakness
3. Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study (e.g. active infection) or safety of the subject

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Centralized; Visits are conducted at the NIH clinical center. All participants are ambulatory.
Decentralized; Visits are conducted via telehealth.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse and disease-related events	Serious (21CFR312.32) adverse events:- Narrative description (clinician)- Causality assessment (related or unrelated to disease)- CTCAE system organ class- CTCAE lower-level term- Falls questionnaire; adults	3 years
Medical data review	- Demographics- Developmental history- Medical history- Social determinants of health (environmental conditions such as economic stability, health care and education access and quality, neighborhood and built environment, and social and community context.- Full physical exam- Review of genetic diagnostic report/results- Prior medical records	3 years
Ophthalmology	- Marginal reflex distance (Ptosis)- Binocular horizontal visual field test- Optical Coherence Tomography- Goldmann Perimetry Degrees: lateral rectus, superior rectus, inferior oblique, medial rectus, superior oblique, inferior rectus	3 years
Patient-reported outcomes	- PROMIS-57 Profile v2.1 (subscale and overall t-scores); adults -depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and satisfaction with participation in social roles- PROMIS Ped-25 Profile v2.0 (subscale and overall t-scores); 8-17 y- PROMIS Parent Proxy CAT v2.0 Fatigue, physical stress experiences, positive affect and wellbeing, psychological stress experiences, anxiety/fear, physical function, pain; 5-7 y- NeuroQoL Upper and lower limb function- Physical Activity Questionnaire for Children (PAQ-C); 8-13 y- Physical Activity Questionnaire for Adolescents (PAQ-A); 14-17 y- International physical activity questionnaire (IPAQ); adults	3 years
Pulmonary function	- Forced vital capacity (% reference norm)- Forced expiratory volume at 1 second (% reference norm) - Slow vital capacity (Liters)- Maximal voluntary ventilation (Liters)- Maximum inspiratory pressure (MIP)- Maximum expiratory pressure (MEP)	3 years
Motor function and performance	- Motor Function Measure (MFM) sub-domains (percent of maximum score)- Six-minute walk test (meters travelled with percent predicted)- Timed functional tests (ascend four stairs, descend four stairs, supine to stand) (seconds)- Grip and pinch strength (kg and % predicted)- Accelerometry (wearable sensor)- Quantitative muscle assessment- Brooke and Vignos assessment	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterize phenotype and disease course over an extended (2-year) period (total 5 years).Collect exploratory biomarker data.	(1) Investigate potential biomarkers of disease status and progression(2) Explore clinical meaningfulness thresholds for research assessments(3) Extract common data elements from existing medical records (real-world evidence)	5 years

Collaborators and Investigators

• Sponsor: National Institute of Nursing Research (NINR)
• Investigators: Principal Investigator: Tokunbor A Lawal, Ph.D., National Institute of Nursing Research (NINR)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): May 5, 2024
• Primary Completion (Estimated): April 30, 2031
• Study Completion (Estimated): December 30, 2031

Study Registration Dates

• First Submitted: February 29, 2024
• First Submitted That Met QC Criteria: February 29, 2024
• First Posted (Actual): March 1, 2024

Study Record Updates

• Last Update Posted (Estimated): April 30, 2024
• Last Update Submitted That Met QC Criteria: April 29, 2024
• Last Verified: March 7, 2024

More Information

Terms related to this study

• Keywords: Natural History; Congenital Myopathy; Muscle Disease; RYR1
• Additional Relevant MeSH Terms: Nervous System Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Muscular Diseases
• Other Study ID Numbers: 10001737; 001737-NR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No