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Protocol Details

Safety and Tolerability of S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts




Sponsoring Institute

National Institute of Neurological Disorders and Stroke (NINDS)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: 65

Referral Letter Required


Population Exclusion(s)


Special Instructions

Currently Not Provided


Phase I;
Small Molecule;

Recruitment Keyword(s)



RYR-1 Myopathy

Investigational Drug(s)

S 48168

Investigational Device(s)



Drug: S48168

Supporting Site

National Institute of Neurological Disorders and Stroke


Ryanodine receptor isoform 1-related congenital myopathies (RYR1-RM) are a group of

rare neuromuscular diseases. RYR1-RM first develops in children. People with RYR1-RM may have muscle weakness, impaired walking, and other problems. There is no treatment for RYR1-RM. Researchers hope the drug S 48168 (ARM 210) can help by fixing leaky RyR1 channels.


To test if S 48168 (ARM 210) is safe for people with RYR1-RM or has significant side effects.


Otherwise healthy people age 18 65 with RYR1-RM.

Prior muscle biopsy that shows loss of RyR1-Calstabin1 association.

Able to walk ten meters, with or without assistance.


Participants will have blood drawn locally for screening tests. After this, participants will have 3 study visits at NIH Clinical Center. Final screening tests will be completed at the first visit. Visit 1 will last 3 5 days; visit 2, 1 2 days; visit 3, 3 4 days. The three visits will occur over a period of 1 month.

Participants will be screened with a medical history and physical exam. Their heart rate, blood pressure, and heart and lung function will be checked. They will give blood and urine samples. A small tube may be inserted in a vein to collect blood. They will take movement function tests. They will complete a questionnaire about their fatigue symptoms. They will answer questions about suicidal thoughts. These tests will be repeated during the study. Photographs/videos may be taken to document symptoms.

Participants will have 2 needle muscle biopsies. One at the beginning of the study and one at the end of the study.

Participants will take S 48168 (ARM 210) by mouth daily for 28 days. They will keep a medication diary. A study investigator will make lifestyle recommendations.

Between visits and after treatment, participants will be contacted by email or telephone. They will talk about how they are feeling.

One week after the last dose of S 48168 (ARM 210), participants will give a blood sample at a local facility.

Participation lasts about 2 months.

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Patients must meet all the following conditions to be eligible for enrollment into the study:

1. Adult males and females, 18 - 65 years of age, inclusive, at screening.

2. Body mass index (BMI) greater than or equal to 18.0 and less than or equal to 36.0 kg/m(2) at screening.

3. Confirmed genetic diagnosis of RYR1-RM and supporting clinical phenotype with demonstrable deficits on at least one of the baseline study assessments.

4. Evidence of functional deficit (defined by MFM-32 <= 80% maximum score) or demonstratable deficits in at least one of the baseline muscle/motor function assessments.

5. Ambulatory. Able to walk ten meters (with or without assistance e.g. with a cane).

6. Must have a CYP2C8 extensive or intermediate metabolizer genotype.

7. Daily use of medicines and dietary supplements need to be approved by the PI and Sponsor, or a drug/supplement-dependent wash-out prior to inclusion.

8. For male subjects: is sterile or agrees to use an appropriate method of contraception, including a condom with spermicide, from study drug administration on the first day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug administration. No restrictions are required for a vasectomized male subject provided the subject is at least 1-year post bilateral vasectomy procedure prior to study drug administration on first day of the first dose. A male subject whose vasectomy procedure was performed less than 1 year prior to study drug administration on the first day of dosing must follow the same restrictions as a non-vasectomized male. Appropriate documentation of surgical procedure should be provided.

9. For male subjects: agrees to not donate sperm from study drug administration on the first day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug.

10. For female subjects of childbearing potential: uses one of the following highly effective birth control methods (from the first dose until 5 half-lives plus 90 days (approximately 94 days):

-Prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch.

-Intrauterine device (IUD).

-Intrauterine hormone-releasing system (IUS).

-Depot/implantable hormone (e.g., Depo-provera , Implanon).

-Bilateral tubal occlusion/ligation.

-Sexual abstinence:

--Refraining from heterosexual intercourse during the entire period of risk associated with the study requirements.

--If the participant decides to become sexually active during the study, then one of the highly effective birth control methods must be used.

11. For female subjects of non-childbearing potential; defined by at least 1 of the following criteria:

-Postmenopausal defined as 12 months of spontaneous amenorrhea and follicle-stimulating hormone (FSH) serum level > 40mIU/mL. Appropriated documentation of FSH levels is required.

-Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure.

-Has a congenital condition resulting in no uterus.

12. Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and study procedures.

13. Able to provide written informed consent and understands the study procedures in the informed consent form (ICF).


The presence of any of the following conditions will exclude a patient from study enrollment:

1. Patient is mentally or legally incapacitated at the time of the screening visit or during the conduct of the study.

2. History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose of study drug.

3.History or presence of hypersensitivity or idiosyncratic reaction to the study drug, related compounds, or inactive ingredients.

4.Positive urine drug or alcohol results at screening.

5.Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).

6.Patients with baseline ALT levels three times above the upper limits of normal (ULN) or baseline AST levels five times the ULN (isolated elevations of total bilirubin <2 X ULN with direct bilirubin below the ULN will be included).

7.Patients with severe pulmonary dysfunction at screening (Forced Vital Capacity (FVC) < 50% predicted) or evidence of pulmonary exacerbation. Pulmonary exacerbations refer to an acute worsening of respiratory symptoms that result from a decline in lung function.

8. Patients with a history of a seizure.

9. Subject has a history of cancer (malignancy) Exceptions: (1) Subjects with adequately treated non-melanomatous carcinoma or carcinoma in situ of the cervix may participate in the trial (2) Subjects with other malignancies who have been successfully treated > 10 years prior to the screening where in the judgment of the investigator has revealed no evidence of recurrence from the time of treatment through the time of the screening except those identified at the beginning of the exclusion criterion or (3) Subjects who in the opinion of the investigator are highly unlikely to sustain a recurrence for the duration of the trial.

10. Patients with uncontrolled diabetes defined as HbA1c > 7% or diabetic neuropathy.

11. Estimated creatinine clearance <40 mL/minute at screening, which may be calculated using the Chronic Kidney Disease Epidemiology Collaborative method (CKD-EPI), due to reduced muscle mass often seen in RYR1-RM patients.

12. Patients with a clinically significant abnormality on their ECG other than hypertensive related, or heart failure (ejection fraction <30%) or other clinically significant structural heart disease on echocardiogram.

13. Patients with a history of myocardial infarction in the last five years, or evidence of congestive heart failure.

14. Pregnant and breastfeeding women.

15. Unable to refrain from or anticipates the use of:

-Any non-approved medicines and/or dietary supplements beginning 14 days prior to the first dose of study drug and throughout the study. Thyroid hormone replacement medication may be permitted if subject has been on same stable dose for the last 3 months prior to the first dose of study drug.

-Any drugs known to be significant inducers or inhibitors of CYP2C8 enzymes for 28 days prior to the first dose of study drug and throughout the study. Any substrates of breast cancer resistance protein (BCRP).

16. Is currently taking any drug which raises gastric pH, including proton pump inhibitors or H2 antagonists. Antacids may be used if taken at night.

17. Donation of blood or significant blood loss within 56 days prior to the first dose of study drug.

18.Plasma donation within 7 days prior to the first dose of study drug.

19.Participation in clinical trials for other therapeutic investigational drugs simultaneously or within the 4 weeks prior to the first dose of study drug.

20.Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study or safety of the subject.

21. Is an NIH employee who is a subordinate/relative/coworker of a study investigator.

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Not Provided

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Principal Investigator

Referral Contact

For more information:

Payam Mohassel, M.D.
National Institute of Neurological Disorders and Stroke (NINDS)

Irene C. Chrismer, R.N.
National Institute of Neurological Disorders and Stroke (NINDS)
National Institutes of Health
Building 60
Room 259
60 Cloister Court
Bethesda, Maryland 20892
(301) 451-4881

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: 1-866-411-1010

Clinical Trials Number:


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