A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome

NCT02829268 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: 201607006R21DK113487
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing loss, and neurodegeneration. The purpose of this study is to assess the safety and tolerability of dantrolene sodium in patients with Wolfram syndrome. In addition, we will assess the efficacy of dantrolene sodium on the cardinal manifestations of Wolfram syndrome, including visual acuity, remaining beta cell functions, and neurological functions. There is a screening period up to 56 days, a 6-month treatment period with an optional extension phase up to 24 months, and a 4-week safety follow-up period. Study assessments include medical \& medication history, physical exams, neurological exams, eye exams, endocrine exams, vital signs, height, weight, electrocardiograms, blood and urine tests, pregnancy test if applicable, and questionnaires.

Conditions

Wolfram Syndrome; Diabetes Mellitus; Optic Nerve Atrophy; Ataxia

Keywords

Wolfram syndrome; Diabetes Mellitus; Optic Nerve Atrophy; Ataxia; Endoplasmic Reticulum Stress

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Treatment-related Adverse Events as Assessed by Liver Function Tests

  The investigators assess the safety and tolerability of dantrolene sodium administered orally at upper end of therapeutic dose range for 6 months in patients with Wolfram syndrome. More specifically, the investigators perform liver function tests to check the levels of certain enzymes and proteins in participants' blood. Levels that are higher or lower than normal can indicate liver problems. The liver function tests include: Alanine transaminase (ALT), Aspartate transaminase (AST), Alkaline Phosphatase (AP), and bilirubin.

  6 months

Secondary Outcomes (4)

• Changes in C-peptide Levels in Participants Assessed by the ELISA Assay

  6 months

• Changes in Visual Functioning in Participants Assessed by Visual Functioning Questionnaire-25.

  6 months

• Changes in Best-corrected Visual Acuity in Participants Measured by LogMar Score

  6 months

• Changes in Neurological Functions in Participants Assessed by the Wolfram Unified Rating Scale (WURS)

  6 months

Study Arms (2)

Pediatric

EXPERIMENTAL

Pediatric patients treated with dantrolene sodium

Drug: dantrolene sodium

Adult

EXPERIMENTAL

Adult patients treated with dantrolene sodium

Drug: dantrolene sodium

Interventions

dantrolene sodium DRUG

The purpose of this study is to assess the safety and tolerability of dantrolene sodium in patients with Wolfram syndrome. In addition, we will assess the efficacy of dantrolene sodium on the cardinal manifestations of Wolfram syndrome, including visual acuity, remaining beta cell functions, and neurological functions. There is a screening period up to 56 days, a 6-month treatment period with an optional extension phase up to 24 months, and a 4-week safety follow-up period. Study assessments include medical \& medication history, physical exams, neurological exams, eye exams, endocrine exams, vital signs, height, weight, electrocardiograms, blood and urine tests, pregnancy test if applicable, and questionnaires.

Also known as: dantrolene

Adult; Pediatric

Eligibility Criteria

• Age: 5 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients must meet all of the following criteria to be eligible for enrolment:
• The patient has a definitive diagnosis of Wolfram syndrome, as determined by the following:
• a. Documented functionally relevant recessive mutations on both alleles of the WFS1 gene or dominant mutation on one allele of the WFS1 gene based on historical test results (if available) or from a qualified laboratory at screening.
• The patient is at least 5 years of age (biological age) at the time of written informed consent.
• The patient, patient's parent(s), or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient. The guardians' consent and patient's assent, as relevant, must be obtained.

You may not qualify if:

• Patients who meet any of the following criteria are not eligible for this study:
• The patient has clinically significant non-Wolfram related CNS involvement which is judged by the investigator to be likely to interfere with the accurate administration and interpretation of protocol assessments.
• The patient has a known defect in oxidative phosphorylation (such as a confirmed mitochondrial myopathy)
• The patient has abnormal liver function (defined as serum transaminases more than twice the upper limit of normal for the reference laboratory)
• The patient has a significant medical or psychiatric co-morbidity that might affect study data or confound the integrity of study results.
• The patient has received treatment with any investigational drug within the 30 days prior to study entry.
• The patient has received blood product transfusions within 90 days prior to screening.
• The patient is unable to comply with the protocol, (e.g. has a clinically relevant medical condition making implementation of the protocol difficult, unstable social situation, known clinically significant psychiatric/behavioural instability, is unable to return for safety evaluations, or is otherwise unlikely to complete the study), as determined by the Investigator.
• The patient has a known history of central apnea and/or ventilation requirements.
• The patient has a known history of chronic obstructive pulmonary disease, pleural effusion, and/or myocardial disease.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Institutes of Health (NIH): collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Related Publications (2)

• Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep. 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6.

  PMID: 26742931 BACKGROUND

• Abreu D, Stone SI, Pearson TS, Bucelli RC, Simpson AN, Hurst S, Brown CM, Kries K, Onwumere C, Gu H, Hoekel J, Tychsen L, Van Stavern GP, White NH, Marshall BA, Hershey T, Urano F. A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome. JCI Insight. 2021 Aug 9;6(15):e145188. doi: 10.1172/jci.insight.145188.

  PMID: 34185708 RESULT

Related Links

• Wolfram Syndrome Center

MeSH Terms

Conditions

Wolfram Syndrome; Diabetes Mellitus; Optic Atrophy; Ataxia

Interventions

Dantrolene

Condition Hierarchy (Ancestors)

Deaf-Blind Disorders; Deafness; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Optic Atrophies, Hereditary; Optic Nerve Diseases; Cranial Nerve Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Sensation Disorders; Neurologic Manifestations; Blindness; Vision Disorders; Eye Diseases, Hereditary; Eye Diseases; Diabetes Insipidus; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Pituitary Diseases; Dyskinesias; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Hydantoins; Imidazolidines; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Fumihiko Urano, MD, PhD
• Organization: Washington University School of Medicine, Department of Medicine, Division of Endocrinology

urano@wustl.edu

314-362-8683

Study Officials

• Fumihiko Urano, MD

  Washington University School of Medicine

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2016
• First Posted: July 12, 2016
• Study Start: January 1, 2017
• Primary Completion: February 1, 2023
• Study Completion: February 1, 2023
• Last Updated: March 13, 2024
• Results First Posted: March 13, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)