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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1b/2a Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome

Conditions
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Wolfram Syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia

Intervention / Treatment
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* Drug: dantrolene sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pediatric<br>Pediatric patients treated with dantrolene sodium | Drug: dantrolene sodium<br>* 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.<br>|
| Experimental: Adult<br>Adult patients treated with dantrolene sodium | Drug: dantrolene sodium<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 with an optional extension phase up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in C-peptide levels in participants assessed by the ELISA assay | The investigators determine the effect of dantrolene sodium on residual beta cell functions. The investigators monitor base-line C-peptide levels in participants' blood. The investigators also monitor C-peptide levels in participant's blood during the oral mixed meal tolerance test. The night before the oral mixed meal tolerance test, the participants will turn their insulin pump basal rate to 50% of the normal rate at midnight or take half of their evening dose of Lantus insulin and fasted from midnight until the test at 8 a.m. The mixed meal consists of 6 ml/kg (maximum 360 ml) of Boost Original (Société des Produits Nestlé S.A., Vevey, Switzerland). Blood for glucose and C-peptide measurement will be drawn at time 0 (fasting) and 30 minutes after the Boost. If a subject's fasting glucose exceeds 11.1 mmol/l, the test will not be performed, but fasting glucose and C-peptide will be obtained. | 6 months with an optional extension phase up to 24 months | 
| Changes in Visual Functioning in participants assessed by Visual Functioning Questionnaire-25. | Visual functions will be assessed by Visual Functioning Questionnaire - 25. | 6 months with an optional extension phase up to 24 months | 
| Changes in best-corrected visual acuity in participants measured by Snellen optotype | Best-corrected visual acuity will be measured by Snellen optotype. Higher logMar scores indicate worse vision. | 6 months with an optional extension phase up to 24 months | 
| Changes in Neurological Functions in participants assessed by the Wolfram Unified Rating Scale (WURS) | Neurological functions will be assessed by the Wolfram Unified Rating Scale (WURS) and standard neurological assessments. | 6 months with an optional extension phase up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Wolfram syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia, Endoplasmic Reticulum Stress