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

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

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.

The Primary Objective of this study is:

To 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 with an optional extension phase up to 24 months. Patients who express the wish to continue in the optional extension phase on dantrolene sodium will be offered this possibility.

The Secondary Objectives of this study are:

• Determine the effect of dantrolene sodium on remaining beta cell functions using a mixed-meal tolerance test and monitoring base-line C-peptide levels, blood glucose levels, proinsulin/C-peptide ratios, hemoglobin A1c levels, and urine glucose levels.
• To determine the efficacy of dantrolene sodium on visual acuity (LogMar scores)
• To determine the efficacy of dantrolene sodium on visual functions using Visual Functioning Questionnaire - 25.
• To evaluate the efficacy of dantrolene sodium on neurological functions using the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.

Inclusion Criteria:

Patients must meet all of the following criteria to be eligible for enrolment:

1. 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.

2. The patient is at least 5 years of age (biological age) at the time of written informed consent.

3. 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:

1. 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.
2. The patient has a known defect in oxidative phosphorylation (such as a confirmed mitochondrial myopathy)
3. The patient has abnormal liver function (defined as serum transaminases more than twice the upper limit of normal for the reference laboratory)
4. The patient has a significant medical or psychiatric co-morbidity that might affect study data or confound the integrity of study results.
5. The patient has received treatment with any investigational drug within the 30 days prior to study entry.
6. The patient has received blood product transfusions within 90 days prior to screening.
7. 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.
8. The patient has a known history of central apnea and/or ventilation requirements.
9. The patient has a known history of chronic obstructive pulmonary disease, pleural effusion, and/or myocardial disease.