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

Washington University School of Medicine21 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Interventions

dantrolene sodiumDRUG

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.

Eligibility

Sex: ALLMin age: 5 YearsMax age: 60 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: 6 months

Secondary Outcomes

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.

Time frame: 6 months

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

Changes in Visual Functioning in participants assessed by Visual Functioning Questionnaire-25. The Visual Functioning Questionnaire-25 (VFQ-25) is divided into several subdomains, each assessing a specific aspect of visual functioning and its impact on an individual's life. There are a total of 11 subdomains in the VFQ-25. To calculate the total score on the VFQ-25, we follow these steps: 1. Calculate Subdomain Scores, 2. Weighted Sum 3. Calculate Total Score VFQ-25 provides scores that range from 0 to 100. The total score represents the overall impact of visual functioning on the individual's quality of life, with higher scores indicating better quality of life and less impact from vision problems.

Time frame: 6 months

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

Best-corrected visual acuity is assessed using the Snellen optotype and then converted into LogMar Scores (Minimum: -0.30, Maximum: 3.0). A higher LogMar score signifies poorer vision.

Time frame: 6 months

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

Neurological functions are assessed by the Wolfram Unified Rating Scale (WURS). The WURS is divided into the following subscales: Physical Assessment and Behavioral Assessment. Physical Assessment (34 items rated on a scale from 0 = no symptoms to 4 = highest severity, minimum: 0, Maximum: 136) and Behavioral Assessment (9 items rated on frequency and severity from 0 = normal behavior to 3 = highest severity, Minimum: 0, Maximum: 27). Subscale scores are summed to calculate the total scores (minimum: 0, Maximum: 163). Higher total scores indicate more severe neurological manifestations.

Time frame: 6 months

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes