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

Diabetes Mellitus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02829268
• Other study ID #: 201607006
• Secondary ID: R21DK113487
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 2017
• Est. completion date: February 2023

Study information

• Verified date: February 2024
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: February 2023
• Est. primary completion date: February 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 5 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Ataxia
• Atrophy
• Diabetes Mellitus
• Optic Atrophy
• Optic Nerve Atrophy
• Syndrome
• Wolfram Syndrome

Intervention

Drug:
• dantrolene sodium
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.

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (3)

Lead Sponsor	Collaborator
Washington University School of Medicine	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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 Wolfra — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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: Calculate Subdomain Scores,; Weighted Sum; 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.	6 months
Secondary	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.	6 months
Secondary	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.	6 months

External Links

•   Wolfram Syndrome Center