Back to resultsA Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
Primary Purpose
Wolfram Syndrome, Diabetes Mellitus, Optic Nerve Atrophy
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
dantrolene sodium
Sponsored by
About this trial
This is an interventional treatment trial for Wolfram Syndrome focused on measuring Wolfram syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia, Endoplasmic Reticulum Stress
Eligibility Criteria
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.
Sites / Locations
- Washington University School of Medicine
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Pediatric
Adult
Arm Description
Pediatric patients treated with dantrolene sodium
Adult patients treated with dantrolene sodium
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
Changes in Visual Functioning in participants assessed by Visual Functioning Questionnaire-25.
Visual functions will be assessed by Visual Functioning Questionnaire - 25.
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.
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.
Full Information
NCT ID
NCT02829268
First Posted
July 6, 2016
Last Updated
April 20, 2023
Sponsor
Washington University School of Medicine
Collaborators
National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
1. Study Identification
Unique Protocol Identification Number
NCT02829268
Brief Title
A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
Official Title
A Phase 1b/2a Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
January 2017 (Actual)
Primary Completion Date
February 2023 (Actual)
Study Completion Date
February 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Wolfram Syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia
Keywords
Wolfram syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia, Endoplasmic Reticulum Stress
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
21 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Pediatric
Arm Type
Experimental
Arm Description
Pediatric patients treated with dantrolene sodium
Arm Title
Adult
Arm Type
Experimental
Arm Description
Adult patients treated with dantrolene sodium
Intervention Type
Drug
Intervention Name(s)
dantrolene sodium
Intervention Description
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.
Primary Outcome Measure Information:
Title
Number of participants with treatment-related adverse events as assessed by liver function tests
Description
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 with an optional extension phase up to 24 months
Secondary Outcome Measure Information:
Title
Changes in C-peptide levels in participants assessed by the ELISA assay
Description
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 with an optional extension phase up to 24 months
Title
Changes in Visual Functioning in participants assessed by Visual Functioning Questionnaire-25.
Description
Visual functions will be assessed by Visual Functioning Questionnaire - 25.
Time Frame
6 months with an optional extension phase up to 24 months
Title
Changes in best-corrected visual acuity in participants measured by Snellen optotype
Description
Best-corrected visual acuity will be measured by Snellen optotype. Higher logMar scores indicate worse vision.
Time Frame
6 months with an optional extension phase up to 24 months
Title
Changes in Neurological Functions in participants assessed by the Wolfram Unified Rating Scale (WURS)
Description
Neurological functions will be assessed by the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.
Time Frame
6 months with an optional extension phase up to 24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fumihiko Urano, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Study Director
Facility Information:
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
publication
Citations:
PubMed Identifier
26742931
Citation
Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep. 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6.
Results Reference
background
PubMed Identifier
34185708
Citation
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.
Results Reference
derived
Links:
URL
https://wolframsyndrome.dom.wustl.edu/
Description
Wolfram Syndrome Center
Learn more about this trial
A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
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