Wolfram SyndromePhase 1/2NCT02829268
A Clinical Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
A Phase 1/2 study testing dantrolene sodium in people with Wolfram Syndrome and Diabetes Mellitus, run by Washington University School of Medicine at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 5 to 60 years
- Conditions the study is for
- Wolfram Syndrome, Diabetes Mellitus, Optic Nerve Atrophy
- What is being tested?
- dantrolene sodium
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2017to Feb 2023
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 to 60 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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:
- 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.
Who cannot join
- 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.
Show all 10Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Washington University School of Medicine
St Louis, Missouri, 63110
About this study
Official title: 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.
Read the detailed 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.
- Conditions
- Wolfram Syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia
- Being tested
- dantrolene sodium
- Keywords
- Wolfram syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia, Endoplasmic Reticulum Stress
- Medical subject headings
- Wolfram Syndrome, Diabetes Mellitus, Optic Atrophy, Ataxia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
dantrolene sodiumDrug
Also called dantrolene
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.
| Study group | Role | What they receive |
|---|---|---|
| Pediatric | Experimental | Pediatric patients treated with dantrolene sodium Receives: Drug: dantrolene sodium |
| Adult | Experimental | Adult patients treated with dantrolene sodium Receives: Drug: dantrolene sodium |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 6 months
Secondary outcomes (4)
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.
Measured: 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:
- 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.
Measured: 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.
Measured: 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.
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jul 2016 (estimated)
- Study startJan 2017
- Primary completionFeb 2023
- Study completionFeb 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Wolfram SyndromeStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Responsible party
- Sponsor
- Investigators
- Fumihiko Urano, MD, Study director, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02829268
- Sponsor's protocol ID
- 201607006
- Other IDs
- R21DK113487
- Status last verified
- Feb 2024
- First submitted
- 6 Jul 2016
- Last updated
- 13 Mar 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: We publish aggregated data in a scientific journal.
Publications
Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep. 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6.
PubMed 26742931Abreu 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.
PubMed 34185708
Study at a glance
From the registry record, last updated by the sponsor on 13 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1b/2a Trial of Dantrolene Sodium in Pediatric and Adult Patients With Wolfram Syndrome
- ClinicalTrials.gov ID
- NCT02829268
- Acronym / sponsor ID
- 201607006
- Conditions
- Wolfram Syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia
- Keywords
- Wolfram syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia, Endoplasmic Reticulum Stress
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 21 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Collaborators
- National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- Jan 2017 (actual)
- Primary completion
- Feb 2023 (actual)
- Study completion
- Feb 2023 (actual)
- First posted
- 12 Jul 2016 (estimated)
- Results
- Posted 13 Mar 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Pediatric | Experimental | Drug: dantrolene sodiumPediatric patients treated with dantrolene sodium |
| Adult | Experimental | Drug: dantrolene sodiumAdult patients treated with dantrolene sodium |
Who may qualify
- Ages
- 5 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- The patient has a definitive diagnosis of Wolfram syndrome, as determined by the following:
- 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.
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| dantrolene sodiumAlso: dantroleneThe 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. | Drug | Adult, Pediatric |
Primary outcome
Number of Participants With Treatment-related Adverse Events as Assessed by Liver Function Tests
Time frame: 6 months
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.
4 secondary outcomes
Changes in C-peptide Levels in Participants Assessed by the ELISA Assay
Time frame: 6 months
Changes in Visual Functioning in Participants Assessed by Visual Functioning Questionnaire-25.
Time frame: 6 months
Changes in Best-corrected Visual Acuity in Participants Measured by LogMar Score
Time frame: 6 months
Changes in Neurological Functions in Participants Assessed by the Wolfram Unified Rating Scale (WURS)
Time frame: 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Mar 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 26742931Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep. 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6.
- Results publication: PubMed 34185708Abreu 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.
- Wolfram Syndrome CenterLink provided by the sponsor.
- Individual participant dataSharing planned: No. We publish aggregated data in a scientific journal.
Related trials for Wolfram Syndrome
Active, not recruitingPhase 2
AMX0035 in Adult Patients With Wolfram Syndrome
Wolfram Syndrome
Active, not recruitingObservational study
Looking for VUS to Confirm Dominant Wolfram-like Syndrome Instead of Recessive Wolfram Syndrome
Optical Coherence Tomography (OCT) of the Retina, Mutation
Not yet recruitingObservational study
Does Recessive Optic Atrophy Due to WFS1 Exist?
Wolfram Syndrome 1, Optic Atrophies, Hereditary
Not yet recruitingObservational study
Mechanisms of Fecal Incontinence in Wolfram Syndrome
Wolfram Syndrome, Fecal Incontinence
RecruitingObservational study
Wolfram Syndrome and WFS1-related Disorders International Registry and Clinical Study
Wolfram Syndrome, Diabetes Mellitus
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fumihiko Urano, MD study director
Washington University School of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing dantrolene sodium in people with Wolfram Syndrome and Diabetes Mellitus, run by Washington University School of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Mar 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Treatment-related Adverse Events as Assessed by Liver Function Tests (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02829268, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Mar 2024.