Ataxia, Diabetes Mellitus, Optic Nerve Atrophy, Wolfram Syndrome
Conditions
Keywords
Wolfram syndrome, Diabetes Mellitus, Optic Nerve Atrophy, Ataxia, Endoplasmic Reticulum Stress
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.
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.
Interventions
DRUGdantrolene 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.
Sponsors
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by Liver Function Tests | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in C-peptide Levels in Participants Assessed by the ELISA Assay | 6 months | 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. | 6 months | 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. |
| Changes in Best-corrected Visual Acuity in Participants Measured by LogMar Score | 6 months | 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. |
| Changes in Neurological Functions in Participants Assessed by the Wolfram Unified Rating Scale (WURS) | 6 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pediatric Pediatric patients treated with dantrolene sodium
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. | 8 |
| Adult Adult patients treated with dantrolene sodium
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. | 11 |
| Total | 19 |
Baseline characteristics
| Characteristic | Pediatric | Total | Adult |
|---|---|---|---|
| Abnormal liver function test results | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical <=18 years | 8 Participants | 8 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 11 Participants | 11 Participants |
| Age, Continuous | 13 years | 18 years | 23 years |
| Best-corrected visual acuity in participants measured by LogMar Score | 0.6 LogMAR STANDARD_DEVIATION 0.2 | 0.7 LogMAR STANDARD_DEVIATION 0.2 | 0.8 LogMAR STANDARD_DEVIATION 0.2 |
| C-peptide levels in participants during the oral mixed meal tolerance test | 0.34 ng/mL STANDARD_DEVIATION 0.07 | 0.25 ng/mL STANDARD_DEVIATION 0.04 | 0.19 ng/mL STANDARD_DEVIATION 0.05 |
| Neurological Functions in participants assessed by the Wolfram Unified Rating Scale (WURS) | 21.3 score on a scale STANDARD_DEVIATION 6.4 | 20.8 score on a scale STANDARD_DEVIATION 3 | 20.5 score on a scale STANDARD_DEVIATION 2.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 7 Participants | 16 Participants | 9 Participants |
| Region of Enrollment United States | 8 participants | 19 participants | 11 participants |
| Sex: Female, Male Female | 6 Participants | 14 Participants | 8 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
| Visual Functioning in participants assessed by Visual Functioning Questionnaire-25 | 68 units on a scale STANDARD_DEVIATION 2.3 | 68.8 units on a scale STANDARD_DEVIATION 3.1 | 74.3 units on a scale STANDARD_DEVIATION 1.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 11 |
| other Total, other adverse events | 8 / 8 | 11 / 11 |
| serious Total, serious adverse events | 0 / 8 | 0 / 11 |
Outcome results
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.
Time frame: 6 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pediatric | Number of Participants With Treatment-related Adverse Events as Assessed by Liver Function Tests | 6 months | 0 Participants |
| Pediatric | Number of Participants With Treatment-related Adverse Events as Assessed by Liver Function Tests | Baseline | 0 Participants |
| Adult | Number of Participants With Treatment-related Adverse Events as Assessed by Liver Function Tests | Baseline | 0 Participants |
| Adult | Number of Participants With Treatment-related Adverse Events as Assessed by Liver Function Tests | 6 months | 2 Participants |
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.
Time frame: 6 months
Population: Patient 012 was excluded from analysis due to LogMar of 3 (No Light Perception)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pediatric | Changes in Best-corrected Visual Acuity in Participants Measured by LogMar Score | Baseline | 0.6 LogMAR | Standard Error 0.2 |
| Pediatric | Changes in Best-corrected Visual Acuity in Participants Measured by LogMar Score | 6 months | 0.6 LogMAR | Standard Error 0.2 |
| Adult | Changes in Best-corrected Visual Acuity in Participants Measured by LogMar Score | Baseline | 0.8 LogMAR | Standard Error 0.2 |
| Adult | Changes in Best-corrected Visual Acuity in Participants Measured by LogMar Score | 6 months | 0.9 LogMAR | Standard Error 0.2 |
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.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pediatric | Changes in C-peptide Levels in Participants Assessed by the ELISA Assay | Baseline | 0.34 ng/mL | Standard Deviation 0.07 |
| Pediatric | Changes in C-peptide Levels in Participants Assessed by the ELISA Assay | 6 months | 0.47 ng/mL | Standard Deviation 0.13 |
| Adult | Changes in C-peptide Levels in Participants Assessed by the ELISA Assay | Baseline | 0.19 ng/mL | Standard Deviation 0.05 |
| Adult | Changes in C-peptide Levels in Participants Assessed by the ELISA Assay | 6 months | 0.30 ng/mL | Standard Deviation 0.09 |
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.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pediatric | Changes in Neurological Functions in Participants Assessed by the Wolfram Unified Rating Scale (WURS) | Baseline | 21.3 score on a scale | Standard Error 6.4 |
| Pediatric | Changes in Neurological Functions in Participants Assessed by the Wolfram Unified Rating Scale (WURS) | 6 months | 18.4 score on a scale | Standard Error 5.7 |
| Adult | Changes in Neurological Functions in Participants Assessed by the Wolfram Unified Rating Scale (WURS) | Baseline | 20.5 score on a scale | Standard Error 2.8 |
| Adult | Changes in Neurological Functions in Participants Assessed by the Wolfram Unified Rating Scale (WURS) | 6 months | 18.6 score on a scale | Standard Error 4.5 |
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: 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pediatric | Changes in Visual Functioning in Participants Assessed by Visual Functioning Questionnaire-25. | Baseline | 68 units on a scale | Standard Error 2.3 |
| Pediatric | Changes in Visual Functioning in Participants Assessed by Visual Functioning Questionnaire-25. | 6 months | 70.5 units on a scale | Standard Error 2.9 |
| Adult | Changes in Visual Functioning in Participants Assessed by Visual Functioning Questionnaire-25. | Baseline | 74.3 units on a scale | Standard Error 1.3 |
| Adult | Changes in Visual Functioning in Participants Assessed by Visual Functioning Questionnaire-25. | 6 months | 73.5 units on a scale | Standard Error 2.4 |