Not provided
| ID | Type | Description | Link |
|---|---|---|---|
| R21DK113487 | U.S. NIH Grant/Contract | View source |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| National Institutes of Health (NIH) | NIH |
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
Not provided
Not provided
Not provided
Not provided
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:
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pediatric | Experimental | Pediatric patients treated with dantrolene sodium |
|
| Adult | Experimental | Adult patients treated with dantrolene sodium |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| dantrolene sodium | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Not provided
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:
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Fumihiko Urano, MD | Washington University School of Medicine | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University School of Medicine | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26742931 | Background | Urano F. Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep. 2016 Jan;16(1):6. doi: 10.1007/s11892-015-0702-6. | |
| 34185708 | Result | 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. |
| Label | URL |
|---|---|
| Wolfram Syndrome Center | View source |
Not provided
We publish aggregated data in a scientific journal.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Count of Participants | Participants | 6 months |
|
6 months
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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 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. |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Fumihiko Urano, MD, PhD | Washington University School of Medicine, Department of Medicine, Division of Endocrinology | 314-362-8683 | urano@wustl.edu |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 30, 2017 | Jan 23, 2024 | Prot_SAP_000.pdf |
Not provided
| ID | Term |
|---|---|
| D014929 | Wolfram Syndrome |
| D003920 | Diabetes Mellitus |
| D009896 | Optic Atrophy |
| D001259 | Ataxia |
| ID | Term |
|---|---|
| D054062 | Deaf-Blind Disorders |
| D003638 | Deafness |
| D034381 | Hearing Loss |
| D006311 | Hearing Disorders |
Not provided
Not provided
| ID | Term |
|---|---|
| D003620 | Dantrolene |
| ID | Term |
|---|---|
| D006827 | Hydantoins |
| D048289 | Imidazolidines |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
|
| 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:
| 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. | 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. | 6 months |
| BG001 | 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Abnormal liver function test results | 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. | Count of Participants | Participants |
|
| C-peptide levels in participants during the oral mixed meal tolerance test | The investigators track C-peptide levels in participants' blood throughout the oral mixed meal tolerance test. Blood samples for glucose and C-peptide measurement are taken at two points: at the start (fasting, time 0) and 30 minutes after the Boost. The difference in C-peptide levels between these two time points is calculated by subtracting the value at 0 minutes from the value at 30 minutes. | Mean | Standard Deviation | ng/mL |
|
| Visual Functioning in participants assessed by Visual Functioning Questionnaire-25 | The Visual Functioning Questionnaire-25 (VFQ-25) is divided into several subdomains. 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. | Mean | Standard Deviation | units on a scale |
|
| 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. | Mean | Standard Deviation | LogMAR |
|
| 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. | Mean | Standard Deviation | score on a scale |
|
| OG001 | 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. |
|
|
| 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. | Posted | Mean | Standard Deviation | ng/mL | 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:
| Posted | Mean | Standard Error | units on a scale | 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. | Patient 012 was excluded from analysis due to LogMar of 3 (No Light Perception) | Posted | Mean | Standard Error | LogMAR | 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. | Posted | Mean | Standard Error | score on a scale | 6 months |
|
|
|
| 0 |
| 8 |
| 0 |
| 8 |
| 8 |
| 8 |
| EG001 | 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, 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. | 0 | 11 | 0 | 11 | 11 | 11 |
| Weakness | Nervous system disorders | Systematic Assessment |
|
| Dizziness | Nervous system disorders | Systematic Assessment |
|
| Elevated Hepatic enzymes | Hepatobiliary disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Gastrointestinal upset | Gastrointestinal disorders | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Hypoglycemia (mild) | Endocrine disorders | Systematic Assessment |
|
| Headaches | Nervous system disorders | Systematic Assessment |
|
| hyponatremia | Renal and urinary disorders | Systematic Assessment |
|
| Hyperglycemia | Endocrine disorders | Systematic Assessment |
|
| Urinary Tract Infection | Renal and urinary disorders | Systematic Assessment |
|
| Hyperkalemia | Renal and urinary disorders | Systematic Assessment |
|
| Urinary Retention | Renal and urinary disorders | Systematic Assessment |
|
| Influenza | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rhinovirus infection | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Knee Infection | Infections and infestations | Systematic Assessment |
|
| Tics | Nervous system disorders | Systematic Assessment |
|
| Knee Effusions | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Hit by car | Injury, poisoning and procedural complications | Systematic Assessment |
|
| Fatigue | Nervous system disorders | Systematic Assessment |
|
Not provided
Not provided
Not provided
| D004427 |
| Ear Diseases |
| D010038 | Otorhinolaryngologic Diseases |
| D015418 | Optic Atrophies, Hereditary |
| D009901 | Optic Nerve Diseases |
| D003389 | Cranial Nerve Diseases |
| D009422 | Nervous System Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D012678 | Sensation Disorders |
| D009461 | Neurologic Manifestations |
| D001766 | Blindness |
| D014786 | Vision Disorders |
| D015785 | Eye Diseases, Hereditary |
| D005128 | Eye Diseases |
| D003919 | Diabetes Insipidus |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D003922 | Diabetes Mellitus, Type 1 |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
| D010900 | Pituitary Diseases |
| D020820 | Dyskinesias |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |