Clinical Trials

A Clinical Trial of Dantrolene Sodium in US

A Clinical Trial of Sodium Valproate in the UK and Europe

Clinical Trials in US, UK and Europe

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

This study is currently recruiting participants. (see Contacts and Locations)

Sponsor Washington University School of Medicine Identifier: NCT02829268


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 24-week 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.

Official Title A Phase 1b Safety Trial of Dantronele Sodium in Pediatric and Adult Patients With Wolfram Syndrome

Primary Outcome Measures

• 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.

Secondary Outcome Measures

• Changes in C-peptide levels in participants assessed by the ELISA assay [ Time Frame: 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. [ Time Frame: 6 months ]
Visual functions will be assessed by Visual Functioning Questionnaire – 25.

• Changes in best-corrected visual acuity in participants measured by Snellen optotype [ Time Frame: 6 months ]
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) [ Time Frame: 6 months ]
Neurological functions will be assessed by the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.


Ages Eligible for Study: 5 Years to 60 Years (Child, Adult)
Sexes Eligible for Study: All
Accepts 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.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02829268


Contact Ashley N Simpson, RN, BSN, CPN +1-314-286-1550
Contact Teresa Arb, RN, BSN, CCRC +1-314-747-1217


United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Ashley Simpson, RN, BSN, CPN 314-286-1550
Contact: Fumihiko Urano, MD 314-362-8683
Principal Investigator: Fumihiko Urano, MD

A Clinical Trial of Treatment to Slow Disease Progression in Children and Adults with Wolfram.

The two possible treatments are:

A- Sodium Valproate treatment
This treatment is for 3 years, until final assessments to see if it works. These are tablets.

B- Placebo treatment
This is also for 3 years. The dummy tablets are identical to the real medicine. The patient and doctor will not know which treatment is which.

This study is in Birmingham, UK; Spain; France; and Poland. 70 people will take part. 2 people will have the medicine to every 1 the placebo, decided by chance.

Stage 1

First visit, up to 28 days before starting
• Ask consent to take part
• Baseline tests and brain scan.
• Check person is eligible to take part

Stage 2

Second visit, randomise to valproate or placebo
• Start treatment

Stage 3

Follow-up visit at 6 weeks
• Visit for safety checks

Stage 4

Visits at 6, 12, 18, 24, 36 months.
• Safety checks, blood tests, eye tests
• MRI brain scans at 12, 24, 36 months

Stage 5

Final visit after treatment finished
• Final safety checks

This trial will tell us if Sodium Valproate is SAFE and EFFECTIVE in Wolfram. If these are shown, then doctors may prescribe this medicine for almost everyone with Wolfram in any country.

For the Sodium Valproate trial, recruitment will start in the UK in Autumn 2017; and in Spain, France and Poland, in Spring 2018.

People will have checks to make sure they have both diabetes mellitus and optic atrophy; a genetic test result; enough vision at the start of the study to be able to assess the effects of treatment; and safety checks.

Possible benefits of taking part
Taking part in a clinical trial can be helpful if the trial medicine works to slow down the progress of the disease. However there is no guarantee that this will happen. There may be benefits in being seen by the study team regularly, as they will monitor the Wolfram disease carefully and treat any complications if they happen.

Possible risks of taking part
Any medicine in a clinical trial may not work, and not slow down the disease; and every medicine has side effects. Sometimes these side effects may be serious or life threatening. Before deciding whether or not to take part, always read the participant information sheets carefully, and ask about possible side effects.

How will we know if a medicine works in Wolfram?
We asked patient support groups in the UK, USA, Spain, and France, to advise us what are the most important outcome measures for trials of new treatments. Each group ranked vision as the most important. This means that any treatment must slow down or stop the worsening of vision.

Prof Tamara Hershey has shown that in people with Wolfram, parts of the brain slowly get smaller with age. This is related to problems with balance. With her kind help, we are using brain scans, to check that any treatment can slow down or stop parts of the brain getting smaller.

In Wolfram, vision gets worse, and parts of the brain get smaller, over years rather than months. In order to show that a treatment works, we need to give the treatment for several years. This is why the Phase II trial of sodium valproate involves giving people the medicine for 3 years.

If it is clear that a medicine in a clinical trial is working, it is possible to stop the trial early and give everyone the medicine.

Can I take these medicines without taking part in a trial?
The medicines being used in the clinical trials are not licensed for use in Wolfram. This means that doctors are not allowed to prescribe them to treat Wolfram syndrome. The reason is that no-one has done studies to show they are safe and to show they work in Wolfram. If a person with Wolfram took one of these medicines outside a trial, and had a serious side effect, the clinical trial would automatically be stopped. If this were to happen, we would never know if these medicines may work in Wolfram.

Future plans for studies
If Dr Urano’s safety study of Dantrolene shows that it is safe, he will then apply for a Phase II study to see if it works in Wolfram. The design of this study will be similar to the Sodium Valproate study above.

We are also seeking European Medicines Agency advice about the design of a Phase III clinical trial comparing Dantrolene Sodium to Valproate and in combination in Wolfram. If this is funded, it will start after the current studies have finished. It will recruit up to 140 people with Wolfram worldwide.

We are very grateful to the following people who gave us their time and helped with this research update letter:
A. Profs Hershey, Marshall, Hamel, Mlynarski, Esteban, OrCAD, Dias, Wright.
B. Wolfram Study Groups in Washington and Birmingham Universities, Boyd Consultants.
C. St. Louis Children’s, Barnes Jewish, Birmingham Children’s, and University Hospital Birmingham
D. Our fantastic family support groups Snow and Ellie White Foundations, Wolfram syndrome UK, Spanish and French associations, Wellchild.