Condition category
Genetic Diseases
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status

Plain English Summary

Background and study aims
Wolfram syndrome is a rare genetic disease. It causes diabetes and blindness in children, then deafness, loss of bladder control, loss of balance, sleep disorders, and sometimes depression. Death is in mid-life from damage to brain cells and brain shrinkage. There is no cure, and nothing to prevent or slow down the disease. The goal is to develop a treatment that will prevent or delay the disease progressing. Sodium valproate treats the disease in cell models of Wolfram syndrome and is already used to treat epilepsy in children. However, it should not be used in people with liver disorders, or in pregnancy, and it can cause side effects including nausea, anaemia, tremor, and mood disturbances. Therefore, its safety and effectiveness needs to be tested for Wolfram patients. The aim of this study is to show that sodium valproate is safe and effective at slowing the disease process.

Who can participate?
Patient aged 5 or older with Wolfram syndrome

What does the study involve?
Participants are randomly allocated to be treated with either sodium valproate or placebo (dummy medicine). Participants are closely monitored for any side effects, for changes in vision, and for changes in brain scans.

What are the possible benefits and risks of participating?
The potential benefit is to see whether sodium valproate can slow down or halt the disease process in Wolfram syndrome. If sodium valproate is taken by women who are pregnant, there is a high risk that it will harm the unborn child. Severe liver damage including liver failure, sometimes resulting in fatalities, has been very rarely reported. Early symptoms may include sudden onset of tiredness, lack of energy, and drowsiness.

Where is the study run from?
1. Birmingham Children’s Hospital NHS Foundation Trust (UK)
2. University Hospitals Birmingham NHS Foundation Trust (UK)
3. Institute des Neurosciences de Montpellier (France)
4. Hôpital Européen Georges Pompidou (France)
5. Medical University of Lodz (Poland)
6. Servicio Andaluz de Salud Área de Gestión Sanitaria Norte de Almeria (Spain)

When is the study starting and how long is it expected to run for?
July 2018 to July 2023

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Shazia Ahmed

Trial website

Contact information



Primary contact

Ms Shazia Ahmed


Contact details

Treat Wolfram Trial office
Open Plan East
5th Floor Institute of Translational Medicine
Mindelsohn Way
B15 2TH
United Kingdom

Additional identifiers

EudraCT number

2017-001215-37 number

Protocol/serial number


Study information

Scientific title

A pivotal, international, randomised, double-blind, efficacy and safety trial of sodium valporate in paediatric and adult patients with Wolfram Syndrome


Treat Wolfram

Study hypothesis

The aim of the trial is to show that Sodium Valproate is safe and effective at slowing the Wolfram syndrome disease process.

Ethics approval

West of Scotland Research Ethics Service, 19/03/2018, ref: 18/WS/0020

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design


Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type


Patient information sheet

No participant information sheet available


Specialty: Genetics, Primary sub-specialty: Genetics; UKCRC code/ Disease: Eye/ Disorders of optic nerve and visual pathways


Patients will be randomized 2:1 to either treatment with sodium valproate or matching placebo (randomised preferably to sodium valproate). Thus using 70 patients as the assumed sample size, 47 patients would be randomised to receive sodium valproate and 23 to receive placebo.

Treatment will initially commence at 10mg/kg/day and be gradually increased by 10mg/kg/day to 40mg/kg/day (maximum 800mg/day 5-11 years; 1600mg/day 12 years of age and over) to ensure safety, for example:
Child under 45kg: start dose up to 10mg/kg/day in 1 or 2 divided doses in 200mg increments, increasing to 40mg/kg/day by week 4; maximum 800mg per day, 400mg per dose.
Child over 45kg or Adult: start dose 600mg/day in 2 divided doses (week 1); 1000mg/day in 2 divided doses (week 2); 1200mg/day in 2 divided doses (week 3); 1600mg/day in 2 divided doses (week 4).

The duration of this trial will be approximately 5 years. Patients will participate for a total of 37 months from the date of consent until the end of the trial.

Stage 1 is screening tests.
Stage 2 is the start of treatment, within 4 weeks of the screening tests.
Stage 3 is a follow-up visit 6 weeks after starting treatment, for safety checks.
Stage 4 includes visits to the hospital at 6, 12, 18, 24, 30 and 36 months, for safety checks and measures of effectiveness. Tests of vision will be done every 6 months; and brain scans every 12 months.
Stage 5 is the final telephone call 4 weeks after the treatment has finished, for safety checks. Once the last participant has completed the last visit, the data collection will be closed and data analysed. The trialists anticipate a trial report within 12 months of the last participant completing the study. This will be the first quarter of 2023.

Intervention type



Not Applicable

Drug names

Primary outcome measure

Visual acuity is measured on the logMAR scale by sight tests in clinic using ETDRS charts at Day -28, Day 0, Day 180, Day 360, Day 540, Day 720, Day 900, Day 1080

Secondary outcome measures

1. Safety, measured by adverse events according to CTCAE v4 at Day 0, Day 7, Day 21, Day 42, Day 90, Day 180, Day 270, Day 360, Day 450, Day 540, Day 630, Day 720, Day 810,Day 900, Day 990, Day 1080, Day 1110
2. Tolerability, measured by dose achieved, days of treatment, and treatment-related dose reductions and discontinuations. Treatment dose escalation period (Day 0 to day 42)
3. Ventral Pons Volume (VPV), a surrogate marker for neurodegeneration, measured and recorded in mm3 by standardised analysis of MR images of the Pons at Day -28, Day 360, Day 720, Day 1080
4. Brainstem volume, measured by MRI as with VPV at Day -28, Day 360, Day 720, Day 1080
5. Retinal nerve thickness, measured by Optical Coherence Tomography at Day -28, Day 360, Day 720, Day 1080
6. Colour vision, measured by Farnsworth plates at Day -28, Day 360, Day 720, Day 1080
7. Visual fields, measured by Humphrey Perimetry at Day -28, Day 360, Day 720, Day 1080
8. Smell, measured by Smell Test (UPSIT) at Day -28, Day 360, Day 720, Day 1080
9. Sleep, measured by Sleep questionnaire and Visual function questionnaires (VQOL_CYP (children) and VFQ25 (adults) at Day -28, Day 42, Day 180, Day 360, Day 540, Day 720, Day 900, Day 1080
10. Balance, measured by Mini-BEST test measured at Day -28, Day 360, Day 720, Day 1080
11. Hearing, measured by pure tone audiometry at Day -28, Day 360, Day 720, Day 1080
12. Wolfram Unified Rating Scale measured at Day -28, Day 360, Day 720, Day 1080
13. Mood, measured by questionnaires measured using the Kidscreen (Patients aged 5-18), Hospital Anxiety and Depression Score (HADS) at day of treatment Day 0, Day 21, Day 42, Day 90, Day 180, Day 270, Day 360, Day 450, Day 540, Day 630, Day 720, Day 810,Day 900, Day 990, Day 1080, Day 1110
14. Quality of life, measured by PedsQL questionnaire (Paediatric patients) at Day -28, Day 42, Day 180, Day 360, Day 540, Day 720, Day 900, Day 1080
15. Urodynamic assessment using the Urodynamics bladder flow rates and urology questionnaire (ICIQ-FLUTS) at Day -28, Day 42, Day 180, Day 360, Day 540, Day 720, Day 900, Day 1080

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

1. The patient has a definitive diagnosis of Wolfram syndrome, as determined by the following:
1.1. Documented diabetes mellitus diagnosed under 16 completed years according to WHO or ADA criteria plus documented optic atrophy diagnosed under 16 completed years AND
1.2. Documented functionally relevant mutations on one or both alleles of the WFS1 gene based on historical test results (if available) or from a qualified laboratory at screening
2. Patient aged 5 years or older
3. The patient’s visual acuity assessed as either the right eye or left eye having a LogMAR score of 1.6 or better on an ETDRS chart, with or without correction
4. Written informed consent
5. Females of childbearing potential will only be included after a negative highly sensitive urine pregnancy test. If sexually active, they must agree to use a highly effective contraception measure and to pregnancy testing at each clinic follow up visit- see 4.1.1 for further information
6. Sexually active men with a female partner of childbearing potential must agree to the use of condoms and the use of a highly effective method of contraception by the female partner
7. Patient willing and able to meet all protocol defined visits for the duration of the trial

Participant type


Age group




Target number of participants

Planned Sample Size: 70; UK Sample Size: 45

Participant exclusion criteria

1. The patient has clinically significant non-Wolfram related Central Nervous System (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 diagnosis of a mitochondrial myopathy
3. The patient has active liver disease, has a personal or family history of liver dysfunction, or has porphyria
4. The patient has a mutation in the POLG gene that is known to be associated with sodium valproate induced liver injury
5. The patient has received treatment with any investigational drug within the 30 days prior to study entry
6. The patient is currently taking sodium valproate; or has a known hypersensitivity to sodium valproate or its excipients
7. Any other acute or chronic medical, psychiatric, social situation or laboratory result that, based on investigator’s judgment, would jeopardize patient safety during trial participation, cause inability to comply with the protocol, or affect the study outcome
8. The patient is currently breastfeeding
9. The patient has Known urea cycle disorders
10. The patient has one of the following disorders: lactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption

Recruitment start date


Recruitment end date



Countries of recruitment

France, Poland, Spain, United Kingdom

Trial participating centre

Birmingham Children’s Hospital NHS Foundation Trust
Steelhouse Lane
B4 6NH
United Kingdom

Trial participating centre

University Hospitals Birmingham NHS Foundation Trust
Trust HQ, PO Box 9551 Queen Elizabeth Medical Centre Edgbaston
B15 2TH
United Kingdom

Trial participating centre

Institute des Neurosciences de Montpellier
Inserm U1051 Pathologies Sensorielles, Neuroplasticité et Thérapies 80, Rue Augustin Fliche

Trial participating centre

Hôpital Européen Georges Pompidou
Functional Unit of Ophthalmology Ophthalmological Rare Diseases Reference Center Assistance Publique Hôpitaux de Paris 20, Rue Leblanc

Trial participating centre

Medical University of Lodz
Department of Paediatrics, Oncology, Haematology and Diabetology 36/50 Sporna Street

Trial participating centre

Consejeria de Salud
Servicio Andaluz de Salud Área de Gestión Sanitaria Norte de Almeria Avda. Gra. Ana Parra s/n Huércal-Overa

Sponsor information


University of Birmingham

Sponsor details

c/o Sean Jennings
Finance Office
Aston Webb
B Block
University of Birmingham
B15 2TT
United Kingdom

Sponsor type




Funder type

Research council

Funder name

Medical Research Council; Grant Codes: MR/P007732/1

Alternative name(s)


Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government


United Kingdom

Results and Publications

Publication and dissemination plan

1. Plan to publish protocol approximately 6 months after the study opens to recruitment – BMJ Open
2. Planned publication of the results in a high-impact peer reviewed journal

IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date


Participant level data

To be made available at a later date

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes