Efficacy and Safety Trial of Sodium Valproate, in Paediatric and Adult Patients With Wolfram Syndrome

NCT03717909 | Completed Phase 2 DMC

• 1 other identifier: RG_16_211
• Study Type: interventional
• Target: 63
• Locations: 4 countries
• Sites: 6

Brief Summary

This trial aims to investigate the efficacy, safety and tolerability of sodium valproate in the treatment of patients with Wolfram syndrome. 70 paediatric and adult patients were initially planned to be randomised 2:1 to receive either sodium valproate or placebo at 6 international centres. 63 patients were recruited when a decision was made to stop the study recruitment in November 2022.

Conditions

Wolfram Syndrome

Keywords

Wolfram Syndrome; Treat Wolfram; Sodium valproate

Outcome Measures

Primary Outcomes (1)

• Visual acuity (VA)

  Visual acuity (VA) is measured on the logMAR scale by sight tests in clinic using Early treatment diabetic retinopathy study (ETDRS) charts. Values are taken for each eye separately, both uncorrected, and corrected with glasses or contact lenses, and can range from 0, which represents perfect vision i.e. 20/20 (values of -0.1 and -0.2 are also possible representing better than perfect vision), to +2 which represents near blindness i.e. 20/2000. Increases in logMAR represent deterioration.

  36 months

Secondary Outcomes (25)

• Safety - adverse events

  37 months

• Tolerability - highest treatment dose

  36 months

• Tolerability - duration of treatment

  36 months

• Tolerability - dosing modifcation

  36 months

• Pons Volume

  37 months (+/- 6 months)

Other Outcomes (8)

• PBMC biomarker 1

  37 months

• Genetic variations

  37 months

• Gene expression changes

  37 months

Study Arms (2)

Experimental Group

EXPERIMENTAL

Sodium Valproate 200Mg E/C Tablet (active treatment)

Drug: Sodium Valproate 200Mg E/C Tablet

Control Group

PLACEBO COMPARATOR

Sodium Valproate matched placebo (inactive treatment)

Drug: Sodium Valproate matched placebo

Interventions

Sodium Valproate 200Mg E/C Tablet DRUG

Treatment with twice-daily oral tablet(s)

Also known as: Sodium Valproate

Experimental Group

Sodium Valproate matched placebo DRUG

Treatment with twice-daily oral 200mg tablet(s)

Also known as: Placebo

Control Group

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 diabetes mellitus diagnosed under 16 completed years according to WHO or ADA criteria plus documented optic atrophy diagnosed under 16 completed years
• AND B) 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.
• The patient is aged 6 years or older and weighing at least 20kg.
• 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 corrected vision.
• Written informed consent (and assent as required).
• Females of child bearing 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.
• 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
• Patient willing and able to meet all protocol defined visits for the duration of the Trial
• Pregnancy
• Adequate counselling must be given to all female patients of childbearing potential regarding the risks associated with Sodium Valproate use in pregnancy because of the potential teratogenic risk to the foetus. In the UK, Treat Wolfram protocol will be following the Valproate Pregnancy Prevention programme as per UK standard practice. Other countries will follow their local procedures as dictated by their local competent authority.
• Female patients who have started their periods but are not sexually active will be given contraception advice. If under 16 years, the advice will be given to the patient and their parents or carers.
• In line with Clinical Trial Facilitation Group Guidance, a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
• Due to the potential teratogenic risk to the foetus, all women of childbearing potential (WOCBP) must use a highly effective method of contraception, without interruption during the entire duration of IMP treatment. A highly effective method of contraception according to the Clinical Trial facilitation Group guidance includes methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include:

You may not qualify if:

• Patients who meet any of the following criteria are not eligible for this Trial:
• 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 diagnosis of a mitochondrial myopathy
• The patient has active liver disease, has a personal or family history of liver dysfunction related to known genetic disorders, or patient has porphyria.
• The patient has received treatment with any investigational drug within the 30 days prior to Trial entry.
• The patient is currently taking sodium valproate; or has a known hypersensitivity to sodium valproate or its excipients.
• 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 Trial outcome.
• The patient is currently breastfeeding.
• The patient has Known urea cycle disorders.
• The patient has one of the following disorders: Lactose intolerance, the Lapp lactase deficiency, or glucose- galactose malabsorption.

Sponsors & Collaborators

• University of Birmingham: lead

Study Sites (6)

CHU de Montpellier, Hopital Gui de Chauliac

Montpellier, 34295, France

Location

Hôpital Européen Georges-Pompidou

Paris, 75015, France

Location

Medical University of Lodz

Lodz, 91-738, Poland

Location

Unidad de Gestión Clínica Almería Periferia. Distrito Sanitario Almería

Almería, 04120, Spain

Location

University Hospitals Birmingham

Birmingham, B15 2TH, United Kingdom

Location

Birmingham Women's and Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

Related Publications (1)

• Dias RP, Brock K, Hu K, Gupta R, Martin U, Peet A, Wilson M, Yu-Wai-Man P, Wright B, Mollan S, Kulkarni A, Meunier I, Billingham L, Nagy Z, Rose H, Koks S, Zatyka M, Astuti D, Lynch T, Morrison KE, Barton D, Cronier S, Malpass R, Evans R, Malhi A, Takhar P, Lamb A, Esteban-Bueno G, Mlynarski W, Orssaud C, Roubertie A, Homer V, Barrett T. Sodium valproate, a potential repurposed treatment for the neurodegeneration in Wolfram syndrome (TREATWOLFRAM): trial protocol for a pivotal multicentre, randomised double-blind controlled trial. BMJ Open. 2025 Feb 26;15(2):e091495. doi: 10.1136/bmjopen-2024-091495.

  PMID: 40010822 DERIVED

MeSH Terms

Conditions

Wolfram Syndrome

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Deaf-Blind Disorders; Deafness; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Optic Atrophies, Hereditary; Optic Atrophy; Optic Nerve Diseases; Cranial Nerve Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Sensation Disorders; Neurologic Manifestations; Blindness; Vision Disorders; Eye Diseases, Hereditary; Eye Diseases; Diabetes Insipidus; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Diabetes Mellitus, Type 1; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Pituitary Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Timothy Barrett, PhD, MB, BS

  University of Birmingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 11, 2018
• First Posted: October 24, 2018
• Study Start: December 28, 2018
• Primary Completion: November 15, 2024
• Study Completion: November 15, 2024
• Last Updated: May 5, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

PL (1); GB (2); ES (1); FR (2)