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.

This phase II clinical trial is planned as a randomised, double-blind, placebo-controlled 3 year intervention Trial in 70 patients with Classical Wolfram Syndrome aged 6 years and over. The primary outcome of the Trial is considered to be clinically relevant and of sufficient magnitude to be beneficial, as a successful Trial outcome will mean that patients will retain a clinically useful degree of visual acuity and it will decline at a slower rate than in the untreated patients. The MRI Pons Volume change has been shown to correlate with changes in the Wolfram Unified Rating Scale.

Patients will be randomised to balance the individual differences across the treatment and placebo groups, therefore reducing the potential for extraneous bias. This will ensure that the treatment effect can be established without the need to account for confounding factors. The value of a placebo arm adds robustness to the Trial by removing the potential for bias from both the investigator and patient perspectives.

Investigators will be blinded to the results of the assessments. Certain assessments will be performed by subspecialists (such as ophthalmologists and neurologists), with the Principal Investigator prevented from having access to the results. This subspecialist-led treatment is in line with the current multi-disciplinary management of these patients and will not result in patients being denied access to effective treatment.

Patients and investigators will be blinded to treatment. The Trial treatment will be a tablet formulation.

This Trial involves 11 clinic visits and 7 follow up telephone calls to reduce the burden of additional travel to the patients.

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 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.

2. The patient is aged 6 years or older and weighing at least 20kg.

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 corrected vision.

4. Written informed consent (and assent as required).

5. 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.

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

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:

• combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:

  • Oral
  • Intravaginal
  • Transdermal

• progestogen-only hormonal contraception associated with inhibition of ovulation:

  • Oral
  • Injectable
  • Implantable 1

• intrauterine device (IUD) 1

• intrauterine hormone-releasing system ( IUS) 1

• bilateral tubal occlusion 1

• vasectomised partner 1, 2

• sexual abstinence 3

  1. Contraception methods that in the context of this guidance are considered to have low user dependency.
  2. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success.
  3. In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible for this Trial:

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 diagnosis of a mitochondrial myopathy
3. The patient has active liver disease, has a personal or family history of liver dysfunction related to known genetic disorders, or patient has porphyria.
4. The patient has received treatment with any investigational drug within the 30 days prior to Trial entry.
5. The patient is currently taking sodium valproate; or has a known hypersensitivity to sodium valproate or its excipients.
6. 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.
7. The patient is currently breastfeeding.
8. The patient has Known urea cycle disorders.
9. The patient has one of the following disorders: Lactose intolerance, the Lapp lactase deficiency, or glucose- galactose malabsorption.

No prior plans. CRCTU's data sharing policy - available here https://www.birmingham.ac.uk/research/crctu/data-sharing-policy.aspx - to be followed in the event of any plan to share.