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

• Register: ClinicalTrials.gov
• Last refreshed on: 21 August 2023
• Main ID: NCT03717909
• Date of registration: 11/10/2018
• Prospective Registration: Yes
• Primary sponsor: University of Birmingham
• Public title: Efficacy and Safety Trial of Sodium Valproate, in Paediatric and Adult Patients With Wolfram Syndrome
• Scientific title: A Pivotal, International, Randomised, Double-blind, Efficacy and Safety Trial of Sodium Valproate, in Paediatric and Adult Patients With Wolfram Syndrome
• Date of first enrolment: December 28, 2018
• Target sample size: 63
• Recruitment status: Active, not recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03717909
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Other. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

France, Poland, Spain, United Kingdom

Contacts

• Name: Timothy Barrett, PhD, MB, BS
• Affiliation: University of Birmingham

Key inclusion & exclusion criteria

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.



Age minimum: 6 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Wolfram Syndrome

Intervention(s)

Drug: Sodium Valproate 200Mg E/C Tablet

Drug: Sodium Valproate matched placebo

Primary Outcome(s)

Visual acuity (VA) [Time Frame: 36 months]

Secondary Outcome(s)

Afferent pupillary defects [Time Frame: 37 months]

Pons Volume [Time Frame: 37 months (+/- 6 months)]

Data on cataracts [Time Frame: 37 months]

Mood [Time Frame: 36 months]

Retinal nerve thickness [Time Frame: 37 months]

Quality of life - VFQ-25 [Time Frame: 37 months]

Sleep - sleeping habits parent report for patients under 18 years [Time Frame: 37 months]

Hearing [Time Frame: 37 months]

Pancreatic beta cell reserve - glycated haemoglobin or equivalent [Time Frame: 37 months]

Quality of life - PedsQL [Time Frame: 37 months]

Visual evoked potentials [Time Frame: 37 months]

Brainstem volume [Time Frame: 37 months (+/- 6 months)]

Quality of life - ICIQ-FLUTS [Time Frame: 37 months]

Strabismus [Time Frame: 37 months]

Sleep - sleeping habits, self-report [Time Frame: 37 months]

Tolerability - highest treatment dose [Time Frame: 36 months]

Colour vision [Time Frame: 37 months]

Wolfram Unified Rating Scale [Time Frame: 37 months]

Safety - adverse events [Time Frame: 37 months]

Balance [Time Frame: 37 months]

Nystagmus [Time Frame: 37 months]

Quality of life - VQoL_C/ YP [Time Frame: 37 months]

Tolerability - dosing modifcation [Time Frame: 36 months]

Tolerability - duration of treatment [Time Frame: 36 months]

Visual fields [Time Frame: 37 months]

Secondary ID(s)

RG_16_211

Source(s) of Monetary Support

Please refer to primary and secondary sponsors