Wolfram syndrome Genetic Diseases Other specified diabetes mellitus
Conditions
Interventions
Current intervention as of 24/11/2023:
Patients will be randomized 2:1 to either treatment with sodium valproate or matching placebo (randomised preferably to sodium valproate). Thus u
maximum 800 mg per day, 400 mg per dose.
Child over 45 kg and 12 years or older, or adult: start dose 600 mg/day in 2 divided doses (week 1)
1000 mg/day in 2 divided doses (week 2)
1200 mg/day in 2 divided doses (week 3)
1600 mg/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 th
and brain scans every 12 months.
Stage 5 is the final telephone call 4 weeks after the treatment has finish
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Current inclusion criteria as of 24/11/2023: 1. Definitive diagnosis of Wolfram syndrome, as determined by the presence of both of the following: 1.1. Documented diabetes mellitus diagnosed under 16 completed years according to WHO or ADA criteria and/or documented optic atrophy diagnosed under 16 completed years. 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. Aged 6 years or older and weighing at least 20 kg. 3. 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. 5. Females of childbearing potential will only be included after a negative pregnancy test as per the national valproate pregnancy prevention programme or equivalent. If sexually active, they must agree to use a highly effective contraception measure and to pregnancy testing at each clinic follow-up visit. 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. The definition of protocol defined visits includes all visits except MRI visits when a patient is not suitable for the procedure (e.g. patient with cochlear implants/braces would still be eligible for the study) or declines the procedure (patient’s own decision). Previous inclusion criteria from 07/02/2020 to 24/11/2023: 1. Definitive diagnosis of Wolfram syndrome, as determined by the presence of both of the following: 1.1. Documented diabetes mellitus diagnosed under 16 completed years according to WHO or ADA criteria and/or documented optic atrophy diagnosed under 16 completed years 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. Aged 5 years or older 3. 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 5. Females of childbearing potential will only be included after a negative pregnancy test as per the national valproate pregnancy prevention programme or equivalent. If sexually active, they must agree to use a highly effective contraception measure and to pregnancy testing at each clinic follow-up visit 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. The definition of protocol defined visits includes all visits except MRI visits when a patient is not suitable for the procedure (e.g. patient with cochlear implants/braces would still be eligible for the study) or declines the procedure (patient’s own decision). Previou
Exclusion criteria
Exclusion criteria: Current exclusion criteria as of 18/01/2019: 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 Previous 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Visual acuity is measured on the logMAR scale by sight tests in clinic using ETDRS charts at Day -28, Day 0 (baseline), Day 180, Day 360, Day 540, Day 720, Day 900, Day 1080 | — |
Secondary
| Measure | Time frame |
|---|---|
| Current secondary outcome measures as of 24/11/2023: 1. Safety, measured by adverse events according to CTCAE v4 at days 0, 7, 21, 42, 90, 180, 270, 360, 450, 540, 630, 720, 810, 900, 990, 1080 and 1110. 2. Tolerability, measured by dose achieved, days of treatment, and treatment-related dose reductions and discontinuations. Treatment dose escalation period measured at day 0 to day 28. 3. Pons volume (PV), a surrogate marker for neurodegeneration, measured and recorded in mm3 by standardised analysis of MR images of the Pons, and brain substructure volumes. Measured at days -28, 360, 720 and 1080. 4. Brainstem volume, measured by MRI as with PV at days -28, 360, 720 and 1080. 5. Retinal nerve thickness, measured by Optical Coherence Tomography at days -28, 360, 720 and 1080. 6. Colour vision, measured using the Hardy Rand and Rittler (HRR) colour vision test at days -28, 360, 720 and 1080. 7. Contrast sensitivity (if available) at days -28, 360, 720 and 1080. 8. Visual fields measured by the local centre standard process (the same technique must be used throughout the patient participation to the study) at days -28, 360, 720 and 1080. 9. Data on cataracts measured by incidence and frequency of cataracts examination of the patient’s eyes by an ophthalmologist at days -28, 360, 720 and 1080. 10. Afferent pupillary defects measured by incidence and frequency of afferent pupillary defects examination of the patient’s eyes by an ophthalmologist at days -28, 360, 720 and 1080. 11. Strabismus measured by incidence and frequency of strabismus examination of the patient’s eyes by an ophthalmologist at days -28, 360, 720 and 1080. 12. Nystagmus measured by incidence and frequency of nystagmus examination of the patient’s eyes by an ophthalmologist at days -28, 360, 720 and 1080. | — |
Countries
England, France, Poland, Spain, United Kingdom
Outcome results
None listed