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?
December 2018 to December 2023
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Miss Pooja Takhar
treatwolfram@trials.bham.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Miss Pooja Takhar
ORCID ID
Contact details
Treat Wolfram Trial office
Open Plan East
5th Floor Institute of Translational Medicine
Mindelsohn Way
Edgbaston
Birmingham
B15 2TH
United Kingdom
-
treatwolfram@trials.bham.ac.uk
Additional identifiers
EudraCT number
2017-001215-37
ClinicalTrials.gov number
Protocol/serial number
37502
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
Acronym
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
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Not specified
Trial type
Treatment
Patient information sheet
No participant information sheet available
Condition
Wolfram syndrome
Intervention
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.
Current interventions as of 18/01/2019:
Treatment will initially commence at a dose based on the patient’s body weight and increase over 4 weeks to a maximum of 800mg/day for patients aged 5- <12 years or 1600mg/day for those aged 12 and over.
For example:
Child under 45kg: Start dose: 10mg/kg/day in 1 or 2 divided doses, increasing in 200mg. increments to 40mg/kg/day by Week 4
Maximum dose: 5- <12 years - 800mg. per day (400mg per dose); 12 years and over – 1600mg. per day (800mg. per dose)
Child over 45kg or Adult: start dose 600mg/day (Week 1); 1000mg/day in in Week 2; 1200mg/day in Week 3 and 1600mg/day in Week 4. All daily doses are given as 2 divided doses. Maximum dose: 5 -<12 years - 800mg. per day (400mg. per dose); 12 years and over - 1600mg. per day (800mg per dose)
Previous interventions:
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
Drug
Phase
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 (baseline), Day 180, Day 360, Day 540, Day 720, Day 900, Day 1080
Secondary outcome measures
Current secondary outcome measures as of 18/01/2019:
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 measured at Day 0 to day 28
3. Ventral Pons Volume (VPV), a surrogate marker for neurodegeneration, measured and recorded in mm3 by standardised analysis of MR images of the Pons measured at Day -28, Day 360, Day 720, Day 1080
4. Brainstem volume, measured by MRI as with VPV measured 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 measured at Day -28, Day 360, Day 720, Day 1080
7. Visual fields measured by Humphrey Perimetry measured at Day -28, Day 360, Day 720, Day 1080
8. Data on cataracts measured by incidence and frequency of cataracts measured at Day -28, Day 360, Day 720, Day 1080
9. Afferent pupillary defects measured by incidence and frequency of afferent pupillary defects measured at Day -28, Day 360, Day 720, Day 1080
10. Strabismus measured by incidence and frequency of strabismus measured at Day -28, Day 360, Day 720, Day 1080
11. Nystagmus measured by incidence and frequency of nystagmus measured at Day -28, Day 360, Day 720, Day 1080
12. Visual evoked potentials measured by changes in visual evoked potentials (if available) measured at Day -28, Day 360, Day 720, Day 1080
13. Smell, measured by Smell Test (UPSIT) measured at Day -28, Day 360, Day 720, Day 1080
14. Balance, measured by Mini-BEST test measured at Day -28, Day 360, Day 720, Day 1080
15. Hearing, measured by pure tone audiometry measured at Day -28, Day 360, Day 720, Day 1080
16. Wolfram Unified Rating Scale (WURS) measured at Day -28, Day 360, Day 720, Day 1080
17. Mood, measured by Questionnaires measured using the Kidscreen (Patients aged 8-18), Hospital Anxiety and Depression Score (HADS) for Adults measured at Day 0, Day 21, Day 42, Day 90, Day 180, Day 360, Day 540, Day 720,Day 900, Day 1080
18. Pancreatic beta cell reserve–tolerance test measured by mixed meal tolerance test measured at Day -28, Day 360, Day 720, Day 1080
19. Pancreatic beta cell reserve-glycated haemoglobin measured by percentage glycated haemoglobin measured at Day -28, Day 360, Day 720, Day 1080
20. Urodynamic assessment is measured using the Urodynamics bladder flow rates and urology questionnaire (ICIQ-FLUTS) measured at Day -28, Day 180, Day 360, Day 540, Day 720, Day 900, Day 1080
21. Quality of Life measured by PedsQL (Paediatric quality of life inventory) for paediatric patients, by Visual function questionnaires for children and for young people [VQOL_C/YP (children) and VFQ25 (adults)] measured at Day-28, Day 180,Day 360, Day 540, Day 720, Day 900, Day 1080
22. Sleep, measured by Paediatric Sleep Questionnaire (PSQ) Parent Report for those under 18, and Pittsburg Sleep Quality Index (PSQI) Self-Report measured at Day-28, Day 180,Day 360, Day 540, Day 720, Day 900, Day 1080
Other Outcome Measures:
1. Biomarkers of sodium valproate (SV) response in patients (proliferative capacity and CDKN1A expression) measured by change in the vitro proliferative capacity and CDKN1A expression of PBMCs (% baseline) measured at: Day-28, Day 360 ,Day 720, Day 1080
2. Biomarkers of sodium valproate (SV) response in patients (effect of SV on proliferative capacity and CDKN1A expression) measured by change in the vitro effect of SV on proliferative capacity and CDKN1A expression measured at Day-28, Day 360 ,Day 720, Day 1080
3. Biomarkers of sodium valproate (SV) response in patients (effect of SV on cytokine production) measured by change in the vitro effect of SV on cytokine production in PBMCs (% of baseline) measured at Day-28, Day 360 ,Day 720, Day 1080
4. Biomarkers of sodium valproate (SV) response in patients (plasma) measured by change in plasma cytokine levels in patients (% of baseline) measured at Day-28, Day 360, Day 720, Day 1080
5. Fractional anisotropy of optic nerves measured using Diffusion Tensor Imaging (DTI) on MRI measured at Day-28, Day 360 ,Day 720, Day 1080
6. Global and regional brain volume measurements to assess atrophy of brain structures by MRI measured at Day-28, Day 360 ,Day 720, Day 1080
Previous 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
28/12/2018
Overall trial end date
28/12/2023
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
Current inclusion criteria as of 18/01/2019:
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:
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. The patient is 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 corrected vision
4. Written informed consent
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
Previous 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
Patient
Age group
Mixed
Gender
Both
Target number of participants
Planned Sample Size: 70; UK Sample Size: 45
Participant 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
Recruitment start date
08/01/2019
Recruitment end date
01/09/2019
Locations
Countries of recruitment
France, Poland, Spain, United Kingdom
Trial participating centre
Birmingham Children’s Hospital NHS Foundation Trust
Steelhouse Lane
Birmingham
B4 6NH
United Kingdom
Trial participating centre
University Hospitals Birmingham NHS Foundation Trust
Trust HQ, PO Box 9551
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom
Trial participating centre
Institute des Neurosciences de Montpellier
Inserm U1051
Pathologies Sensorielles, Neuroplasticité et Thérapies
80, Rue Augustin Fliche
Montpellier
34095
France
Trial participating centre
Hôpital Européen Georges Pompidou
Functional Unit of Ophthalmology
Ophthalmological Rare Diseases Reference Center
Assistance Publique Hôpitaux de Paris
20, Rue Leblanc
Paris
75015
France
Trial participating centre
Medical University of Lodz
Department of Paediatrics, Oncology, Haematology and Diabetology
36/50 Sporna Street
Lodz
91-738
Poland
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
Almeria
04600
Spain
Sponsor information
Organisation
University of Birmingham
Sponsor details
c/o Sean Jennings
Finance Office
Aston Webb
B Block
University of Birmingham
Birmingham
B15 2TT
United Kingdom
-
researchgovernance@contacts.bham.ac.uk
Sponsor type
University/education
Website
Funders
Funder type
Research council
Funder name
Medical Research Council; Grant Codes: MR/P007732/1
Alternative name(s)
MRC
Funding Body Type
government organisation
Funding Body Subtype
National government
Location
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
15/07/2024
Participant level data
To be made available at a later date
Basic results (scientific)
Publication list