A pivotal, international, randomised, double-blind, efficacy and safety trial of sodium valproate in paediatric and adult patients with Wolfram Syndrome
| ISRCTN | ISRCTN10176118 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10176118 |
| EudraCT/CTIS number | 2017-001215-37 |
| IRAS number | 222620 |
| ClinicalTrials.gov number | NCT03717909 |
| Secondary identifying numbers | CPMS 37502, IRAS 222620 |
- Submission date
- 16/04/2018
- Registration date
- 20/04/2018
- Last edited
- 27/11/2023
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Genetic Diseases
Plain English summary of protocol
Current plain English summary as of 24/11/2023:
Background and study aims
Wolfram syndrome is a rare genetic disease. It can cause diabetes and vision impairment in children, deafness, poor bladder function, balance problems, sleep disorders and sometimes depression. Life expectancy is reduced due to brain degeneration. There is currently no cure and nothing to prevent or slow down disease progression. The goal of this trial is to develop a treatment that will prevent or delay disease progression. Sodium valproate treats the disease in cell models of Wolfram syndrome and is already used to treat other conditions in children and adults, such as epilepsy. However, like all medicines, it has side effects. These include nausea, anaemia, tremor and mood disturbances. Sodium valproate must not be given to pregnant women. Therefore, the aim of this study is to show that sodium valproate is safe and effective at slowing disease progression in Wolfram syndrome patients.
Who can participate?
Patients aged 6 and older with Wolfram syndrome who have sufficient assessable vision (via visual acuity) during the course of the trial.
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.
Where is the study run from?
1. Birmingham Children’s Hospital NHS Foundation Trust (UK)
2. University Hospitals Birmingham NHS Foundation Trust (UK)
3. Montpellier University Hospital (France)
4. Hôpital Européen Georges Pompidou (France)
5. Medical University of Lodz (Poland)
6. Unidad de Gestión Clínica Almería Periferia (Spain)
When is the study starting and how long is it expected to run for?
December 2018 to October 2024
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Miss Amy Lamb
treatwolfram@trials.bham.ac.uk
Previous plain English summary from 07/02/2020 to 24/11/2023:
Background and study aims
Wolfram syndrome is a rare genetic disease. It can cause any of diabetes and vision impairment in children, deafness, poor bladder function, balance problems, sleep disorders, and sometimes depression. Life expectancy is reduced due to brain degeneration. There is currently no cure, and nothing to prevent or slow down the disease. The goal of this trial 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 other conditions in children and adults. However, like all medicines, it has side effects. These include nausea, anaemia, tremor, and mood disturbances; and it must not be given to pregnant women. Therefore, the aim of this study is to show that sodium valproate is safe, and effective at slowing the disease process in Wolfram.
Who can participate?
People with Wolfram syndrome who have sufficient vision to be able to assess during the course of the trial.
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.
Where is the study run from?
1. Birmingham Children’s Hospital NHS Foundation Trust (UK)
2. University Hospitals Birmingham NHS Foundation Trust (UK)
3. Montpellier University Hospital (France)
4. Hôpital Européen Georges Pompidou (France)
5. Medical University of Lodz (Poland)
6. Unidad de Gestión Clínica Almería Periferia, (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?
Mrs Amandip Malhi
treatwolfram@trials.bham.ac.uk
Previous 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?
Mrs Amandip Malhi
treatwolfram@trials.bham.ac.uk
Contact information
Scientific
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 |
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | No participant information sheet available |
| Scientific title | A pivotal, international, randomised, double-blind, efficacy and safety trial of sodium valproate in paediatric and adult patients with Wolfram Syndrome |
| Study acronym | Treat Wolfram |
| Study objectives | The aim of the trial is to show that Sodium Valproate is safe and effective at slowing the Wolfram syndrome disease process. |
| Ethics approval(s) | 1. Approved 19/03/2018, West of Scotland REC (Research Ethics, Clinical Research and Development, West Glasgow Ambulatory Care Hospital, Dalnair Street, Glasgow, G3 8SJ, United Kingdom; +44 (0)141 232 1808; WoSREC1@ggc.scot.nhs.uk), ref: 18/WS/0020 2. Approved 17/04/2018, Health Research Authority (3rd Floor, Barlow House, 4 Minshull Street, Manchester, M1 3DZ, United Kingdom; +44 (0)207 104 8193; hra.approval@nhs.net), ref: 18/WS/0020 |
| Health condition(s) or problem(s) studied | Wolfram syndrome |
| Intervention | 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 using 70 patients as the assumed sample size, 47 patients would be randomised to receive sodium valproate and 23 to receive placebo. Current intervention: Treatment will initially commence at a dose based on the patient’s body weight and increase over 4 weeks to a maximum of 800 mg/day for patients aged 6 to 12 years or 1600 mg/day for those aged 12 and over. For example: Child under 45 kg: start dose up to 10 mg/kg/day in 1 or 2 divided doses in 200-mg or 400-mg increments, increasing to 40 mg/kg/day by week 4; 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 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 includes follow-up visits 3, 6 and 12 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 6 months of the last participant completing the study. Previous intervention from 07/02/2020 to 24/11/2023: 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. Treatment will initially commence at a dose based on the patient’s body weight and increase over 4 weeks to a maximum of 800 mg/day for patients aged 5 to 12 years or 1600 mg/day for those aged 12 and over. For example: Child under 45 kg: start dose up to 10 mg/kg/day in 1 or 2 divided doses in 200-mg or 400-mg increments, increasing to 40 mg/kg/day by week 4; 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 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 includes follow-up visits 3, 6 and 12 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. Previous intervention from 18/01/2019 to 07/02/2020: 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) Original intervention: 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Sodium valproate gastro-resistant 200 mg oral tablets |
| 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 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. 13. Presence of changes in the inside of the eye, such as retinopathy, maculopathy and optic atrophy, assessed by fundoscopy at days -28, 360, 720 and 1080. 14. Visual evoked potentials measured by changes in visual evoked potentials (if available) measured by electrophysiology at days -28, 360, 720 and 1080. 15. Balance measured by Mini-BEST test measured at days -28, 360, 720 and 1080. 16. Hearing measured by pure tone audiometry measured at days -28, 360, 720 and 1080. 17. Severity of Wolfram syndrome symptoms assessed using the Wolfram Unified Rating Scale (WURS) at days -28, 360, 720 and 1080. 18. Mood assessed using the Kid-screen questionnaire for patients aged 8-18 years and the Hospital Anxiety and Depression Score (HADS) for adults at day -28 OR day 0 (depending on whether eligibility has been confirmed), and then days 21, 42, 90, 180, 360, 540, 720, 900 and 1080. 19. Insulin secretion assessed by mixed meal tolerance test and/or C-peptide measured at days -28, 360, 720 and 1080. 20. Glycated haemoglobin levels in blood measured at days -28, 360, 720 and 1080. 21. Quality of life measured by PedsQL (Paediatric quality of life inventory) for paediatric patients, by visual function questionnaires for children [VQoL-C and FVQ-C (8-12)], young people [VQoL-YP and FVQ-YP (13-18)], and adults [VFQ25 self-report or interviewer- administered for adults] at days -28, 180, 360, 540, 720, 900 and 1080. 22. Sleep, measured by the Sleep-related Breathing disorder scale extracted from the Pediatric Sleep Questionnaire (referred to as PSQ) parent report for those aged under 18 years, and Pittsburgh 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: 23. 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 days -28, 180, 360, 720 and 1080. 24. 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 days -28, 180, 360, 720 and 1080. 25. Biomarkers of sodium valproate (SV) response in patients (plasma) measured by change in plasma cytokine levels in patients (% of baseline) measured at days -28, 180, 360, 720 and 1080. 26. Fractional anisotropy of optic nerves measured using Diffusion Tensor Imaging (DTI) on MRI measured at days -28, 180, 360, 720 and 1080. 27. Global and regional brain volume measurements to assess atrophy of brain structures by MRI measured at days -28, 180, 360, 720 and 1080. 28. Change in urodynamic function measured by urodynamic function tests/flow ratio measured at days -28, 180, 360, 720 and 1080, and urology questionnaires [ICIQ-FLUTS (adult females), ICIQ-MLUTS (adult males) and ICIQ-CLUTS (children)] measured at days -28, 180, 360, 540, 720, 900 and 1080 Previous secondary outcome measures from 10/02/2020 to 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. 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 days -28, 360, 720 and 1080 4. Brainstem volume, measured by MRI as with VPV 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. 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 8. 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 9. 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 10. Strabismus measured by incidence and frequency of strabismus examination of the patient’s eyes by an ophthalmologist at days -28, 360, 720 and 1080 11. Nystagmus measured by incidence and frequency of nystagmus examination of the patient’s eyes by an ophthalmologist at days -28, 360, 720 and 1080 12. Presence of changes in the inside of the eye, such as retinopathy, maculopathy and optic atrophy, assessed by fundoscopy at days -28, 360, 720 and 1080 13. Visual evoked potentials measured by changes in visual evoked potentials (if available) measured by electrophysiology at days -28, 360, 720 and 1080 14. Balance measured by Mini-BEST test measured at days -28, 360, 720 and 1080 15. Hearing measured by pure tone audiometry measured at days -28, 360, 720 and 1080 16. Severity of Wolfram syndrome symptoms assessed using the Wolfram Unified Rating Scale (WURS) at days -28, 360, 720 and 1080 17. Mood assessed using the Kidscreen questionnaire for patients aged 8-18 years and the Hospital Anxiety and Depression Score (HADS) for adults at day -28 OR day 0 (depending on whether eligibility has been confirmed), and then days 21, 42, 90, 180, 360, 540, 720, 900 and 1080 18. Insulin secretion assessed by mixed meal tolerance test and/or C-peptide measured at days -28, 360, 720 and 1080 19. Glycated haemoglobin levels in blood measured at days -28, 360, 720 and 1080 20. Quality of life measured by PedsQL (Paediatric quality of life inventory) for paediatric patients, by visual function questionnaires for children [VQoL-C and FVQ-C (8-12)], young people [VQoL-YP and FVQ-YP (13-18)], and adults [VFQ25 self report or interviewer- administered for adults] at days -28, 180, 360, 540, 720, 900 and 1080 21. Sleep, measured by Sleep-related Breathing disorder scale extracted from the Pediatric Sleep Questionnaire (referred to as PSQ) parent report for those aged under 18 years, and Pittsburgh 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: 22. 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 days -28, 180, 360, 720 and 1080 23. 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 days -28, 180, 360, 720 and 1080 24. Biomarkers of sodium valproate (SV) response in patients (plasma) measured by change in plasma cytokine levels in patients (% of baseline) measured at days -28, 180, 360, 720 and 1080 25. Fractional anisotropy of optic nerves measured using Diffusion Tensor Imaging (DTI) on MRI measured at days -28, 180, 360, 720 and 1080 26. Global and regional brain volume measurements to assess atrophy of brain structures by MRI measured at days -28, 180, 360, 720 and 1080 27. Change in urodynamic function measured by urodynamic function tests/flow ratio measured at days -28, 180, 360, 720 and 1080, and urology questionnaires [ICIQ-FLUTS (adult females), ICIQ-MLUTS (adult males) and ICIQ-CLUTS (children)] measured at days -28, 180, 360, 540, 720, 900 and 1080 Previous secondary outcome measures from 18/01/2019 to 10/02/2020: 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 Original 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 study start date | 28/12/2018 |
| Completion date | 31/10/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 6 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 70; UK Sample Size: 48 |
| Total final enrolment | 63 |
| Key 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). Previous inclusion criteria from 18/01/2019 to 07/02/2020: 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 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 Original 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 |
| Key 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 |
| Date of first enrolment | 08/01/2019 |
| Date of final enrolment | 01/11/2021 |
Locations
Countries of recruitment
- England
- France
- Poland
- Spain
- United Kingdom
Study participating centres
Birmingham
B4 6NH
United Kingdom
Queen Elizabeth Medical Centre
Edgbaston
Birmingham
B15 2TH
United Kingdom
80 Rue Augustin Fliche
Montpellier
34295
France
Ophthalmological Rare Diseases Reference Center
Assistance Publique Hôpitaux de Paris
20, Rue Leblanc
Paris
75015
France
36/50 Sporna Street
Lodz
91-738
Poland
Distrito Sanitario Almería
Unidad de Gestión Clínica Almería Periféria
Almeria
04600
Spain
Sponsor information
University/education
c/o Dr Birgit Whitman
Research Support Group
Aston Webb Building
Room 119
The University of Birmingham
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| researchgovernance@contacts.bham.ac.uk | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/06/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Current publication and dissemination plan as of 24/11/2023: 1. Plan to publish protocol in BMJ Open in early 2024. 2. Planned publication of the results in a high-impact peer-reviewed journal Previous publication and dissemination plan from 07/02/2020 to 24/11/2023: 1. Plan to publish protocol in BMJ Open once the study has opened to recruitment and sufficient time has elapsed to ensure no further protocol amendment is required. (A protocol amendment is currently being prepared and anticipated approval is in the first half of 2020). 2. Planned publication of the results in a high-impact peer-reviewed journal Previous 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 plan | The CRCTU has a defined procedure in place for data sharing which ensures that the necessary legal and ethical requirements are met. For more information please read their Data Sharing Policy which is based on guidelines published by the Information Commissioners Office, the Medical Research Council (MRC) Methodology Hubs called “Good Practice Principles for Sharing Individual Participant Data from Publicly Funded Clinical Trials” and is compliant with Cancer Research UK Policy on Data Sharing and Preservation. Application for access to data is made via completion of data request form from the interested parties (stating the reason for the request, type of data requested, how the data will be stored /used and other information like ethical approval etc) and the request will be reviewed by the Trial management group. The data will be stored on University of Birmingham (Sponsor) servers and the data retained as per the study protocol and current regulatory approval authorisation (data will be stored for at least 25 years after the end of the study). The patient consent form states “ I understand that anonymised data and samples from the trial may be provided to other 3rd parties (e.g. pharmaceutical companies or other academic institutions) for research, safety monitoring or licensing purposes. This data will be provided to countries inside and outside the European Economic Area. My identity will remain anonymous.” This consent allows the clinical data to be accessed for research and safety monitoring drug licensing purposes. Website for more information: https://www.birmingham.ac.uk/research/crctu/data-sharing-policy.aspx |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
27/11/2023: IPD sharing plan added. Contact details updated.
24/11/2023: The following changes were made to the study record:
1. IRAS number, ethics approval details and total final enrolment added.
2. The interventions, secondary outcome measures, inclusion criteria and publication and dissemination plan were updated.
3. The recruitment end date was changed from 30/06/2021 to 01/11/2021.
4. The intention to publish date was changed from 30/09/2024 to 30/06/2025.
13/05/2021: Contact details updated.
29/09/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/09/2020 to 30/06/2021.
2. The overall end date was changed from 28/12/2023 to 31/10/2024.
10/02/2020: The secondary outcome measures have been updated to include methods of measurement for outcome measures 6, 8-11 and 13.
07/02/2020: The following changes have been made:
1. The plain English summary has been changed.
2. The trial website has been removed.
3. The NCT code has been added.
4. The intervention has been changed.
5. The trial phase has been changed from 'Not applicable' to 'Phase II'.
6. The drug name has been added.
7. The secondary outcome measures have been changed.
8. The participant inclusion criteria have been changed.
9. The Participant inclusion criteria: Target number of participants has been changed from "Planned Sample Size: 70; UK Sample Size: 45" to "Planned Sample Size: 70; UK Sample Size: 48".
10. The recruitment end date has been changed from 01/09/2019 to 30/09/2020.
11. Institute des Neurosciences de Montpellier has been removed from the trial participating centres, and CHU de Montpellier - Hôpital Gui de Chauliac has been added.
12. The sponsor contact details have been changed.
13. The publication and dissemination plan has been changed.
14. The intention to publish date has been changed from 15/07/2024 to 30/09/2024.
12/09/2019: Contact details updated.
25/03/2019: The condition was updated from "Specialty: Genetics, Primary sub-specialty: Genetics; UKCRC code/ Disease: Eye/ Disorders of optic nerve and visual pathways" to "Wolfram syndrome".
18/01/2019: The following changes were made to the trial record:
1. The overall trial start date was changed from 01/07/2018 to 28/12/2018.
2. The recruitment start date was changed from 15/07/2018 to 08/01/2019.
3. The recruitment end date was changed from 15/07/2020 to 01/09/2019.
4. The overall trial end date was changed from 15/07/2023 to 28/12/2023.
5. The interventions, outcome measures, and inclusion/exclusion criteria were updated.
