Efficacy and Safety Trial of Sodium Valproate, in Paediatric and Adult Patients With Wolfram Syndrome
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|ClinicalTrials.gov Identifier: NCT03717909|
Recruitment Status : Recruiting
First Posted : October 24, 2018
Last Update Posted : February 10, 2020
|Condition or disease||Intervention/treatment||Phase|
|Wolfram Syndrome||Drug: Sodium Valproate 200Mg E/C Tablet Drug: Sodium Valproate matched placebo||Phase 2|
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 5 years and over. The primary outcomes of the Trial are 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 Ventral Pons Volume (VPV) 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||70 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||A Pivotal, International, Randomised, Double-blind, Efficacy and Safety Trial of Sodium Valproate, in Paediatric and Adult Patients With Wolfram Syndrome|
|Actual Study Start Date :||December 28, 2018|
|Estimated Primary Completion Date :||January 31, 2022|
|Estimated Study Completion Date :||January 31, 2022|
Experimental: Experimental Group
Sodium Valproate 200Mg E/C Tablet (active treatment)
Drug: Sodium Valproate 200Mg E/C Tablet
Treatment with twice-daily oral tablet(s)
Other Name: Sodium Valproate
Placebo Comparator: Control Group
Sodium Valproate matched placebo (inactive treatment)
Drug: Sodium Valproate matched placebo
Treatment with twice-daily oral 200mg tablet(s)
Other Name: Placebo
- Visual acuity (VA) [ Time Frame: 36 months ]Visual acuity (VA) is measured on the logMAR scale by sight tests in clinic using Early treatment diabetic retinopathy study (ETDRS) charts. Values are taken for each eye after correction, and can range from 0, which represents perfect vision i.e. 20/20 (values of -0.1 and -0.2 are also possible representing better than perfect vision), to +2 which represents near blindness i.e. 20/2000. Increases in logMAR represent deterioration.
- Safety - adverse events [ Time Frame: 37 months ]measured by adverse events frequency, type and grade according to CTCAE v4
- Tolerability - highest treatment dose [ Time Frame: 36 months ]measured by dose achieved
- Tolerability - duration of treatment [ Time Frame: 36 months ]measured by days of treatment
- Tolerability - dosing modifcation [ Time Frame: 36 months ]measured by treatment-related dose reductions and discontinuations
- Ventral Pons Volume (VPV) [ Time Frame: 37 months (+/- 6 months) ]a surrogate marker for neurodegeneration, measured and recorded in mm3 by standardised analysis of MRI images of the Pons
- Brainstem volume [ Time Frame: 37 months (+/- 6 months) ]measured by MRI as with VPV
- Retinal nerve thickness [ Time Frame: 37 months ]measured by Optical Coherence Tomography
- Colour vision [ Time Frame: 37 months ]measured by Farnsworth plates
- Visual fields [ Time Frame: 37 months ]measured by Humphrey Perimetry
- Data on cataracts [ Time Frame: 37 months ]measured by incidence and frequency of cataracts
- Afferent pupillary defects [ Time Frame: 37 months ]measured by incidence and frequency of afferent pupillary defects. Afferent pupillary defects are recorded as present or absent.
- Strabismus [ Time Frame: 37 months ]measured by incidence and frequency of strabismus. Presence or absence of strabismus will be recorded. Strabismus will also be graded for type and size.
- Nystagmus [ Time Frame: 37 months ]measured by incidence and frequency of nystagmus. Presence or absence of nystagmus will be recorded. Nystagmus will also be graded for size, amplitude and direction.
- Visual evoked potentials [ Time Frame: 37 months ]measured by changes in visual evoked potentials (if available)
- Smell [ Time Frame: 37 months ]measured by UPSIT
- Sleep - sleeping habits parent report for patients under 18 years [ Time Frame: 37 months ]measured by the Pediatric Sleep Questionnaire (PSQ) Parent Questionnaire 2014. This report is a Parent Report for patients under 18. This questionnaire records usual sleep habits.
- Sleep - sleeping habits, self-report [ Time Frame: 37 months ]measured by the Pittsburg Sleep Quality Index (PSQI) Self-Report. This questionnaire is completed by the patient. This questionnaire records usual sleep habits during the past month.
- Balance [ Time Frame: 37 months ]measured by Mini-BESTest
- Hearing [ Time Frame: 37 months ]measured by pure tone audiometry
- Wolfram Unified Rating Scale [ Time Frame: 37 months ]Wolfram Unified Rating Scale (WURS). Assessments are performed in five areas (physical; seizure; behavioral; capability and clinical) by scoring listed items 0-2, 0-3, 0-4, 0-5 or 0-6 depending on the scale. Totals for each category are recorded and the WURS total, summing physical and behavioral categories, is also recorded. A low score would be considered a better outcome in all areas apart from capability where a high score would be considered a better outcome. A Wolfram Syndrome history is also recorded detailing incidence and onset of listed symptoms.
- Mood [ Time Frame: 36 months ]measured by Kidscreen for patients aged 8-18 or the Hospital Axiety and Depression Scale (HADS) for adult patients. Kidscreen records the patients mood and feeling in 5 areas (physical activities and health; general mood and feelings about self; family and free time; friends; school and learning). HADS records how the patient has been feeling over the past week by scoring feelings relating to anxiety or depression. A total score for Anxiety and a total score for depression is recorded. A score of 0-7 = normal; 8-10 = borderline abnormal (borderline case) and 11-21 = abnormal (case).
- Quality of life - PedsQL [ Time Frame: 37 months ]measured by PedsQL questionnaire (pediatric quality of life inventory) for paediatric patients. PedsQL records how much of a problem each situation causes the patient; each situation is scored from 0 (never a problem) to 4 (always a problem). A score of 0 would be considered a better outcome.
- Quality of life - ICIQ-FLUTS [ Time Frame: 37 months ]measured by the ICIQ-FLUTS questionnaire. This questionnaire records urinary symptoms in three categories (filling, voiding and incontinence) from 0-4 and how much each symptom bothers the patient from 0 (not at all) to 10 (a great deal). scored for each category are totaled. Low scores would be considered a better outcome.
- Quality of life - VQoL_C/ YP [ Time Frame: 37 months ]measured by the vision related quality of life questionnaire for children and for young people. This questionnaire records how patients feel about their eyesight in relation to the listed statements. Each statement is scored from 1 (not at all true) to 4 (completely true). The score denoting a better outcome is dependent on the question.
- Quality of life - VFQ-25 [ Time Frame: 37 months ]measured by the National Eye Institute Visual Function Questionnaire 25 (VFQ-25). This questionnaire records information in three categories. Questions in the general health and vision category are scored 1-5 or 6 and a low score would be considered a better outcome. Questions in the difficulty with activities category are scored 1 (no difficulty at all) to 6 (stopped doing this for other reasons or not interested in doing this); a low score would be considered a better outcome. Questions in the vision problems category are scored 1 (all of the time) to 5 (none of the time); a high score would be considered a better outcome.
- Pancreatic beta cell reserve - tolerance test [ Time Frame: 37 months ]measured by mixed meal tolerance test
- Pancreatic beta cell reserve - glycated haemoglobin [ Time Frame: 37 months ]measured by percentage glycated haemoglobin
- Biomarkers of sodium valproate response in patients (proliferative capacity and CDKN1A expression) [ Time Frame: 37 months ]measured by change in the in vitro proliferative capacity and CDKN1A expression of PBMCs (% of baseline)
- Biomarkers of sodium valproate response in patients (effect of SV on proliferative capacity and CDKN1A expression) [ Time Frame: 37 months ]measured by change in the in vitro effect of SV on proliferative capacity and CDKN1A expression of PBMCs (% of baseline)
- Biomarkers of sodium valproate response in patients (effect of SV on cytokine production) [ Time Frame: 37 months ]measured by change in the in vitro effect of SV on cytokine production in PBMCs (% of baseline)
- Biomarkers of sodium valproate response in patients (plasma) [ Time Frame: 37 months ]measured by change in plasma cytokine levels in patients (% of baseline)
- Fractional anisotropy of the optic nerves [ Time Frame: 37 months (+/- 6 months) ]measured using Diffusion Tensor Imaging (DTI) on MRI
- Global and regional brain volume measurements [ Time Frame: 37 months (+/- 6 months) ]to assess atrophy of brain structures by MRI
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03717909
|Contact: Timothy Barrett, PhD, MB, BS||+44(0)email@example.com|
|Contact: Shazia Ahmed||+44(0)firstname.lastname@example.org|
|Birmingham Children Hospital||Recruiting|
|Birmingham, United Kingdom, B4 6NH|
|Principal Investigator:||Timothy Barrett, PhD, MB, BS||University of Birmingham|