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

• ClinicalTrials.gov Identifier: NCT03717909
• Recruitment Status: Unknown
• First Posted: October 24, 2018
• Last Update Posted: November 4, 2020
• Sponsor: University of Birmingham
• Information provided by (Responsible Party): University of Birmingham

Study Description

Brief Summary:

This trial aims to investigate the efficacy, safety and tolerability of sodium valproate in the treatment of patients with Wolfram syndrome. 70 paediatric and adult patients will be randomised 2:1 to receive either sodium valproate or placebo at 6 international centres.

Condition or disease	Intervention/treatment	Phase
Wolfram Syndrome	Drug: Sodium Valproate 200Mg E/C Tablet; Drug: Sodium Valproate matched placebo	Phase 2

Detailed Description:

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• 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

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. Safety - adverse events [ Time Frame: 37 months ]
   measured by adverse events frequency, type and grade according to CTCAE v4
2. Tolerability - highest treatment dose [ Time Frame: 36 months ]
   measured by dose achieved
3. Tolerability - duration of treatment [ Time Frame: 36 months ]
   measured by days of treatment
4. Tolerability - dosing modifcation [ Time Frame: 36 months ]
   measured by treatment-related dose reductions and discontinuations
5. 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
6. Brainstem volume [ Time Frame: 37 months (+/- 6 months) ]
   measured by MRI as with VPV
7. Retinal nerve thickness [ Time Frame: 37 months ]
   measured by Optical Coherence Tomography
8. Colour vision [ Time Frame: 37 months ]
   measured by Farnsworth plates
9. Visual fields [ Time Frame: 37 months ]
   measured by Humphrey Perimetry
10. Data on cataracts [ Time Frame: 37 months ]
    measured by incidence and frequency of cataracts
11. 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.
12. 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.
13. 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.
14. Visual evoked potentials [ Time Frame: 37 months ]
    measured by changes in visual evoked potentials (if available)
15. Smell [ Time Frame: 37 months ]
    measured by UPSIT
16. 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.
17. 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.
18. Balance [ Time Frame: 37 months ]
    measured by Mini-BESTest
19. Hearing [ Time Frame: 37 months ]
    measured by pure tone audiometry
20. 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.
21. 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).
22. 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.
23. 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.
24. 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.
25. 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.
26. Pancreatic beta cell reserve - tolerance test [ Time Frame: 37 months ]
    measured by mixed meal tolerance test
27. Pancreatic beta cell reserve - glycated haemoglobin [ Time Frame: 37 months ]
    measured by percentage glycated haemoglobin

Other Outcome Measures:

1. 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)
2. 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)
3. 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)
4. Biomarkers of sodium valproate response in patients (plasma) [ Time Frame: 37 months ]
   measured by change in plasma cytokine levels in patients (% of baseline)
5. Fractional anisotropy of the optic nerves [ Time Frame: 37 months (+/- 6 months) ]
   measured using Diffusion Tensor Imaging (DTI) on MRI
6. Global and regional brain volume measurements [ Time Frame: 37 months (+/- 6 months) ]
   to assess atrophy of brain structures by MRI

Eligibility Criteria

• Ages Eligible for Study: 5 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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

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.

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. 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 1:

  • Oral
  • Intravaginal
  • Transdermal

• progestogen-only hormonal contraception associated with inhibition of ovulation 1:

  • Oral
  • Injectable
  • Implantable 2
• intrauterine device (IUD) 2
• intrauterine hormone-releasing system ( IUS) 2
• bilateral tubal occlusion 2
• vasectomised partner 2,3

• sexual abstinence 4

  1. Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the contraception method (see section 4.3)
  2. Contraception methods that in the context of this guidance are considered to have low user dependency.
  3. 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.
  4. 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.

Contacts and Locations

Contacts

Contact: Timothy Barrett, PhD, MB, BS; +44(0)1214147966; t.g.barrett@bham.ac.uk

Contact: Pooja Takhar; +44(0)1213718107; p.takhar@bham.ac.uk

Locations

France

CHU de Montpellier, Hopital Gui de Chauliac; Recruiting

Montpellier, France, 34295

Hôpital Européen Georges-Pompidou; Recruiting

Paris, France, 75015

Poland

Medical University of Lodz; Active, not recruiting

Lodz, Poland, 91-738

Spain

Unidad de Gestión Clínica Almería Periferia. Distrito Sanitario Almería; Recruiting

Almería, Spain, 04120

United Kingdom

University Hospitals Birmingham; Recruiting

Birmingham, United Kingdom, B15 2TH

Birmingham Children Hospital; Recruiting

Birmingham, United Kingdom, B4 6NH

Sponsors and Collaborators

University of Birmingham

Investigators

• Principal Investigator: Timothy Barrett, PhD, MB, BS; University of Birmingham

More Information

• Responsible Party: University of Birmingham
• ClinicalTrials.gov Identifier: NCT03717909
• Other Study ID Numbers: RG_16_211
• First Posted: October 24, 2018
• Last Update Posted: November 4, 2020
• Last Verified: September 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Birmingham:

Wolfram Syndrome; Treat Wolfram; Sodium valproate

Additional relevant MeSH terms:

Wolfram Syndrome; Syndrome; Disease; Pathologic Processes; Deaf-Blind Disorders; Deafness; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Optic Atrophies, Hereditary; Optic Atrophy; Optic Nerve Diseases; Cranial Nerve Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Sensation Disorders; Neurologic Manifestations; Blindness; Vision Disorders; Eye Diseases, Hereditary; Eye Diseases; Diabetes Insipidus; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases