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

Brief Title

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

Official Title

A Pivotal, International, Randomised, Double-blind, Efficacy and Safety Trial of Sodium Valproate, in Paediatric and Adult Patients With Wolfram Syndrome

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.
    

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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Visual acuity (VA)

Secondary Outcome

 Safety - adverse events

Condition

Wolfram Syndrome

Intervention

Sodium Valproate 200Mg E/C Tablet

Study Arms / Comparison Groups

 Experimental Group
Description:  Sodium Valproate 200Mg E/C Tablet (active treatment)

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

70

Start Date

December 28, 2018

Completion Date

January 31, 2022

Primary Completion Date

January 31, 2022

Eligibility 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.
      

Gender

All

Ages

5 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Timothy Barrett, PhD, MB, BS, +44(0)1214147966, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT03717909

Organization ID

RG_16_211


Responsible Party

Sponsor

Study Sponsor

University of Birmingham


Study Sponsor

Timothy Barrett, PhD, MB, BS, Principal Investigator, University of Birmingham


Verification Date

September 2020