Efficacy Study of Daily Administration of VPA in Patients Affected by Wolfram Syndrome

NCT04940572 | Unknown Phase 2 DMC

• 1 other identifier: 2020-004594-43
• Study Type: interventional
• Target: 23
• Locations: 2 countries
• Sites: 2

Brief Summary

Open label, phase II study non randomized single group assignment of 20 evaluable patients 13 years and older, over 37,5 kg body-weight, with sensorineural hearing loss of at least 20 dB at 8 kHz in high frequency average (HFA), and with documented genetic mutations in the WFS1 gene and with at least one other major documented clinical symptom pertaining to Wolfram syndrome (i.e. diabetes mellitus, diabetes insipidus, optic atrophy). Every patients will receive over three years a treatment by VPA (Depakine chrono).

Conditions

Wolfram Syndrome

Outcome Measures

Primary Outcomes (1)

• Preservation of auditory function.

  Preservation of auditory function defined as no decrease higher than 5 dB in hearing at 8 kHz in high frequency average (HFA) over three years in patients with Wolfram syndrome with a deficit of at least 20d dB at 8 kHz treated with VPA at optimal dose corresponding to the plasma level between 40 and 100 mg/l (ie, 300 to 700 micro mol/l).

  Baseline - Week 156

Secondary Outcomes (8)

• Safety endpoint

  Baseline - Week 156

• Ventral Pons Volume measure

  Baseline - Week 156

• Insulin and or desmopressin requirements

  Baseline - Week 156

• Visual acuity assessment

  Baseline - Week 156

• Retinal nerve thikness measure

  Baseline - Week 156

Study Arms (1)

Depakine (VPA)

EXPERIMENTAL

Depakine Chrono 500 mg (VPA) VPA will be administered orally: * From D1 to D3: During the first week 10-15 mg sodium valproate/kg bodyweight per day will be taken daily. * From D3 to W156: The dose will be increased every 3 days in steps of 10 mg sodium valproate/kg bodyweight per day with VPA plasma concentration monitoring until the total daily dose corresponding to the optimal plasma level between 40 and 100 mg/l (ie, 300 to 700 micromol/l) is reached, till the 156 weeks corresponding to the end of treatment (EOT) visit. The total daily dose will be taken in one or two doses during meals.

Drug: Depakine

Interventions

Depakine DRUG

Refer to arm description.

Depakine (VPA)

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient has a definite diagnosis of Wolfram syndrome, as determined by the following:
• Documented diabetes mellitus diagnosed under 16 completed years according to WHO or ADA criteria OR documented optic atrophy diagnosed under 16 completed years AND 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
• The patient has sensorineural hearing loss of at least 20 db at 8 kHz in HFA
• The patient is 13 years of age or older, and has a body-weight over 37.5 kg
• Written informed consent for the principal study
• Women of childbearing potential who are prescribed with sodium valproate must use effective contraception without interruption during the entire duration of treatment and at least 90 days after last administration . These patients will be provided with comprehensive information on pregnancy prevention and will be referred for contraceptive advice if they are not using effective contraception. At least one effective method of contraception (preferably a user independent form such as an intra-uterine device or implant) or two complementary forms of contraception including a barrier method should be used.
• Women with childbearing potential are required to have a confirmed negative blood pregnancy test before starting medication administration at baseline. Women with childbearing potential agree to repeat blood pregnancy tests during at each study visit.
• Sexually active men with a female partner of childbearing potential must agree to the use of condoms and the use of a effective method of contraception by the female partner.
• Patient willing and able to meet all protocol defined visits for the duration of the Trial.
• Patients with active hearing implants, containing a magnetic system are allowed to participate to study, and will not have MRI during study participation.

You may not qualify if:

• The patient is unable or unwilling to comply with the protocol requirements
• The patient has received treatment with any investigational drug within the 30 days prior to the screening visit
• The patient is currently taking VPA
• The patient has an history of allergy or hypersensitivity to VPA or its excipients/ingredients
• The patient is known to be affected by a pathology for which the symptoms or associated treatments can alter the hearing function and/or affect the ear
• 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
• The patient has a contra-indication to VPA: mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase γ (POLG), e.g. Alpers-Huttenlocher Syndrome, active liver disease, personal or family history of liver dysfunction related to known genetic disorders, porphyria, lactose intolerance, the Lapp lactase deficiency, glucose- galactose malabsorption, urea cycle disorders…
• 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 participation
• The patient has a known history of central apnea
• An unwillingness on the part of male patients to use highly effective form of birth control if engaging in sexual intercourse with a woman who could become pregnant from the time of the first dose of study medication until completion of follow-up procedures.
• An unwillingness on the part of female patients to use highly effective form of birth control if engaging in sexual intercourse and to have frequent pregnancy tests during treatment and until completion of follow-up procedures.
• The patient is currently pregnant or breastfeeding
• The patient is swallowing disorders

Sponsors & Collaborators

• Centre d'Etude des Cellules Souches: lead
• Genethon: collaborator

Study Sites (2)

HEGP

Paris, 75015, France

RECRUITING

Centro periférico de Especialidades de Almería

Almería, 04009, Spain

RECRUITING

MeSH Terms

Conditions

Wolfram Syndrome

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

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; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Diabetes Mellitus, Type 1; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Pituitary Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Central Study Contacts

Yann GUIVARCH

CONTACT

01 69 90 85 35; yguivarch@istem.fr

Marc PESCHANSKI, MD, PhD

CONTACT

01 69 90 85 22; MPESCHANSKI@istem.fr

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open label study

Study Record Dates

• First Submitted: May 11, 2021
• First Posted: June 25, 2021
• Study Start: November 26, 2021
• Primary Completion: November 1, 2025
• Study Completion: December 1, 2025
• Last Updated: November 28, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

ES (1); FR (1)