AUDIOWOLF: A phase II, open-label, efficacy study of daily administration of sodium valproate in patients clinically affected by Wolfram syndrome due to monogenic mutation

• Register: EUCTR
• Last refreshed on: 3 December 2024
• Main ID: EUCTR2020-004594-43-FR
• Date of registration: 11/03/2021
• Prospective Registration: Yes
• Primary sponsor: CECS/I-Stem
• Public title: AUDIOWOLF: A phase II, open-label, efficacy study of daily administration of sodium valproate in patients clinically affected by Wolfram syndrome due to monogenic mutation
• Scientific title: AUDIOWOLF: A phase II, open-label, efficacy study of daily administration of sodium valproate in patients clinically affected by Wolfram syndrome due to monogenic mutation - AUDIOWOLF
• Date of first enrolment: 27/05/2021
• Target sample size: 23
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-004594-43
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: Placebo: Other:
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France, Spain

Contacts

• Name: Regulatory Affairs
• Affiliation: GENETHON

• Name: Regulatory Affairs
• Affiliation: GENETHON

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion criteria:
Patients must meet all of the following criteria to be eligible for enrolment:
1. The patient has a definite diagnosis of Wolfram syndrome, as determined by the following:
a. Documented diabetes mellitus diagnosed under 16 completed years according to WHO or ADA criteria OR 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 has sensorineural hearing loss of at least 20 db at 8 kHz in HFA
3. The patient is 13 years of age or older, and has a body-weight over 37.5 kg
4. Written informed consent for the principal study
5. 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 .
6. 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.
7. 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.

Are the trial subjects under 18? yes
Number of subjects for this age range: 23
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 11
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Patients will be excluded from the study for any of the following reasons:
1. The patient is unable or unwilling to comply with the protocol requirements
2. The patient has received treatment with any investigational drug within the 30 days prior to the screening visit
3. The patient is currently taking VPA
4. The patient has an history of allergy or hypersensitivity to VPA or its excipients/ingredients
5. 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
6. 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
7. The patient has a contra-indication to VPA: mitochondrial disorders caused by mutations in the nuclear gene encoding the mitochondrial enzyme polymerase ? (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…
8. 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
9. The patient has a known history of central apnea
10. 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.
11. 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.
12. The patient is currently pregnant or breastfeeding
13. The patient has swallowing disorders



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Wolfram syndrome
MedDRA version: 20.0 Level: PT Classification code 10078338 Term: Wolfram syndrome System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Trade Name: DEPAKINE CHRONO® 500 mg
Product Name: DEPAKINE CHRONO 500 mg
Pharmaceutical Form: Prolonged-release tablet

Primary Outcome(s)

Primary end point(s): 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, assessed by audiometry tests (PTA), Speech interference index (SII) and High frequency pure tone audiometry hearing test (HFPTA) 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).

Timepoint(s) of evaluation of this end point: Screening, Baseline, week 13/26/39/52/78/104/130/156 or in case of Early termination

Secondary Objective: Safety: Overall incidence of adverse events and serious adverse events as well as laboratory assessments will be evaluated for each group and for the study as a whole.

• Efficacy:
o Insulin requirement
o Desmopressin requirement
o Ventral Pons Volume (VPV) measured by MRI
o Balance measured by Mini-BESTest
o Visual function
o Retinal nerve thickness
o Sleep quality using:
- Pediatric Sleep Questionnaire (PSQ) in pediatric population
- Pittsburg Sleep Quality Index (PSQI) Self-Report in adults patients

Main Objective: 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 deficit of at least 20 dB at 8 kHz treated with an optimal dose of VPA corresponding to the plasma level ofbetween 40 and 100 mg/L (ie, 300 to 700 micromol/l)

Secondary Outcome(s)

Secondary end point(s): - Safety
Overall incidence of adverse events and serious adverse events, patient withdrawals as well as changes from baseline in laboratory safety assessments and vital signs parameters will be evaluated for each group and for the study as a whole.

- Efficacy:
o Ventral Pons Volume measured and recorded in mm3 by standardised analysis of MRI at baseline, at visit 8 (Week 52) and at the final visit
o Insulin and or desmopressin requirements will be assessed whenever the patient is under one or both treatments in order to document potential benefit from VPA on diabetes mellitus or diabetes insipidus
o Visual acuity will be assessed using standard ETDRS measures and visual field recording at baseline, every six months during the first year of follow-up and at the final visit
o Retinal nerve thikness measure by OCT measures at baseline, every six months during the first year of follow-up and at the final visit
o Balance, measured by Mini-BESTest at baseline, at visit 8 (Week 52) and at the final visit
o Sleep will be investigated by a specific Sleep questionnaire at baseline, at visit 8 (Week 52) and final visit:
o For patients under 18 years: sleeping habits measured by the Pediatric Sleep Questionnaire (PSQ) Parent Questionnaire.
o For adults: sleeping habits, measured by the Pittsburg Sleep Quality Index (PSQI) Self-Report.

Timepoint(s) of evaluation of this end point: Secondary safety endpoints and insulin/desmopressin requirements
timepoints of evaluation : screening, baseline, weeks
1/4/13/26/39/52/78/104/130/156/160 and in case of early
termination

Other Secondary efficacy enpoint timepoints for evaluation:
- VPV, miniBESTest, sleep questionnaire: baseline, week 52/156 or early termination
- ETDRS, visual field, OCT: screening, baseline, week 26/52/156 or early termination

Secondary ID(s)

ISTEM02

Source(s) of Monetary Support

CECS/I-Stem

Ethics review

Status: Approved
Approval date: 27/05/2021
Contact: