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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre D'Etude Des Cellules Souches

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

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

Trial duration

8 Oct 2021 → 16 Sep 2025

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

CECS/I-Stem

External identifiers

EU CT number

2024-514896-17-00

EudraCT number

2020-004594-43

ClinicalTrials.gov

NCT04940572

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

Preservation of auditory function defined as no decrease higher than 5 dB in hearing at 8 kHz in high frequency average (HFA) over three yearsin 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 between 40 and 100 mg/l (ie, 300 to 700 micromol/l).

Secondary objectives 8

1. 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.
2. Efficacy: Insulin requirement
3. Efficacy: Desmopressin requirement
4. Efficacy: Ventral Pons Volume (VPV) measured by MRI
5. Efficacy: Balance measured by Mini-BESTest
6. Efficacy: Visual function
7. Efficacy: Retinal nerve thickness
8. Efficacy: Sleep quality using Pediatric Sleep Questionnaire (PSQ) in pediatric population and Pittsburg Sleep Quality Index (PSQI) Self-Report in adult patients

Conditions and MedDRA coding

Wolfram syndrom

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

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(WOCBP)(ie fertile, following menarche, until becoming post-menoposal unless permanently sterile, according to the CTFG guidelines on contraception) who are prescribed sodium valproate must use effective contraception without interruption during the entire duration of treatment and at least until 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 before inclusion. 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 must be used in case of heterosexual intercourse.
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 pregnancy tests at each study visit. Additional urinary pregnancy tests may be performed according to local pregnancy prevention program with Depakine.
7. Sexually active male patients with a female partner of childbearing potential must agree to the use of condoms and the use of an effective method of contraception by the female partner.
8. Patient willing and able to meet all protocol defined visits for the duration of the Trial.
9. Patients with active hearing implants, containing a magnetic system are allowed to participate to study, and will not have MRI during study participation.

Exclusion criteria 13

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 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…
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 severe central apnea with apnea/hypopnea index (AHI)>30
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. Patient with severe swallowing disorders

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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) 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 (i.e., 300 to 700 micro mol/l).

Secondary endpoints 7

1. 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.
2. Efficacy: Ventral Pons Volume measured and recorded in mm3 by standardised analysis of MRI at baseline, at visit 6 (Week 52) and at the last visit
3. Efficacy: 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
4. Efficacy: 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
5. Efficacy: Retinal nerve thickness measure by OCT measures at baseline, every six months during the first year of follow-up and at the final visit
6. Efficacy: Balance, measured by Mini-BESTest (Appendix 1) at baseline, at visit 6 (Week 52) and at the final visit
7. Efficacy: Sleep will be investigated by a specific Sleep questionnaire at baseline, at visit 6 (Week 52) and final visit, for patients under 18 years: sleeping habits measured by the Pediatric Sleep Questionnaire (PSQ) Parent Questionnaire, and for adults: sleeping habits, measured by the Pittsburg Sleep Quality Index (PSQI) Self-Report

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre D'Etude Des Cellules Souches

Sponsor organisation

Centre D'Etude Des Cellules Souches

Address

28 Rue Henri Desbrueres

City

Corbeil Essonnes

Postcode

91100

Country

France

Scientific contact point

Organisation

Centre D'Etude Des Cellules Souches

Contact name

General Manager

Public contact point

Organisation

Centre D'Etude Des Cellules Souches

Contact name

General Manager

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications