Wolfram SyndromePhase 2AUDIOWOLFNCT04940572
Efficacy Study of Daily Administration of VPA in Patients Affected by Wolfram Syndrome
A Phase 2 study testing Depakine in people with Wolfram Syndrome, run by Centre d'Etude des Cellules Souches at 2 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 13 years and older
- Conditions the study is for
- Wolfram Syndrome
- What is being tested?
- Depakine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 2 sitesin 2 countries
- Study dates
- 26 Nov 2021to 1 Dec 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 13 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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
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- 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
Trial locations and contacts
2 sites in 2 countries.
2 sites in 2 countries
Spain1 site, 1 recruiting
- Recruiting
Centro periférico de Especialidades de Almería
Almería, 04009
Gema Esteban Bueno, MD, + 34653115070, gema.esteban.bueno@gmail.com
Paula Callejo García, PhD, +34 954 782 246, paula.callejo@juntadeandalucia.es
About this study
Official 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.
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).
Read the detailed description
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).
The effective dose and duration of this 3 years therapy has to be determined individually with the aim to obtain preservation of auditory function defined as no decrease higher than 5 dB on one ear compared to baseline at 8 kHz on high frequencies average and to reduce the dose of insulin and/or desmopressin needed, therefore monitoring of the patients plasma concentration of VPAis required for dose adjustment.
Generally a plasma level between 40 and 100 mg/l (ie, 300 to 700 micromol/l) sodium valproate is aimed to be reached.
Initially 10-15 mg of sodium valproate/kg bodyweight per day will be taken in one or two doses during meals. The dose will then be increased every 3 days in steps of 10 mg sodium valproate/kg bodyweight per day till the optimal plasma level is reached but does not exceed 100 milligrams per liter (ie, 700 micromol/l) during 156 weeks (refer to Appendix 5).
Analysis will compare Pure tone audiometry (PTA), Speech interference index (SII) and High frequency pure tone audiometry hearing test between baseline and final visit.
- Conditions
- Wolfram Syndrome
- Being tested
- Depakine
- Medical subject headings
- Wolfram Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DepakineDrug
Refer to arm description.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Depakine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline - Week 156
Secondary outcomes (8)
Safety endpoint
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.
Measured: Baseline - Week 156
Ventral Pons Volume measure
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.
Measured: Baseline - Week 156
Insulin and or desmopressin requirements
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
Measured: Baseline - Week 156
Visual acuity assessment
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
Measured: Baseline - Week 156
Retinal nerve thikness measure
Retinal nerve thikness measured by OCT measures at baseline, every six months during the first year of follow-up and at the final visit
Measured: Baseline - Week 156
Balance measured by Mini-BESTest
Balance, measured by Mini-BESTest (Appendix 1) at baseline, at visit 8 (Week 52) and at the final visit.
Measured: Baseline - Week 156
Quality of sleep assessment on pediatric population - Qualitative questionnaire (no scale)
Sleep will be investigated by Pediatric Sleep Questionnaire at baseline, at visit 8 (Week 52) and at final visit.
Measured: Baseline - Week 156
Quality of sleep assessment on adult population - Qualitative questionnaire (no scale)
Sleep will be investigated by Pittsburg Sleep Quality Index Self-Report on adult population at baseline, at visit 8 (Week 52) and at final visit.
Measured: Baseline - Week 156
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jun 2021
- Study start26 Nov 2021
- Primary completion1 Nov 2025 (estimated)
- Study completion1 Dec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Wolfram SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Open label study
- Masking
- None (open label)
- Enrolment
- 23 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Centre d'Etude des Cellules Souches
- Sponsor type
- University, hospital or other
- Collaborators
- Genethon
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04940572
- Sponsor's protocol ID
- 2020-004594-43
- Acronym
- AUDIOWOLF
- Status last verified
- Nov 2023
- First submitted
- 11 May 2021
- Last updated
- 28 Nov 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 28 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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.
- ClinicalTrials.gov ID
- NCT04940572
- Acronym / sponsor ID
- AUDIOWOLF / 2020-004594-43
- Conditions
- Wolfram Syndrome
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 23 participants (estimated)
- Lead sponsor
- Centre d'Etude des Cellules SouchesUniversity, hospital or other
- Collaborators
- Genethon
- Study start
- 26 Nov 2021 (actual)
- Primary completion
- 1 Nov 2025 (estimated)
- Study completion
- 1 Dec 2025 (estimated)
- First posted
- 25 Jun 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
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).
The effective dose and duration of this 3 years therapy has to be determined individually with the aim to obtain preservation of auditory function defined as no decrease higher than 5 dB on one ear compared to baseline at 8 kHz on high frequencies average and to reduce the dose of insulin and/or desmopressin needed, therefore monitoring of the patients plasma concentration of VPAis required for dose adjustment.
Generally a plasma level between 40 and 100 mg/l (ie, 300 to 700 micromol/l) sodium valproate is aimed to be reached.
Initially 10-15 mg of sodium valproate/kg bodyweight per day will be taken in one or two doses during meals. The dose will then be increased every 3 days in steps of 10 mg sodium valproate/kg bodyweight per day till the optimal plasma level is reached but does not exceed 100 milligrams per liter (ie, 700 micromol/l) during 156 weeks (refer to Appendix 5).
Analysis will compare Pure tone audiometry (PTA), Speech interference index (SII) and High frequency pure tone audiometry hearing test between baseline and final visit.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Open label study
| Arm | Type | Receives |
|---|---|---|
| Depakine (VPA) | Experimental | Drug: DepakineDepakine 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. |
Who may qualify
- Ages
- 13 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (10 listed)
- The patient has a definite diagnosis of Wolfram syndrome, as determined by the following:
- 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.
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DepakineRefer to arm description. | Drug | Depakine (VPA) |
Primary outcome
Preservation of auditory function.
Time frame: Baseline - Week 156
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).
8 secondary outcomes
Safety endpoint
Time frame: Baseline - Week 156
Ventral Pons Volume measure
Time frame: Baseline - Week 156
Insulin and or desmopressin requirements
Time frame: Baseline - Week 156
Visual acuity assessment
Time frame: Baseline - Week 156
Retinal nerve thikness measure
Time frame: Baseline - Week 156
Balance measured by Mini-BESTest
Time frame: Baseline - Week 156
Quality of sleep assessment on pediatric population - Qualitative questionnaire (no scale)
Time frame: Baseline - Week 156
Quality of sleep assessment on adult population - Qualitative questionnaire (no scale)
Time frame: Baseline - Week 156
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Nov 2023.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
2 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Depakine in people with Wolfram Syndrome, run by Centre d'Etude des Cellules Souches at 2 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 28 Nov 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in France, Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Yann GUIVARCH (01 69 90 85 35 ext. +33, yguivarch@istem.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Preservation of auditory function. (time frame: Baseline - Week 156). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Nov 2023.