Repurposing carbamazepine for treatment of skeletal dysplasia in children
| ISRCTN | ISRCTN37815869 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN37815869 |
| EudraCT/CTIS number | 2018-002633-38 |
| IRAS number | 244715 |
| Secondary identifying numbers | CPMS 40280 |
- Submission date
- 28/01/2019
- Registration date
- 23/05/2019
- Last edited
- 15/11/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Musculoskeletal Diseases
Plain English summary of protocol
Background and study aims
Metaphyseal chondrodysplasia type Schmid (MCDS) is an ultra-rare inherited disorder. It is associated with curvature of leg bones, flaring at the end of long bones, and joint problems. These symptoms can make movement difficult by impairing walking and causing pain in the joints and legs throughout life. Current treatment focuses on pain relief and surgery. This study aims to find a treatment for the cause of MCDS and test whether the drug carbamazepine (CBZ) can improve the health of patients with MCDS.
Who can participate?
Children who have MCDS and have not yet reached bone maturity
What does the study involve?
The study comprises two stages.
Stage 1 is open to UK participants only. The study involves an initial period of 12 months of observation during which participants do not receive CBZ treatment. This observation period includes up to five visits to hospital that involve collecting demographic and medical history, physical examinations, laboratory safety assessments, measurement of growth and bone alignment (including x-rays) and multiple questionnaires.
Participants then enter a dose titration and tolerability stage for the next 12 months. In this stage, participants receive CBZ treatment, with the aim of finding the best dose for them. The drug is given in either tablet or liquid form, depending on the child’s preference. The safety and tolerability of CBZ are assessed. For this part of the study, participants visit the hospital up to six times and receive weekly phone calls while the best dose is found for the individual (up to 11 calls). Ad hoc safety visits can also be performed, if clinically indicated. Similar data is collected to the data collected in the observation year. Once a dose is selected, the participant receives treatment at that dose until they have been treated with CBZ for a total of 24 months. Additionally, eligible Stage 1 participants may opt to continue treatment for further 12 months (treatment with CBZ up to 36 months) subject to a separate informed consent at visit 2.5. Participants are required to visit hospital at 3-monthly intervals throughout their CBZ treatment to assess the impact of the treatment. Similar data to that collected in the observation year is collected throughout the CBZ treatment phase.
Stage 2 is open to both UK and International participants. The study involves an initial period of 6 months of observation during which participants do not receive CBZ treatment. This observation period includes up to four visits to hospital that involve collecting demographic and medical history, physical examinations, laboratory safety assessments, measurement of growth and bone alignment (including x-rays) and multiple questionnaires.
Participants then enter a 12-month CBZ treatment stage during which they are required to visit hospital 3-monthly to assess the impact of the treatment. Ad hoc safety visits can also be performed, if clinically indicated. Again, similar data is collected in the treatment stage to the data collected in the observational stage.
What are the possible benefits and risks of participating?
The potential benefit is that CBZ could improve the treatment of MCDS. If CBZ is taken during pregnancy, there is a risk that it will harm the unborn child. There is a potential risk that people treated with CBZ could develop common side effects such as dizziness and tiredness; feeling unsteady or finding it difficult to control movements; feeling or being sick; changes in liver enzyme levels (usually without any symptoms); skin reactions which may be severe; or leucopenia (a reduced number of the cells which fight infection making it easier to catch infections).
Where is the study run from?
Stage 1 is run from:
1. The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
2. Guy's and St. Thomas’ NHS Foundation Trust, London, UK
Stage 2 is run from:
1. The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
2. Guy's and St. Thomas’ NHS Foundation Trust, London, UK
3. Murdoch Children Research Institute, Melbourne, Australia
4. Rizzoli Orthopaedic Institute, Bologna, Italy
When is the study starting and how long is it expected to run for?
December 2017 to May 2024
Who is funding the study?
European Commission: Horizon 2020
Who is the main contact?
1. Dr Michael Wright
Michael.Wright19@nhs.net
2. Irena Bibby
mcdstrialsupport@newcastle.ac.uk
3. Dr Dean Allerton
mcdstrialsupport@newcastle.ac.uk
Contact information
Scientific
Institute of Genetic Medicine
International Centre for Life
Central Parkway
Newcastle-upon-Tyne
NE1 3BZ
United Kingdom
 ORCID ID |
0000-0001-7483-5404 |
|---|---|
| Michael.Wright19@nhs.net |
Public
Newcastle Clinical Trials Unit
Newcastle University
1-4 Claremont Terrace
Newcastle-upon-Tyne
NE2 4AE
United Kingdom
| Phone | +44 (0)191 208 7968 |
|---|---|
| mcdstrialsupport@newcastle.ac.uk |
Public
Newcastle Clinical Trials Unit
1-4 Claremont Terrace
Newcastle University
Newcastle-upon-Tyne
NE2 4AE
United Kingdom
| mcdstrialsupport@newcastle.ac.uk |
Study information
| Study design | Non-randomized; Both; Design type: Treatment, Drug, Health Economic |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | An open label phase I/IIa trial repurposing carbamazepine (CBZ) for the treatment of skeletal dysplasia in children |
| Study acronym | MCDS-Therapy |
| Study objectives | The aim of the trial is to evaluate the effect of carbamazepine on children with a diagnosis of MCDS with confirmed COL10A1 pathogenic mutation. |
| Ethics approval(s) | Approved 19/11/2018, Yorkshire & The Humber - Sheffield Research Ethics Committee (NHSBT Newcastle Blood Donor Centre, Newcastle upon Tyne, NE2 4NQ; Tel: +44 (0)207 104 8082; Email: nrescommittee.yorkandhumber-sheffield@nhs.net), ref: 18/YH/0428 |
| Health condition(s) or problem(s) studied | Skeletal dysplasia |
| Intervention | Current interventions as of 16/05/2024: This is a two-stage open-label, single-arm phase I/IIa trial of carbamazepine in children with skeletal dysplasia who are outpatients. Stage 1 of the trial includes: 1. 12 months baseline observation 2. 12 months dose titration and tolerability 3. 12-month treatment phase + additional optional 12 months of treatment for eligible participants Stage 2 of the trial includes: 1. 6 months baseline observation 2. 12-month treatment phase Previous interventions: This is a two-stage open-label, single-arm phase I/IIa trial of carbamazepine in children with skeletal dysplasia who are outpatients. The trial includes a 12-month baseline observation period and a 12-month initial dose determination stage (Stage 1) followed by long-term assessment of efficacy and safety at the chosen dose (Stage 2). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I/II |
| Drug / device / biological / vaccine name(s) | Carbamazepine |
| Primary outcome measure | Current primary outcome measures as of 16/05/2024: 1. Laboratory safety assessments, adverse events and physical examinations collected post IMP administration 2. Outcome of dose-titration safety review at 6 months post IMP treatment initiation Stage 2: 1. Alteration from baseline in growth velocity over 12 months 2. Growth velocity follow-up data at 12 months post treatment initiation Previous primary outcome measures: Stage 1: 1. Laboratory safety assessments at screening, month 0, month 6 and month 12 2. Adverse events and physical examinations collected over a 12-month period post IMP administration 3. Outcome of dose-titration safety review at 3 and 12 months post IMP treatment initiation Stage 2: 1. Growth velocity at baseline and over 24 months 2. Growth velocity follow-up data at 24 months post treatment initiation |
| Secondary outcome measures | Current secondary outcome measures as of 16/05/2024: Stage 1: 1. Pain perception measured by PEDSQL Pain Coping Inventory and PEDSQL Pain Questionnaire over 24 months Stage 2: 1. Height percentile at baseline and over 12 months 2. Long bone alignment and configuration measured by X-ray analysis at baseline and over 12 months 3. Pain perception measured by PEDSQL Pain Coping Inventory and PEDSQL Pain Questionnaire at baseline and over 12 months 4. Health-related quality of life measured by Paediatric Quality of Life Inventory (PedsQL) and EQ-5D-Y at baseline and over 12 months Previous secondary outcome measures: Stage 1: 1. Pain perception measured by PEDSQL Pain Coping Inventory and PEDSQL Pain Questionnaire at baseline and 12 months Stage 2: 1. Height percentile at baseline and over 24 months 2. Long bone alignment and configuration measured by X-ray analysis at baseline and over 24 months 3. Pain perception measured by PEDSQL Pain Coping Inventory and PEDSQL Pain Questionnaire at baseline and over 24 months 4. Health-related quality of life measured by Paediatric Quality of Life Inventory (PedsQL) and EQ-5D-Y at baseline and over 24 months 5. MCDS biomarker signatures (+/- CBZ treatment) measured using blood samples |
| Overall study start date | 01/12/2017 |
| Completion date | 31/05/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Child |
| Sex | Both |
| Target number of participants | Planned Sample Size: 40 |
| Total final enrolment | 27 |
| Key inclusion criteria | Current inclusion criteria as of 16/05/2024: 1. Participants where a pathogenic mutation in the gene encoding the COL10A1 protein has been identified by sequence analysis 2. Ambulant at the time of consent/assent, with open epiphyses 3. Willing and able to attend for safety monitoring assessments 4. Willing and able to adhere to the trial visit schedule and other protocol requirements 5. Capable of giving informed consent, or if appropriate, participants having an acceptable individual capable of giving consent on the participant’s behalf (e.g. parent or legal guardian of a child under 16 years of age) 6. Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations) 7. If female and of childbearing potential, the participant must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] at baseline and agree to regular pregnancy testing during the trial 8. Sexually active female participants of childbearing potential must practice true abstinence in line with their preferred and usual lifestyle, or use two acceptable effective methods of contraception whilst on treatment and for a period of 28 days after discontinuation: a barrier method such as a condom or occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository and an established non-barrier method such as oral, injected, or implanted hormonal methods (hormonal preparations must contain not less than 50µg oestrogen). Use of some alternative non-hormonal method of contraception should be considered: an intrauterine device or intrauterine system for the entire duration of the treatment period and for a period of 28 days after discontinuation. Previous inclusion criteria: 1. Pathogenic mutation in the gene encoding the COL10A1 protein has been identified by sequence analysis 2. Ambulant at the time of consent/assent, with open epiphyses 3. Willing to attend for safety monitoring assessments 4. Willing and able to adhere to the trial visit schedule and other protocol requirements 5. Capable of giving informed consent, or if appropriate, participants having an acceptable individual capable of giving consent on the participant’s behalf (e.g. parent or legal guardian of a child under 16 years of age) 6. Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations) 7. The patient, if female and of childbearing potential, must have a negative pregnancy test [urine beta-human chorionic gonadotropin (β-hCG)] at baseline and agree to regular pregnancy testing during the trial 8. Sexually active female patients of childbearing potential are required to practice true abstinence in line with their preferred and usual lifestyle or use two acceptable effective methods of contraception, a barrier method such as a condom or occlusive cap (diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/suppository and an established non-barrier method such as oral, injected, or implanted hormonal methods (hormonal preparations must contain not less than 50 µg oestrogen) use of some alternative non-hormonal method of contraception should be considered, an intrauterine device or intrauterine system for the entire duration of the treatment period |
| Key exclusion criteria | Current exclusion criteria as of 16/05/2024: 1. Patients who have reached skeletal maturity* 2. Patients who have a planned surgery or planned osteotomy (which in the opinion of the Chief Investigator, Principal Investigator and/or the clinical members of the TMG deems the patient unsuitable for the trial)** 3. Patients who have had a prior adverse reaction to carbamazepine or similar drugs such as oxcarbazepine, or to any related tricyclic antidepressants. 4. Patients known to have atrioventricular block 5. Patients who have a history of bone marrow suppression/depression 6. Patients who have evidence of chronic hepatic or renal impairment 7. Patients who have acute intermittent porphyria 8. Patients who have received a monoamine oxidase inhibitor within 14 days of commencing therapy 9. Patients who have abnormal blood screening results at the time of treatment initiation will be excluded unless the Investigator believes the abnormality to be non-significant clinically 10. Patients of Han Chinese, Thai and other Asian origins who carry the HLA-B*1502 allele *Skeletal maturity will be assessed as part of the eligibility criteria. Individuals who may reach skeletal maturity before the end of the study should not be included. Patients will be assessed clinically on a case-by-case basis through discussion of the site PI with the CI and/or the clinical members of the TMG during the screening process. If a participant reaches skeletal maturity during the treatment phase of the trial, they will be asked to continue on the trial for an additional 6 months from the point of skeletal maturity. Patients will stay on their medication and attend study visits, to evaluate if CBZ may have any effect on MCDS patients after they reach skeletal maturity. **Patients who have planned surgery or planned osteotomy will not automatically be ineligible for the trial. Every potential participant with planned surgery or osteotomy will be assessed clinically on a case-by-case basis through discussion of the site PI, with the CI and/or the clinical members of the TMG during the screening process. Previous exclusion criteria: 1. Reached skeletal maturity 2. Prior adverse reaction to carbamazepine or similar drugs such as oxcarbazepine, or to any related tricyclic antidepressants. 3. Have atrioventricular block 4. History of bone marrow suppression/depression 5. Evidence of chronic hepatic or renal impairment 6. Acute intermittent porphyria 7. Received a monoamine oxidase inhibitor within 14 days of commencing therapy 8. Abnormal blood screening results at the time of treatment initiation will be excluded unless the Investigator believes the abnormality to be non-significant clinically 9. Patients of Han Chinese, Thai and other Asian origins who carry the HLA-B*1502 allele |
| Date of first enrolment | 01/04/2019 |
| Date of final enrolment | 31/05/2022 |
Locations
Countries of recruitment
- Australia
- Belgium
- England
- France
- Germany
- Italy
- United Kingdom
Study participating centres
International Centre for Life
The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle-upon-Tyne
NE7 7DN
United Kingdom
London
SE1 9RT
United Kingdom
-
France
-
Belgium
-
Italy
-
Australia
Sponsor information
Hospital/treatment centre
c/o Mr Sean Scott
Level 1
Regent Point
Regent Farm Road
Newcastle-upon-Tyne
NE3 3HD
England
United Kingdom
| Phone | +44 (0)191 2824461 |
|---|---|
| tnu-tr.sponsormanagement@nhs.net | |
"ROR" |
https://ror.org/05p40t847 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- European Union, Comisión Europea, Europäische Kommission, EU-Kommissionen, Euroopa Komisjoni, Ευρωπαϊκής Επιτροπής, Европейската комисия, Evropské komise, Commission européenne, Choimisiúin Eorpaigh, Europskoj komisiji, Commissione europea, La Commissione europea, Eiropas Komisiju, Europos Komisijos, Európai Bizottságról, Europese Commissie, Komisja Europejska, Comissão Europeia, Comisia Europeană, Európskej komisii, Evropski komisiji, Euroopan komission, Europeiska kommissionen, EC, EU
Results and Publications
| Intention to publish date | 31/05/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Publication is planned in a high-impact peer-reviewed journal and it will be published approximately 1 year after the overall trial end date. Additionally, an accessible summary of the results will be provided directly to patients and their parents/guardians at the earliest point that still permits appropriate publication and exploitation of the results. Further documents are not currently available but may be made available once the protocol has been published. |
| IPD sharing plan | Until publication of the trial results, access to the full dataset will be restricted to the Trial Management Group and to authors of the publication. The data generated within the MCDS-Therapy trial will be made available beyond the project for investigators who seek to answer important questions on health and disease in the context of research projects that are consistent with the legal and ethical standard practices of EU relevant policies. Hence, in line with these principles, investigators affiliated with bona fide research organisations that seek to answer important research questions related to drug repurposing and MCDS will be able to request access to experimental data and biological samples. The data will be anonymised and consent will be obtained for sharing of data and biological samples for ethically approved future research, which is not yet certain but will be relevant to skeletal dysplasias, bone disease or ER stress biomarkers. The custodian of the data generated by the trial is the CI, Dr Michael Wright (Michael.Wright@nuth.nhs.uk). |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Other files | version 1.0 | 13/03/2023 | 24/10/2024 | No | No |
| Statistical Analysis Plan | Stage 1 version 1.0 |
28/05/2021 | 24/10/2024 | No | No |
| Statistical Analysis Plan | Stage 2 version 1.0 |
09/02/2024 | 24/10/2024 | No | No |
| Basic results | 15/11/2024 | No | No | ||
| Protocol file | version 9.0 | 16/10/2023 | 15/11/2024 | No | No |
Additional files
Editorial Notes
15/11/2024: The following changes were made to the trial record:
1. The IRAS number was added.
2. The basic results have been uploaded as an additional file.
3. Uploaded protocol (not peer-reviewed) as an additional file.
24/10/2024: Statistical analysis plans and health economic analysis plan added.
16/05/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 30/11/2020 to 31/05/2022.
2. The overall study end date was changed from 01/12/2022 to 31/05/2024.
3. The intention to publish date was changed from 01/12/2023 to 31/05/2025.
4. The interventions, primary and secondary outcome measures, inclusion and exclusion criteria, and contact details were updated.
5. The trial was initially designed to have a cohort of 12 participants in the dose determination stage, and a cohort of 28 participants in the treatment stage. However, due to the COVID-19 pandemic delays, this has been amended to stage 1; n = 11 and stage 2; n = 29. The overall planned sample size remains the same (n = 40).
6. Total final enrolment added.
7. The study participating centres were updated to remove University of Freiburg.
8. The plain English summary was updated accordingly.
12/04/2021: The scientific contact has been updated and the plain English summary has been updated accordingly.
09/04/2021: The public contact has been updated and the plain English summary has been updated accordingly.
22/04/2020: Due to current public health guidance, recruitment for this study has been paused.
28/05/2019: Internal review.
23/05/2019: Trial's existence confirmed by the NIHR.
