Condition category
Musculoskeletal Diseases
Date applied
28/01/2019
Date assigned
23/05/2019
Last edited
28/05/2019
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

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. The aim of this study is 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 involves an initial observation period of 12 months. During this time, participants do not receive CBZ treatment. The observation period includes up to five visits to hospital, and includes collecting demographic and medical history, physical examinations, measurement of growth and bone alignment (including x-rays) and pain questionnaires before treatment. Participants then enter a dosing 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 would be 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). 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. They need to visit hospital for up to nine visits to assess the impact of the treatment through continuing to collect similar data to that of the observation year.

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. Guys and St. Thomas’ Hospital, London, UK
Stage 2 is run from:
1. The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
2. Guys and St. Thomas’ Hospital, London, UK
3. The Institut national de la santé et de la recherche médicale, Paris, France
4. University of Antwerp, Antwerp, Belgium
5. University of Freiburg, Freiburg, Germany
6. Murdoch Children Research Institute, Melbourne, Australia
7. Rizzoli Orthopaedic Institute, Bologna, Italy

When is the study starting and how long is it expected to run for?
December 2017 to December 2022

Who is funding the study?
European Commission: Horizon 2020

Who is the main contact?
1. Dr Michael Wright
Michael.Wright@nuth.nhs.uk
2. Dominique French
Dominique.french@newcastle.ac.uk
3. Afnan Nadeem
Afnan.nadeen@newcastle.ac.uk

Trial website

https://www.mcds-therapy.eu

Contact information

Type

Scientific

Primary contact

Dr Michael Wright

ORCID ID

http://orcid.org/0000-0001-7483-5404

Contact details

Institute of Genetic Medicine
International Centre for Life
Central Parkway
Newcastle-upon-Tyne
NE1 3BZ
United Kingdom
-
Michael.Wright@nuth.nhs.uk

Type

Public

Additional contact

Dr Dominique French

ORCID ID

Contact details

Newcastle Clinical Trials Unit
1-4 Claremont Terrace
Newcastle University
Newcastle-upon-Tyne
NE1 3BZ
United Kingdom
+44 (0)191 208 2524
Dominique.french@newcastle.ac.uk

Type

Public

Additional contact

Dr Afnan Nadeem

ORCID ID

Contact details

Newcastle Clinical Trials Unit
1-4 Claremont Terrace
Newcastle University
Newcastle-upon-Tyne
NE1 3BZ
United Kingdom
-
Afnan.nadeen@newcastle.ac.uk

Additional identifiers

EudraCT number

2018-002633-38

ClinicalTrials.gov number

Nil known

Protocol/serial number

40280

Study information

Scientific title

An open label phase I/IIa trial repurposing carbamazepine (CBZ) for the treatment of skeletal dysplasia in children

Acronym

MCDS-Therapy

Study hypothesis

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

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

Study design

Non-randomised; Both; Design type: Treatment, Drug, Health Economic

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Skeletal dysplasia

Intervention

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, 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

Phase

Phase I/II

Drug names

Carbamazepine

Primary outcome measure

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

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 trial start date

01/12/2017

Overall trial end date

01/12/2022

Reason abandoned (if study stopped)

Eligibility

Participant 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

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

Planned Sample Size: 40; UK Sample Size: 12

Participant 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

Recruitment start date

01/04/2019

Recruitment end date

30/11/2020

Locations

Countries of recruitment

Australia, Belgium, France, Germany, Italy, United Kingdom

Trial participating centre

Freeman Hospital (lead centre)
Institute of Genetic Medicine International Centre for Life The Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle-upon-Tyne
NE7 7DN
United Kingdom

Trial participating centre

Evelina Children’s Hospital
Guy’s and St Thomas NHS Foundation Trust
London
SE1 9RT
United Kingdom

Trial participating centre

The Institut national de la santé et de la recherche médicale (INSERM)
Paris
-
France

Trial participating centre

University of Antwerp
Antwerp
-
Belgium

Trial participating centre

University of Freiburg
Freiburg
-
Germany

Trial participating centre

Murdoch Children Research Institute
Melbourne
-
Australia

Trial participating centre

Rizzoli Orthopaedic Institute
Bologna
-
Italy

Sponsor information

Organisation

The Newcastle upon Tyne Hospitals NHS Foundation Trust

Sponsor details

c/o Mr Sean Scott
Level 1
Regent Point
Regent Farm Road
Newcastle-upon-Tyne
NE3 3HD
United Kingdom
+44 (0)191 2824461
tnu-tr.sponsormanagement@nhs.net

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

European Commission; Grant Codes: 754825

Alternative name(s)

European Union, EC

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

Results and Publications

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 statement
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).

Intention to publish date

01/12/2023

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

28/05/2019: Internal review. 23/05/2019: Trial's existence confirmed by the NIHR.