| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metaphyseal chondrodysplasia type Schmid (MCDS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metaphyseal chondrodysplasia, Schmid type (MCDS), is a very rare inherited disorder characterized by short stature with abnormally short arms and legs (short-limbed dwarfism) and bowed legs (genu varu |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The principal research objectives for Stage 1 are to:
To aassess the safety and tolerability of carbamazepine (CBZ) in the treatment of children with MCDS who are ambulant but have not yet reached skeletal maturity (open epiphyses).
To determine an appropriate dose regimen of CBZ to inform the treatment of children with MCDS in Stage 2.
The principal research objectives for Stage 2 are:
To evaluate efficacy of carbamazepine for the treatment of children with MCDS who are ambulant but have not yet reached skeletal maturity (open epiphyses).
To determine if the level of efficacy warrants a subsequent formal development programme for carbamazepine in this indication.
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| E.2.2 | Secondary objectives of the trial |
The secondary research objectives for Stage 1 are:
To evaluate the effect of CBZ on pain in children with MCDS over 12 months.
The secondary research objectives for Stage 2 are:
To evaluate the effect of CBZ on height in children with MCDS over 24 months.
To evaluate the effect of CBZ on bone conformation in children with MCDS over 24 months.
To evaluate the effect of CBZ on pain in children with MCDS over 24 months.
To evaluate the effect of CBZ on health related quality of life of children with MCDS over 24 months.
To identify novel biomarkers relevant to CBZ treatment of MCDS which can be used to monitor therapy and disease progression. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Participants where a pathogenic mutation in the gene encoding the COL10A1 protein has been identified by sequence analysis
• Ambulant at the time of consent/assent, with open epiphyses
• Willing to attend for safety monitoring assessments
• Willing and able to adhere to the trial visit schedule and other protocol requirements.
• 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)
• Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations)
• 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.
• 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 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.
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| E.4 | Principal exclusion criteria |
• Patients who have reached skeletal maturity
• Patients who have had a prior adverse reaction to carbamazepine or similar drugs such as oxcarbazepine, or to any related tricyclic antidepressants.
• Patients known to have atrioventricular block
• Patients who have a history of bone marrow suppression/depression
• Patients who have evidence of chronic hepatic or renal impairment
• Patients who have acute intermittent porphyria
• Patients who have received a monoamine oxidase inhibitor within 14 days of commencing therapy
• 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
• Patients of Han Chinese, Thai and other Asian origins who carry the HLA-B*1502 allele
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage 1
Laboratory safety assessments, adverse events recording and physical examinations collected over a 12 month period post IMP administration.
Outcome of dose-titration safety review at 3 and 12 months post IMP administration.
Stage 2
Alteration from baseline in growth velocity over 24 months.
Growth velocity follow-up data at 24 months post treatment initiation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage 1 - 12 months
Stage 2 - 24 months |
|
| E.5.2 | Secondary end point(s) |
Stage 1
Alteration from baseline in pain perception over 12 months as measured by:
• PEDSQL Pain Coping Inventory
• PEDSQL Pain Questionnaire
Stage 2
Alteration from baseline in height percentile over 24 months.
Alteration from baseline in long bone alignment and configuration over 24 months as measured by X-ray analysis.
Alteration from baseline in pain perception over 24 months as measured by:
• PEDSQL Pain Coping Inventory
• PEDSQL Pain Questionnaire
Alteration from baseline in HRQOL scores over 24 months as measured by:
• Paediatric Quality of Life Inventory (PedsQL)
• EQ-5D-Y
Use of samples (blood) from the cell, and mouse models, patients enrolled into this trial and control samples to identify MCDS biomarker signatures (+/- CBZ treatment) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Stage 1 - 12 months
Stage 2 - 24 months |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Clinical trial of a licensed medicinal product in new condition of use (new target population) |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| France |
| Germany |
| Italy |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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