Investigating bezafibrate as a treatment for Barth syndrome
| ISRCTN | ISRCTN58006579 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN58006579 |
| EudraCT/CTIS number | 2015-001382-10 |
| Secondary identifying numbers | CPMS 40281 |
- Submission date
- 17/12/2018
- Registration date
- 07/01/2019
- Last edited
- 10/03/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nutritional, Metabolic, Endocrine
Plain English summary of protocol
Background and study aims
Barth Syndrome is a rare, life threatening, genetic disease which affects young males. It is caused by abnormal fats in the powerhouses of cells (mitochondria) and those who suffer with it often develop heart failure, heart rhythm abnormalities, bacterial infections, poor growth or feeding, weak muscles, developmental delay, severe exercise intolerance, lethargy and fatigue; all of which affect their daily life. In addition, about one third of males living with this disease in the UK have required a heart transplant. Research has shown that several treatments can improve the fat abnormalities in Barth Syndrome, one of which is a drug called bezafibrate. The aim of this study is to find out whether bezafibrate can be given safely and effectively to people with Barth Syndrome.
Who can participate?
Males aged 6 and above with a Barth syndrome under the care of of the NHS Barth Syndrome Service
What does the study involve?
Participants are randomly allocated to take either bezafibrate or an inactive (placebo) treatment for 4 months, followed by a one month break, and then 4 months of the other treatment (e.g. placebo if bezafibrate taken for the first 4 months and vice versa). Half of the participants take bezafibrate first; the other half take placebo first. Tests are performed after each 4-month treatment period, looking for benefit in blood cells, exercise capacity, heart function or quality of life. Laboratory work is also conducted to see the effect of bezafibrate on participants’ cells and mitochondria.
What are the possible benefits and risks of participating?
There is no current treatment for Barth Syndrome itself and symptoms are treated individually on a clinical basis. Therefore, the use of bezafibrate in this clinical trial is the first potential treatment available for the alleviation of the abnormal cardiolipin ratio demonstrated in these patients. Risks of taking part include the risks of the side effects of taking bezafibrate. In addition to this, participants are required to make additional visits to Bristol as part of the study, which will cause some inconvenience and participants will also be required to undergo additional tests that they would not usually be asked to do.
Where is the study run from?
University Hospitals Bristol NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
April 2015 to January 2021
Who is funding the study?
National Institute for Health Research, Efficacy and Mechanism Evaluation Programme (UK)
Who is the main contact?
Lucy Dabner
cardioman-trial@bristol.ac.uk
Contact information
Public
Clinical Trials and Evaluation Unit
Bristol Royal Infirmary, Level 7
Marlborough Street
Bristol
BS2 8HW
United Kingdom
| Phone | +44 (0)117 342 2374 |
|---|---|
| cardioman-trial@bristol.ac.uk |
Study information
| Study design | Randomized; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised cross over trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| Scientific title | Treatment of Barth Syndrome by CARDIOlipin MANipulation (CARDIOMAN): a randomised placebo-controlled pilot trial conducted by the nationally commissioned Barth Syndrome Service |
| Study acronym | CARDIOMAN |
| Study objectives | Current study hypothesis as of 04/04/2019: Bezafibrate (and/or resveratrol in-vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin to L4- cardiolipin, ameliorating disease phenotype in those living with the disease, providing that the drug is free of significant side-effects at clinically effective doses. Previous study hypothesis: 1. Bezafibrate will modify the cellular ratio of monolysocardiolipin to L4- cardiolipin, ameliorating disease phenotype in those living with the disease, providing the drug is free of significant side-effects at clinically effective doses. 2. Bezafibrate (and/or resveratrol in-vitro) may have beneficial effects independent of any effect on cardiolipin ratio due to their abilities to influence a range of mitochondrial pathologies. |
| Ethics approval(s) | NRES Committee South West - Central Bristol, 12/11/2015, ref: 15/SW/0228 |
| Health condition(s) or problem(s) studied | Barth syndrome |
| Intervention | Current interventions as of 04/04/2019: All participants will receive 4 months of the intervention (bezafibrate) and 4 months of the placebo. Participants are randomised in a 1:1 ratio to the allocated treatment arm they receive first. The sequence of random allocations will be generated by computer and will be concealed from all clinical and research personnel. Those first allocated to the intervention at randomisation will be given bezafibrate followed by the placebo. Those first allocated to the placebo at randomisation will be given the placebo followed by bezafibrate. Both arms will have a minimum of 1 month washout period between the intervention and placebo administered, where no treatment is given. Intervention: Bezafibrate taken orally in tablet formulation. 1. Children aged 6-9 years: Commence on 100mg once daily for the first month and if well tolerated increase to 100mg twice daily for the remaining 3 month treatment period 2. Children aged 10-17 years: commence on 200mg once daily for the first month and if well tolerated increase to 200mg twice daily for the remaining 3 month treatment period 3. Adults (≥ 18 years): 200mg twice daily Placebo: Tablet formulation with no active substance taken orally at the same time points. The placebo will look, taste and smell as similar as possible to the intervention. Patients are followed up at the end of each treatment period (4 and 9 months) for information on exercise tolerance, drug action and tolerance, adverse events and quality of life. Previous interventions: All participants will receive 4 calendar months of the intervention (bezafibrate) and 4 calendar months of the placebo. Participants are randomised in a 1:1 ratio to the allocated treatment arm they receive first. The sequence of random allocations will be generated by computer and will be concealed from all clinical and research personnel. Those first allocated to the intervention at randomisation will be given bezafibrate followed by the placebo. Those first allocated to the placebo at randomisation will be given the placebo followed by bezafibrate. Both arms will have a 1 calendar month washout period between the intervention and placebo administered, where no treatment is given. Intervention: Bezafibrate taken orally in tablet formulation. 1. Children aged 6-9 years: Commence on 100mg once daily for the first month and if well tolerated increase to 100mg twice daily for the remaining 3 month treatment period 2. Children aged 10-17 years: commence on 200mg once daily for the first month and if well tolerated increase to 200mg twice daily for the remaining 3 month treatment period 3. Adults (≥ 18 years): 200mg twice daily Placebo: Capsule formulation with no active substance taken orally at the same time points. The placebo will look, taste and smell as similar as possible to the intervention. Patients are followed up at the end of each treatment period (4 and 9 months) for information on exercise tolerance, drug action and tolerance, adverse events and quality of life. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Bezafibrate |
| Primary outcome measure | Peak oxygen consumption on bicycle ergometry (i.e. peak VO2), assessed at baseline and in the final week of each treatment phase |
| Secondary outcome measures | 1. Monolysocardiolipin/tetralinoleoyl-cardiolipin MLCL/L4-CL ratio/cardiolipin profile in blood cells assessed via blood tests taken at baseline, 4 months and 9 months 2. PCr/ATP ratio in cardiac muscle assessed via 31P Magnetic Resonance Spectroscopy at baseline, 4 months and 9 months 3. Skeletal muscle oxidative function assessed via 31P Magnetic Resonance Spectroscopy at baseline, 4 months and 9 months 4. Quality of life (QoL) assessed using age-appropriate PedsQL questionnaires at baseline, 4 months and 9 months 5. Absolute neutrophil count assessed via blood test at baseline, 4 months and 9 months 6. Amino acid expression (plasma arginine and cysteine levels) assessed via blood test at baseline, 4 months and 9 months 7. Cardiac function (LVEF and shortening fraction) assessed via echocardiogram at baseline, 4 months and 9 months 8. Mitochondrial size in lymphocytes assessed via blood test at baseline, 4 months and 9 months 9. Numbers of mitochondria (per lymphocyte) assessed via blood test at baseline, 4 months and 9 months 10. Total area of mitochondria per lymphocyte assessed via blood test at baseline, 4 months and 9 months 11. Area of mitochondria as proportion of cytoplasm assessed via blood test at baseline, 4 months and 9 months 12. Mitochondria function and cristae organisation in lymphocytes assessed via blood test at baseline, 4 months and 9 months 13. Arrhythmia profile measured by 12-lead ECG at rest and during exercise (for potential rhythm abnormalities) at baseline, 4 months and 9 months |
| Overall study start date | 01/10/2014 |
| Completion date | 21/01/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Mixed |
| Lower age limit | 6 Years |
| Sex | Male |
| Target number of participants | Planned Sample Size: 15; UK Sample Size: 15 |
| Total final enrolment | 11 |
| Key inclusion criteria | 1. Male aged ≥6 years old 2. Clinical diagnosis of Barth syndrome with characteristic abnormality of the L4-cardiolipin/monolysocardiolipin ratio plus identified mutation in the tafazzin gene 3. Under the care of the NHS Barth Syndrome Service 4. Stable cardiac condition 5. Able to swallow bezafibrate tablets |
| Key exclusion criteria | 1. Known hypersensitivity to bezafibrate, to any component of the product or to other fibrates 2. Known photoallergic or phototoxic reactions to fibrates. 3. Hepatic dysfunction and/or liver function tests greater than 2x normal 4. A shortening fraction of <25 (or a significant drop in shortening fraction in the previous year) 5. Documented atrial or ventricular arrhythmia (atrial/ventricular tachycardia or atrial/ventricular fibrillation) that has not been stabilised with treatment. 6. Renal impairment (creatinine clearance < 90 mL/min) 7. Pre-existing known gallbladder disease. 8. Recent unspecified significant deterioration in general health 9. Prisoners and adults lacking capacity to provide informed consent |
| Date of first enrolment | 29/03/2019 |
| Date of final enrolment | 12/04/2019 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Bristol
BS2 8HW
United Kingdom
Sponsor information
Hospital/treatment centre
Research and Innovation
Level 3
Education Centre
Upper Maudlin Street
Bristol
BS2 8AE
England
United Kingdom
"ROR" |
https://ror.org/04nm1cv11 |
|---|
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 31/12/2021 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The patient information leaflet and trial protocol will be available on request. Please contact cardioman-trial@bristol.ac.uk. When all of the data has been collected and analysed, the researchers will hold a social gathering to feed the information back to the patient/families directly and to thank them for their participation. They will send a lay summary to all people/families in the UK with Barth Syndrome. Findings from the study will be submitted for publication in a peer-reviewed journal, selecting one with open access arrangements, under the NIHR Terms of Agreement, in order to allow rapid dissemination to the Barth syndrome community. The trialists will also present the findings at national/international paediatric, paediatric cardiology and metabolic disease conferences. |
| IPD sharing plan | Anonymised individual patient data (baseline, intervention, outcome data and adverse events) will be made available for secondary research, conditional on assurance from the secondary researcher that the proposed use of the data is compliant with the with the UK Policy Framework for Health and Social Care Research and MRC Policy on Data Preservation and Sharing regarding scientific quality, ethical requirements and value for money. Please contact Prof. Barney Reeves (cardioman-trial@bristol.ac.uk) to discuss any data requests. Data will be made available after the study has been closed and the primary publication is out. It will be made available indefinitely. Only data from patients who have consented for their data to be shared with other researchers will be provided. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Results article | 31/05/2021 | 01/06/2021 | Yes | No | |
| Basic results | version 1.0 | 20/10/2021 | 20/10/2021 | No | No |
| Protocol article | 31/05/2021 | 11/11/2022 | Yes | No | |
| Results article | Qualitative interview substudy of self-regulation with ethical approval granted as part of this clinical trial within which it was conducted | 29/09/2021 | 11/11/2022 | Yes | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Results article | 01/08/2024 | 10/03/2025 | Yes | No |
Additional files
Editorial Notes
10/03/2025: Publication reference added.
11/11/2022: The following changes have been made:
2. Protocol reference added.
2. Publication reference added.
20/10/2021: The basic results of this trial have been uploaded as an additional file.
01/06/2021: Publication reference added.
28/04/2021: The following changes have been made:
1. The overall trial end date has been changed from 31/07/2020 to 21/01/2021 and the plain English summary has been updated to reflect this change.
2. The intention to publish date has been changed from 31/07/2021 to 31/12/2021.
08/05/2019: The total final enrolment was added.
04/04/2019: The following changes were made to the trial record:
1. The study hypothesis, interventions and publication and dissemination plan were updated.
2. The recruitment start date was changed from 01/03/2019 to 29/03/2019.
3. The recruitment end date was changed from 23/11/2019 to 12/04/2019.
25/03/2019: The condition has been changed from "Specialty: Metabolic and Endocrine Disorders, Primary sub-specialty: Metabolic and Endocrine Disorders; Health Category: Metabolic and Endocrine; Disease/Condition: Metabolic disorders" to "Barth syndrome" following a request from the NIHR.
