Treatment of Barth Syndrome by Cardiolipin Manipulation (CARDIOMAN) With Bezafibrate: Protocol for a Randomized Placebo-Controlled Pilot Trial Conducted in the Nationally Commissioned Barth Syndrome Service.

Autor:	Dabner L; Bristol Trials Centre (Clinical Trials and Evaluation Unit), Bristol Medical School, University of Bristol, Bristol, United Kingdom., Pieles GE; Bristol Congenital Heart Centre, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom.; National Institute of Health Research (NIHR) Biomedical Research Centre (Cardiovascular theme), University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, United Kingdom., Steward CG; School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom., Hamilton-Shield JP; NIHR Biomedical Research Centre (Nutrition theme), University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, United Kingdom., Ness AR; NIHR Biomedical Research Centre (Nutrition theme), University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, United Kingdom.; Bristol Dental School, University of Bristol, Bristol, United Kingdom., Rogers CA; Bristol Trials Centre (Clinical Trials and Evaluation Unit), Bristol Medical School, University of Bristol, Bristol, United Kingdom., Bucciarelli-Ducci C; National Institute of Health Research (NIHR) Biomedical Research Centre (Cardiovascular theme), University Hospitals Bristol and Weston NHS Foundation Trust and University of Bristol, Bristol, United Kingdom.; Bristol Heart Institute, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom., Greenwood R; Research Design Service South West, National Institute for Health Research, Bristol, United Kingdom., Ellis L; Bristol Trials Centre (Clinical Trials and Evaluation Unit), Bristol Medical School, University of Bristol, Bristol, United Kingdom., Sheehan K; University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom., Reeves BC; Bristol Trials Centre (Clinical Trials and Evaluation Unit), Bristol Medical School, University of Bristol, Bristol, United Kingdom.
Jazyk:	angličtina
Zdroj:	JMIR research protocols [JMIR Res Protoc] 2021 May 31; Vol. 10 (5), pp. e22533. Date of Electronic Publication: 2021 May 31.
DOI:	10.2196/22533
Abstrakt:	Background: Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population. Objective: The aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease. Methods: The CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO 2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase. Results: A total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021. Conclusions: This trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome. Trial Registration: International Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579. International Registered Report Identifier (irrid): DERR1-10.2196/22533. (©Lucy Dabner, Guido E Pieles, Colin G Steward, Julian P Hamilton-Shield, Andrew R Ness, Chris A Rogers, Chiara Bucciarelli-Ducci, Rosemary Greenwood, Lucy Ellis, Karen Sheehan, Barnaby C Reeves. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 31.05.2021.)
Databáze:	MEDLINE
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