JMIR Publications

ABSTRACT

Background:

Barth syndrome is a rare, life-threatening, X-linked recessive genetic disease affecting predominantly 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 but to date no human trials have been performed in this population.

Objective:

To determine if 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.

Methods:

The CARDIOMAN study is a UK single centre, double-blinded, randomised, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was given in two 15-week phases with a minimum of one month washout period between phases where no treatment was given. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include: Monolysocardiolipin/tetralinoleoyl-cardiolipin MLCL/L4-CL ratio and cardiolipin profile in blood cells; amino acid expression; PCr/ATP ratio in cardiac and skeletal muscle oxidative function on 31P Magnetic Resonance Spectroscopy; quality of life by PedsQL questionnaire; absolute neutrophil count; cardiac function and rhythm profiles at rest and during exercise; mitochondrial organisation and function assessments. Outcomes were assessed at baseline and in the final week of each treatment phase.

Results:

Twelve patients were scheduled to participate across three consecutive research clinics in March to April 2019. Eleven participants were recruited in total and follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in early 2021.

Conclusions:

This trial was approved by the UK (South West – Central Bristol) National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform future conduct of RCTs in rare-disease populations as well as testing the efficacy of bezafibrate as a potential treatment of the disease and advancing the mechanistic understanding of Barth syndrome. Clinical Trial: International Standard Randomized Controlled Trial Number (ISRCTN): ISRCTN58006579 (https://doi.org/10.1186/ISRCTN58006579)