Phase 3b/4 Randomized, Double‑Blind, Placebo‑Controlled Study of Daily Subcutaneous Elamipretide in Genetically Confirmed Barth Syndrome Patients

The primary objective is to assess the efficacy of once‑daily subcutaneous administration of elamipretide in patients with genetically confirmed Barth Syndrome, addressing the unmet need for disease‑modifying therapy in this mitochondrial cardiomyopathy. Secondary objectives include: • evaluation of the safety and tolerability of the investigational regimen; • characterization of the pharmacokinetic profile of elamipretide and its metabolites.

Twenty‑four male participants were enrolled, all of whom had genetically confirmed Barth Syndrome and met the predefined inclusion parameters. Eligible subjects were required to be at least 5 years of age at screening, with a left ventricular ejection fraction of 50 % or greater as measured by echocardiography, and to be capable of self‑administering the investigational product or have a qualified caregiver to do so. Enrollment was limited to individuals who could provide informed consent (or assent with parental consent when appropriate) and who agreed to adhere to the trial duration. Participants with female partners of childbearing potential were required to use a highly effective contraception method throughout the study period. The cohort consisted exclusively of patients, identified as a vulnerable population, and represented an age range extending from early childhood through adolescence and young adulthood.

The study is a Phase 3b/4, randomized, double‑blind, parallel‑group, placebo‑controlled trial evaluating once‑daily subcutaneous injections of 40 mg elamipretide in male subjects ≥5 years with genetically confirmed Barth Syndrome. After an initial screening visit to confirm eligibility, participants are randomly assigned in a 1:1 ratio to receive either elamipretide or matching placebo for 72 weeks. Study visits occur at baseline (Day 0) and at weeks 4, 12, 24, 36, 48, 60, and 72 for efficacy and safety assessments, including the composite functional score, individual 6‑minute walk test, timed up‑and‑go, and sit‑to‑stand tests, as well as global impression scales and muscle‑strength measurements. An end‑of‑study visit is performed within 4 weeks after the final dose to collect final data. Participant involvement therefore spans approximately 78 weeks, including screening and follow‑up. Early termination may occur due to serious adverse events, pregnancy, non‑adherence to dosing or study procedures, withdrawal of consent, or investigator decision based on safety or protocol violations.

The investigational product, elamipretide, is supplied as a sterile solution for injection containing elamipretide trihydrochloride. The assigned dose is 40 mg administered once daily by subcutaneous injection. The injection volume and concentration are standardized to deliver the target dose consistently across participants.

The control arm receives a matching placebo consisting of an identical‑appearing injection vehicle without active ingredient. The placebo is administered subcutaneously on the same schedule (once daily) to maintain blinding of participants and investigators.

Dosing occurs each day throughout the treatment period, with administration performed by qualified study personnel or trained caregivers. Compliance is monitored by electronic case report forms documenting injection date and time, and by periodic review of returned medication containers. Any missed or delayed doses are recorded, and participants receive reminders according to the protocol. The trial enrolls subjects with genetically confirmed Barth Syndrome to evaluate the efficacy and safety of daily subcutaneous elamipretide compared with placebo.

The primary efficacy assessment is the change from baseline to week 72 in a composite normalized score derived from three functional performance tests: the 6‑minute walk test (6MWT), the 3‑time up‑and‑go (3TUG), and the 5‑times sit‑to‑stand (5XSST). Each test contributes to the composite metric, which quantifies overall functional capacity.

Secondary efficacy evaluations include the individual changes from baseline to week 72 in the 6MWT, 3TUG, and 5XSST, as well as patient‑reported and clinician‑reported disease severity using the Patient Global Impression of Severity Scale (PGI‑S) and the Clinician Global Impression of Severity Scale (CGI‑S). Muscle strength outcomes are assessed by the change in knee extensor and hip flexor strength measured with handheld dynamometry (HHD).

All efficacy parameters will be measured at screening (baseline) and at the week 72 visit. Functional tests and dynamometry will be performed by trained study personnel using standardized protocols. Global impression scales will be completed by the patient and the treating clinician, respectively, at the same time points. Data will be analyzed by comparing the week 72 values to baseline values for each endpoint, employing appropriate statistical methods to evaluate treatment effects.