Improving Management and Secondary Prevention Through Azithromycin Comparative Trial in Rheumatic Heart Disease in Nigeria)- IMPACT-RHD Nigeria (IMPACT-RHD)

Study Description Rheumatic heart disease (RHD) remains a major cause of preventable cardiovascular morbidity in low- and middle-income countries, particularly in sub-Saharan Africa. The disease results from repeated or inadequately treated episodes of acute rheumatic fever (ARF), leading to progressive valvular damage, most commonly involving the mitral valve and, in some cases, combined mitral and aortic valve disease. Secondary antibiotic prophylaxis is the cornerstone of RHD control because it reduces recurrent Group A streptococcal infection and helps prevent further ARF episodes and progression of cardiac injury.

Intramuscular benzathine benzyl penicillin G (BPG) administered at regular intervals is the current standard for secondary prophylaxis. Although BPG is effective, sustained adherence is often limited by injection pain, fear of needles, travel and clinic-access barriers, inconsistent drug supply, and health-system constraints. These challenges are particularly important in settings where long-term monthly follow-up is difficult to maintain. Oral prophylactic regimens may offer a more acceptable and scalable alternative if they can provide comparable protection against recurrent ARF and progression of valvular disease.

Azithromycin is active against Group A beta-hemolytic streptococci and offers a shorter dosing schedule that may improve adherence relative to longer oral penicillin regimens. In addition, oral prophylaxis may be particularly relevant for patients in whom repeated intramuscular injections are poorly tolerated or difficult to deliver consistently. The study focuses on adolescents aged 10-18 years because this population is clinically relevant to recurrent ARF prevention, relatively homogeneous, and well suited to school- and clinic-based follow-up systems commonly used in African settings. Compared with broader age ranges, this narrower age group is expected to reduce heterogeneity and allow a more focused evaluation of the effectiveness, acceptability, and feasibility of secondary antibiotic prophylaxis in Nigeria.

The primary objective of the IMPACT-RHD study is to determine whether oral azithromycin is non-inferior to intramuscular benzathine penicillin G for secondary prophylaxis among adolescents aged 10-18 years with mild to moderate RHD, based on prevention of clinically confirmed recurrent ARF during follow-up and echocardiographic progression to more severe valvular disease over 24 months.

This study is a randomized, controlled, open-label clinical trial to be conducted across selected secondary schools and cardiology clinics affiliated with five tertiary hospitals in Nigeria: Ladoke Akintola University of Technology Teaching Hospital, Ogbomoso; Bowen University Teaching Hospital, Ogbomoso; University of Uyo Teaching Hospital, Uyo; Jos University Teaching Hospital, Jos; and Olabisi Onabanjo University Teaching Hospital, Sagamu.

Eligible participants with confirmed RHD will be enrolled and followed for 24 months. Diagnosis and clinical assessment will be based on protocol-defined criteria for rheumatic fever and rheumatic heart disease. Participants will be randomized in a 1:1 ratio to receive either standard intramuscular BPG or oral azithromycin as secondary prophylaxis.

Participants will attend scheduled follow-up visits every 3 months, with additional unscheduled visits for suspected ARF when needed. Follow-up procedures will include clinical assessment for recurrent ARF, adherence evaluation, safety monitoring, protocol-specified prophylaxis administration or dispensing, throat swab collection at selected intervals, and echocardiography at baseline and 24 months. The planned sample size is 474 participants, with 237 participants in each treatment arm.

The study will be conducted in accordance with applicable national ethical standards. Approval will be obtained from the National Health Research Ethics Committee of Nigeria and the institutional review boards of the participating centers before study initiation.

Randomization will be computer-generated using permuted blocks to maintain balanced allocation in a 1:1 ratio between the intramuscular BPG group and the oral azithromycin group. The trial includes two secondary prophylaxis regimens. Participants assigned to the control arm will receive intramuscular benzathine penicillin G as the standard of care. Participants assigned to the intervention arm will receive oral azithromycin according to the protocol-defined dosing schedule.

Study outcomes include recurrence of acute rheumatic fever, progression of rheumatic heart disease on echocardiography, safety, adherence, patient-reported outcomes, and health economic evaluation. Detailed outcome definitions, assessment schedules, and analysis plans are provided in the corresponding protocol sections.

At scheduled follow-up visits, participants will undergo interval clinical review, adverse-event monitoring, adherence assessment, and protocol-specified treatment administration or dispensing. Echocardiography and patient-reported outcome assessments will be repeated at key time points according to the study schedule. Patient-reported outcomes will assess treatment acceptance, treatment satisfaction, and health-related quality of life using protocol-specified validated instruments. These assessments will be administered at predefined study time points to compare participant experience across treatment groups.

The study is powered for a non-inferiority comparison using a prespecified margin and planned enrollment of 474 participants, including allowance for loss to follow-up. Primary analyses will be conducted on intention-to-treat and per-protocol populations using appropriate regression methods for binary outcomes.

Secondary analyses will evaluate disease progression and changes in patient-reported outcomes over time using methods appropriate for repeated measurements.