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

Oral Azithromycin Versus Intramuscular Penicillin for Secondary Prevention of Rheumatic Heart Disease in Nigerian Secondary School Students: A Comparative Study to Improve Outcomes in Rheumatic Heart Disease Management

Background: Nigeria, among other Low and Middle-income countries, bears one of the highest burdens of RHD in Africa, affecting young to middle-aged adults within their productive years. This leads to loss of productivity, high out-of-pocket costs, and increased mortality risk. Challenges such as such as poverty, overcrowding, limited antibiotic access, and inconsistent prophylaxis contribute to the persistence of the disease. Secondary prophylaxis using intramuscular Benzathine Penicillin G (BPG) serves as the current standard for prevention, but has demonstrated poor adherence due to injection pain, fear, physical, and socioeconomic constraints. Oral Azithromycin offers a potential alternative by overcoming these barriers, providing an effective, acceptable, affordable and sustainable preventive strategy in Nigeria.

Methods and design: A randomised, non-inferiority, open-label, controlled clinical trial conducted across cardiology clinics of four tertiary hospitals in major Nigerian cities, for a duration of 24 months. This study will recruit participants aged 15 to 45 years with mild to moderate RHD cases (stage A or B as defined by World Heart Federation criteria) confirmed by a blinded adjudication panel, comprising 5 expert cardiologists, who will determine the echocardiographic stage of RHD on enrollment and at completion of the study period. Randomisation of participants will be done in a 1:1 ratio to receive either the standard regimen of intramuscular BPG (1.2 million units) every 28 days or a 3-day course of oral Azithromycin (500mg daily) repeated monthly. A total sample size of 474 participants will provide 90% power to demonstrate non-inferiority, using a margin of 4% with allowance for 15% on follow-up losses.

Objectives: The proportion of participants in the oral Azithromycin arm versus the IM BPG arm who demonstrate echocardiographic progression to worsen RHD stages or experience a recurrence of Acute Rheumatic Fever (ARF) within the period of two years will be compared. Additionally, accessing the adherence rates, causes of RHD-related hospitalisations, safety profiles, cost-effectiveness, and patient-reported outcomes, including treatment satisfaction and Health-Related Quality of Life (HRQoL).

Significance: This trial is designed to highlight the most effective and readily adoptable secondary prevention strategy for Nigeria's young-to-middle-aged population by evaluating patients' adherence, ease of administration, safety profile, drug availability, cost effectiveness, and other practical considerations in resource-limited settings. Establishing a prevention strategy that addresses the socioeconomic, physical barriers of injection-based prophylaxis and improving long-term adherence and clinical outcomes in Nigeria.

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.

Inclusion Criteria:

• They must be between 10 and 18 years old and have a confirmed diagnosis of mild or moderate RHD.
• They must be under follow-up care at one of the four trial sites and be capable of attending monthly visits or be picked during routine secondary school screening to be performed as part of the study.
• At enrollment, patients must demonstrate cognitive capacity to consent (or assent, if a minor) and a willingness to adhere to the study schedule.
• Females of childbearing potential must agree to avoid pregnancy during the trial.
• Individuals must not have initiated any alternative RHD prophylaxis regimen before enrollment; the trial will provide all prophylaxis during the study

Exclusion Criteria:

• known allergy to penicillin or any history of anaphylaxis to antibiotics.
• Girls who are pregnant or breastfeeding will be excluded, as well as any patient with severe comorbidities likely to complicate prophylaxis or follow-up. For example, patients with advanced heart failure (NYHA class III-IV), significant chronic kidney or liver disease, uncontrolled diabetes, or other serious chronic illnesses (e.g. active tuberculosis, immunodeficiency).
• Patients with psychiatric conditions or cognitive impairment that preclude informed consent or reliable adherence will also be excluded.
• Any patient currently enrolled in another interventional trial, or who is unwilling or unlikely to comply with monthly visits, will be excluded.