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.
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.
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.
Parallel
Benzathine Penicillin
DrugBenzathine Penicillin 2.4 Million Units to be given intramuscularly every month for 24 months
Azithromycin (Azithro)
DrugOral Azithromycin 500 mg once daily for three days to be repeated every month will be given
Recurrence of acute rheumatic fever and progression of valvular cardiomyopathy
Recurrence of acute rheumatic fever and echocardiographic progression of valvular cardiomyopathy that occurs after 24 months of enrolment
Progression to more advanced RHD in the oral antibiotics arm compared to those in the BPG arm.
The primary outcome of the study will be the proportion of participants in the oral antibiotics arm who progress to more advanced RHD compared to those in the BPG arm.
Treatment acceptance and satisfaction.
Treatment acceptance and satisfaction using the Assessment criteria for Compliance, evaluation, and Performance Testing(ACCEPT) Questionnaire. The questionnaire scale uses a 0-100 scale where 0 represents the lowest level of treatment acceptance and 100 represents the highest level of treatment acceptance. In addition to the general acceptance score, the instrument summarizes data into five distinct dimensions, each also scored 0-100, which include acceptance/medications inconvenience, acceptance/long term treatment, acceptance/regimen constraints, acceptance/side effects, and General level of acceptance. The score provides an individualised assessment of teh risk /benefit ratio from the patient's perspective. eg. a lower score in a specific dimension, such as the regimen constraints, can highlight exactly which barriers are impacting a patient's adherence or persistence.
Health-related Quality of Life
Health-related quality of life using World Health Organization Health-Related Quality of Life-Brief Version (WHOQoL-BREF) Questionnaire.WHOQOL-BREF scores are summarized across four domains-physical health, psychological health, social relationships, and environment-with higher scores indicating better perceived quality of life. In addition, the instrument includes two general items assessing overall quality of life and general health. Each domain score is usually transformed to a 0-100 scale. The tool does not produce a single total overall score; results are interpreted by domain.
Cost and cost-effectiveness comparison of Azithromycin and Benzathine Penicillin
Economic outcomes will include the comparative assessment of direct and, where applicable, indirect costs associated with oral antibiotics versus intramuscular benzathine penicillin, as well as evaluation of incremental cost-effectiveness in relation to predefined clinical outcomes among adolescents in Nigeria. This will include direct treatment costs, delivery-related resource use, and the relative value of each regimen in achieving desired clinical outcomes.
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