Intramuscular versus enteral penicillin prophylaxis to prevent progression of rheumatic heart disease: Study protocol for a noninferiority randomized trial (the GOALIE trial).

Rheumatic Heart Disease (RHD) persists as a major cardiovascular driver of mortality and morbidity among young people in low-and middle-income countries. Secondary antibiotic prophylaxis (SAP) with penicillin remains the cornerstone of RHD control, however, suboptimal treatment adherence undermines most secondary prevention programs. Many of the barriers to optimal SAP adherence are specific to the intramuscular form of penicillin and may potentially be overcome by use of oral penicillin. This noninferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years. The Intramuscular vs Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5 to 17 years identified by echocardiographic screening with mild RHD (Stage A or B as defined by 2023 World Heart Federation criteria) to Benzathine Benzyl Penicillin G (BPG arm, every-28-day intramuscular penicillin) or Phenoxymethyl Penicillin (Pen V arm, twice daily oral penicillin) for a period of 2 years. A blinded echocardiography adjudication panel of 3 RHD experts and 2 cardiologists is determining the echocardiographic stage of RHD at enrollment and will do the same at study completion by consensus review. Treatment adherence and study retention are supported through peer support groups and case management strategies. The primary outcome is the proportion of children in the Pen V arm who progress to more advanced RHD compared to those in the BPG arm. Secondary outcomes are patient-reported outcomes (treatment acceptance, satisfaction, and health related quality of life), costs, and cost-effectiveness of oral compared to intramuscular penicillin prophylaxis for RHD. A total sample size of 1,004 participants will provide 90% power to demonstrate noninferiority using a margin of 4% with allowance for 7% loss to follow-up. Participant enrollment commenced in October 2023 and final participant follow-up is expected in December 2026. The graphical abstract (Fig. 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up. The GOALIE trial is critical in global efforts to refine a pragmatic approach to secondary prevention for RHD control. GOALIE insists that the inferiority of oral penicillin be proven contemporarily and against the most important near-term clinical outcome of progression of RHD severity. This work also considers other factors that could influence the adoption of oral prophylaxis and change the calculus for acceptable efficacy including patient-reported outcomes and costs. ClinicalTrials.gov: NCT05693545.

Rwebembera J ，Ndagire E ，Carvalho N ，Webel AR ，Sable C ，Okello E ，Sarnacki R ，Spaziani AM ，Mucunguzi A ，Engelman D ，Grobler A ，Steer A ，Beaton A ... -  《-》

Determining the impact of Benzathine penicillin G prophylaxis in children with latent rheumatic heart disease (GOAL trial): Study protocol for a randomized controlled trial.

Rheumatic heart disease (RHD) remains a high prevalence condition in low- and middle-income countries. Most individuals with RHD present late, missing the opportunity to benefit from secondary antibiotic prophylaxis. Echocardiographic screening can detect latent RHD, but the impact of secondary prophylaxis in screen-detected individuals is not known. This trial aims to determine if secondary prophylaxis with every-4-week injectable Benzathine penicillin G (BPG) improves outcomes for children diagnosed with latent RHD. This is a randomized controlled trial in consenting children, aged 5 to 17 years in Northern Uganda, confirmed to have borderline RHD or mild definite RHD on echocardiography, according to the 2012 World Heart Federation criteria. Qualifying children will be randomized to every-4-week injectable intramuscular BPG or no medical intervention and followed for a period of 2 years. Ongoing intervention adherence and retention in the trial will be supported through the establishment of peer support groups for participants in the intervention and control arms. A blinded echocardiography adjudication panel consisting of four independent experts will determine the echocardiographic classification at enrollment and trajectory through consensus review. The primary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic progression of latent RHD compared to those in the control arm. The secondary outcome is the proportion of children in the BPG-arm who demonstrate echocardiographic regression of latent RHD compared to those in the control arm. A sample size of 916 participants will provide 90% power to detect a 50% relative risk reduction assuming a 15% progression in the control group. The planned study duration is from 2018-2021. Policy decisions on the role of echocardiographic screening for RHD have stalled because of the lack of evidence of the benefit of secondary prophylaxis. The results of our study will immediately inform the standard of care for children diagnosed with latent RHD and will shape, over 2-3 years, practical and scalable programs that could substantially decrease the burden of RHD in our lifetime. ClinicalTrials.gov: NCT03346525. Date Registered: November 17, 2017.

Beaton A ，Okello E ，Engelman D ，Grobler A ，Scheel A ，DeWyer A ，Sarnacki R ，Omara IO ，Rwebembera J ，Sable C ，Steer A ... -  《-》

Long-term antibiotic prophylaxis for prevention of rheumatic fever recurrence and progression to rheumatic heart disease.

Bray JJ ，Thompson S ，Seitler S ，Ali SA ，Yiu J ，Salehi M ，Ahmad M ，Pelone F ，Gashau H ，Shokraneh F ，Ahmed N ，Cassandra M ，Marijon E ，Celermajer DS ，Providencia R ... -  《Cochrane Database of Systematic Reviews》

Acceptability and Implementation Challenges of Benzathine Penicillin G Secondary Prophylaxis for Rheumatic Heart Disease in Ethiopia: A Qualitative Study.

Monthly intramuscular injections of benzathine penicillin G (BPG) remain the cornerstone of secondary prophylaxis for acute rheumatic fever and rheumatic heart disease (RHD). The barriers to successful delivery of BPG may be patient- or service-delivery-dependent. The aim of the present study was to explore the perceived acceptability and implementation challenges of BPG treatment for RHD, from the perspective of healthcare providers (HCPs). A descriptive qualitative study using semi-structured interview guides was conducted in four public hospitals in Ethiopia. Physicians and nurses who had at least 1 year of experience in delivering RHD secondary prophylaxis were recruited. The interviews were audio recorded, transcribed verbatim, and translated into English for analysis using framework method thematic analysis. Identified behavioral factors were mapped onto a theoretical framework of acceptability (TFA), and the Capability, Opportunity, Motivation-Behavior (COM-B) model. Twenty-two interviews were conducted with HCPs (mean age 39 years, 55% nurses). Insights into BPG use and acceptability were categorized into four major themes related to: (1) individual factors (e.g., fear of anaphylactic reaction), (2) health system barriers (e.g., BPG shortage), (3) patient/caregiver perceptions (e.g., reliance on injectables, over expectation of treatment outcomes), and (4) product (e.g., injection pain, needle blockage). HCPs identified facilitators and barriers which highlight the complexities associated with BPG as secondary prophylaxis for RHD in Ethiopia. Based on these data, we suggest RHD control programs should (1) provide cross-disciplinary training and education programs to support safe and context-appropriate delivery of BPG (2) improve resourcing of health facilities to facilitate safe drug delivery, (3) establish a comprehensive system for auditing severe adverse reactions post-BPG injection to generate robust pharmacovigilance data, and consider alternative approaches to BPG delivery including access to improved formulations (e.g., BPG suspension formulations in pre-filled syringes). - Key barriers included (a) resistance from healthcare providers to administer benzathine penicillin G (BPG) due to their concerns about injection-related severe adverse events, and potential repercussions should an event occur, (b) poor community and healthcare provider awareness of the disease and its treatment, (c) lack of resources to manage adverse events, and (d) injection pain.- Key enablers included (a) perceived superior treatment benefits of BPG and (b) co-administration of lidocaine/analgesics to reduce injection pain.- Recommendations to address identified challenges include (a) improved training/education on RHD diagnosis, disease progression, and treatment, (b) improved access to supportive resources, (c) active adverse reaction monitoring and reporting, and (d) encouraging the provision/access of globally subsidized BPG suspension formulations in pre-filled syringes.

Birru EM ，Batty KT ，Manning L ，Enkel SL ，Moore BR ... -  《-》

Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.

Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown. We conducted a randomized, controlled trial of secondary antibiotic prophylaxis in Ugandan children and adolescents 5 to 17 years of age with latent rheumatic heart disease. Participants were randomly assigned to receive either injections of penicillin G benzathine (also known as benzathine benzylpenicillin) every 4 weeks for 2 years or no prophylaxis. All the participants underwent echocardiography at baseline and at 2 years after randomization. Changes from baseline were adjudicated by a panel whose members were unaware of the trial-group assignments. The primary outcome was echocardiographic progression of latent rheumatic heart disease at 2 years. Among 102,200 children and adolescents who had screening echocardiograms, 3327 were initially assessed as having latent rheumatic heart disease, and 926 of the 3327 subsequently received a definitive diagnosis on the basis of confirmatory echocardiography and were determined to be eligible for the trial. Consent or assent for participation was provided for 916 persons, and all underwent randomization; 818 participants were included in the modified intention-to-treat analysis, and 799 (97.7%) completed the trial. A total of 3 participants (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, as compared with 33 (8.2%) in the control group (risk difference, -7.5 percentage points; 95% confidence interval, -10.2 to -4.7; P<0.001). Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis). Among children and adolescents 5 to 17 years of age with latent rheumatic heart disease, secondary antibiotic prophylaxis reduced the risk of disease progression at 2 years. Further research is needed before the implementation of population-level screening can be recommended. (Funded by the Thrasher Research Fund and others; GOAL ClinicalTrials.gov number, NCT03346525.).

Beaton A ，Okello E ，Rwebembera J ，Grobler A ，Engelman D ，Alepere J ，Canales L ，Carapetis J ，DeWyer A ，Lwabi P ，Mirabel M ，Mocumbi AO ，Murali M ，Nakitto M ，Ndagire E ，Nunes MCP ，Omara IO ，Sarnacki R ，Scheel A ，Wilson N ，Zimmerman M ，Zühlke L ，Karthikeyan G ，Sable CA ，Steer AC ... -  《-》