Available online 24 May 2024

Author links open overlay panel, , , , , , , , , , , , ABSTRACTBackground

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, sub-optimal 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 non-inferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years.

Methods/Design

The Intramuscular versus Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5-17 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 1004 participants will provide 90% power to demonstrate non-inferiority 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 (Figure 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up.

Discussion

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.

Trial Registration

ClinicalTrials.gov: NCT05693545

Section snippetsBACKGROUND

Rheumatic heart disease (RHD) remains a high prevalence condition in low-and-middle-income countries, currently affecting at least 40 million people, many of whom suffer premature death.1,2 Most patients with RHD present late, missing the opportunity to benefit from secondary antibiotic prophylaxis (SAP).3 Screening echocardiography in RHD endemic settings is able to identify a large number of children with mild RHD,4,5 but until recently the effectiveness of SAP to protect children with mild

Study Design

The GOALIE Trial (ClinicalTrials.gov: NCT05693545) is a 2-year, phase III, parallel group, partially blinded (outcomes adjudicators blinded; patients, data collectors, local practitioners not blinded), pragmatic, single-site, randomized controlled non-inferiority trial comparing the outcomes of children aged 5–17 years with mild RHD who receive every-28-day IM BPG SAP to those who receive twice-daily oral Phenoxymethyl Penicillin (Pen V) SAP. A total of 1004 participants will be enrolled in the

Discussion

Increasing access to echocardiographic screening continues to unmask an unprecedented global burden of RHD, with disease endemicity concentrated in low-and-middle-income countries, where 80% of the world's children live.35,36 This burden is projected to remain severe over the next decade,37 calling for targeted strategies for disease management and control. The GOAL trial provided novel evidence for the impact of secondary antibiotic prophylaxis in reducing progression of mild RHD, supporting

Conclusion

The GOALIE trial represents enduring global efforts for continued refinement of the secondary prevention strategy of RHD control. With concerted efforts, parallel developments, innovations and discoveries in all control strategies, achievement of global control of RHD in our lifetime is a foreseeable possibility.

Uncited Figure

Figure 1

CRediT authorship contribution statement

Joselyn Rwebembera: Methodology, Investigation, Writing – original draft. Emma Ndagire: Investigation, Writing – review & editing. Natalie Carvalho: Methodology, Investigation, Writing – review & editing, Supervision. Allison R Webel: Methodology, Investigation, Writing – review & editing. Craig Sable: Methodology, Investigation, Writing – review & editing. Emmy Okello: Conceptualization, Methodology, Investigation, Resources, Writing – review & editing, Funding acquisition. Rachel Sarnacki:

Declaration of competing interest

None

Acknowledgements

We acknowledge the unwavering support of the trial advisory committee including Drs. Jonathan Carapetis, Liesl Zuhlke, Nigel Wilson, Ana Olga Mocumbi, Peter Lwabi, and Ganesan Karthikeyan; and the echocardiography adjudication panel members Drs. Craig Sable, Maria Nunes, John Lawrenson, Jen Klein, and Meghan Zimmerman.

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