Determining the Impact of Penicillin in Latent RHD: The GOAL Trial

NCT03346525 | Unknown Phase 2 DMC

• 2 other identifiers: GOAL: RHD RCTE.W. "Al" Thrasher Award
• Study Type: interventional
• Target: 807
• Locations: 1 country
• Sites: 1

Brief Summary

Rheumatic heart disease (RHD) affects at least 32.9 million people, mostly children living in low-resource settings. Long-term intramuscular benzathine penicillin G (BPG) prophylaxis is proven to prevent progression of chronic valve changes in patients with established rheumatic heart disease (RHD) and to allow regression of valve changes in patients with a history of acute rheumatic fever (ARF) with mild RHD. However, in low-resource settings ARF is an elusive diagnosis, and most patients (85%) are diagnosed only when RHD is severe and irreversible, medications ineffective, and surgical intervention is expensive and/or unavailable. Identification of latent RHD might be an opportunity to substantially reduce RHD morbidity and mortality. However, detection of latent RHD is only important if outcomes are improved. The appropriate management of children with latent RHD is unknown and no formal recommendations exist. While some clinicians prescribe penicillin prophylaxis for children with latent RHD, clinical equipoise exists regarding the best practice. To fill this gap, the investigators propose a randomized controlled trial in children with latent RHD to evaluate the efficacy of BPG prophylaxis compared to no prophylaxis. Our primary outcome measure is progression of valvular changes on echocardiogram at 2 years. A sample size of 916 children is needed to detect a 50% reduction of progression (expected range 7.5-12.5% progression in BPG-arm vs. 15%-25% progression in control-arm) with 90% power. AIM 1: To compare the proportion of children (aged 5-17 years) with latent RHD receiving BPG prophylaxis who progress to worse valvular disease at 2-years compared to children not receiving BPG prophylaxis. Hypothesis 1: Prophylaxis with BPG will result in fewer children with latent RHD showing progression of echocardiographic valve changes at 2 years compared to children with latent RHD not receiving BPG prophylaxis. (The investigators expect at least a 50% relative reduction in progression in the BPG arm: range 15%-25% control arm vs. 7.5-12.5% BPG-arm.) AIM 2: To compare the proportion of children (aged 5-17 years) with latent RHD receiving BPG prophylaxis who regress to improved valvular disease at 2-years compared to children not receiving BPG prophylaxis. Hypothesis 2: Prophylaxis with BPG will result in more children with latent RHD showing regression of echocardiographic valve changes by 2 years compared to children with latent RHD not receiving BPG prophylaxis. (The investigators expect at least a 50% relative increase in regression in the BPG arm: range 10-20% control arm vs. 20-40% BPG arm.) This study is highly significant because it will establish if BPG prophylaxis improves outcomes for children with latent RHD. Feasibility will be ensured through the experience, resources, community support, and accessible patient population of our investigational team. The results of our study will have high impact, immediately informing international policy on the standard of care for children diagnosed with latent RHD and shaping, over 2-3 years, practical and scalable programs that could substantially decrease the global burden of RHD.

Conditions

Rheumatic Heart Disease in Children; Latent Rheumatic Heart Disease; Rheumatic Heart Disease; Heart Diseases

Keywords

echocardiography; penicillin prophylaxis; intramuscular benzathine penicillin G; benzathine penicillin G; low-resource setting

Outcome Measures

Primary Outcomes (1)

• progression of valvular changes on echocardiogram at 2 years

  To compare the proportion of children (aged 5-17 years) with latent RHD receiving BPG prophylaxis who progress to worse valvular disease at 2-years compared to children not receiving BPG prophylaxis

  2 years

Secondary Outcomes (1)

• regression of vavular changes on electrocardiogram at 2 years

  2 years

Study Arms (2)

BPG Arm

EXPERIMENTAL

Intramuscular BPG prophylaxis (600,000 IU for children \<30kg, 1.2 million IU for children ≥30kg), every 28 days

Drug: intramuscular benzathine penicillin G (BPG) prophylaxis

Control Arm

NO INTERVENTION

No prophylaxis

Interventions

intramuscular benzathine penicillin G (BPG) prophylaxis DRUG

Intramuscular BPG prophylaxis (600,000 IU for children \<30kg, 1.2 million IU for children ≥30kg), every 28 days.

Also known as: benzathine penicillin G, BPG, penicillin prophylaxis

BPG Arm

Eligibility Criteria

• Age: 5 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Children will be eligible for study participation if they are (1) between the ages of 5-17 years and (2) have a new diagnosis of latent RHD detected through primary school echo screening and confirmed by blinded consensus review. All children will be recruited from schools in Gulu District in Uganda.

You may not qualify if:

• Patients will be excluded from the study for the following reasons:
• Known history of ARF or RHD
• Newly diagnosed RHD by echo screening consider to be "missed clinical RHD" as compared to true latent RHD including: \> mild pathological valvular regurgitation at the mitral valve or aortic valve, mitral stenosis (mean MV gradient ≥ 5mmHg) (WHF, definite B), aortic stenosis (mean AV gradient ≥ 20mmHg)
• Structural or functional cardiac defects, other than those consistent with RHD, that were known prior to or detected through echo screening (except patent foramen ovale, small atrial septal defect, small ventricular septal defect, small patent ductus arteriosus).
• Prior allergic reaction to penicillin
• Any known conditions predisposing to thrombocytopenia or hypercoagulability, or other contraindications to intramuscular injection
• Any known co-morbid conditions (HIV, renal deficiencies, severe malnutrition among others) that have resulted in prescription of regular antibiotic prophylaxis

Sponsors & Collaborators

• Children's National Research Institute: lead
• Thrasher Research Fund: collaborator
• University of Cape Town: collaborator
• Uganda Heart Institute: collaborator
• Karp Family Foundation: collaborator
• Gift of Life International: collaborator
• Murdoch Childrens Research Institute: collaborator

Study Sites (1)

GOAL Office

Gulu, 20010, Uganda

Location

Related Publications (26)

• WHO - Global Burden of Disease. 2015;2015.

  BACKGROUND

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• Beaton A, Okello E, Rwebembera J, Grobler A, Engelman D, Alepere J, Carapetis J, DeWyer A, Lwabi P, Mirabel M, Mocumbi AO, Nakitto M, Ndagire E, Nunes MCP, Omara IO, Sarnacki R, Scheel A, Wilson N, Zuhlke L, Karthikeyan G, Sable CA, Steer AC. Refining Risk Stratification Among Children With Latent Rheumatic Heart Disease. Circulation. 2023 Jun 13;147(24):1848-1850. doi: 10.1161/CIRCULATIONAHA.122.063194. Epub 2023 Jun 12. No abstract available.

  PMID: 37307310 DERIVED

• 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, Zuhlke L, Karthikeyan G, Sable CA, Steer AC. Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease. N Engl J Med. 2022 Jan 20;386(3):230-240. doi: 10.1056/NEJMoa2102074. Epub 2021 Nov 13.

  PMID: 34767321 DERIVED

• Scheel A, Mirabel M, Nunes MCP, Okello E, Sarnacki R, Steer AC, Engelman D, Zimmerman M, Zuhlke L, Sable C, Beaton A. The inter-rater reliability and individual reviewer performance of the 2012 world heart federation guidelines for the echocardiographic diagnosis of latent rheumatic heart disease. Int J Cardiol. 2021 Apr 1;328:146-151. doi: 10.1016/j.ijcard.2020.11.013. Epub 2020 Nov 10.

  PMID: 33186665 DERIVED

• Beaton A, Okello E, Engelman D, Grobler A, Scheel A, DeWyer A, Sarnacki R, Omara IO, Rwebembera J, Sable C, Steer 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. Am Heart J. 2019 Sep;215:95-105. doi: 10.1016/j.ahj.2019.06.001. Epub 2019 Jun 8.

  PMID: 31301533 DERIVED

MeSH Terms

Conditions

Rheumatic Heart Disease; Heart Diseases

Interventions

Penicillin G

Condition Hierarchy (Ancestors)

Rheumatic Fever; Streptococcal Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Andrea Beaton, MD

  Cincinnati Children's

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Pediatric Cardiologist, Associate Professor of Pediatrics

Study Record Dates

• First Submitted: November 15, 2017
• First Posted: November 17, 2017
• Study Start: June 26, 2018
• Primary Completion: November 30, 2020
• Study Completion: November 30, 2020
• Last Updated: October 1, 2019

Record last verified: 2019-09

Data Sharing

• IPD Sharing: Will not share

Locations

UG (1)