Oral Presentation Lancefield International Symposium for Streptococci and Streptococcal Diseases 2025

Addressing Evidence Gaps in ARF Treatment - from the Aotearoa hydroxychloroquine pilot to an international adaptive platform trial  (118488)

Rachel H Webb 1 2 3 , Tom Hills 4 5 , Nikki Moreland 6 , Anna Ralph 7 , Nigel Wilson 8
  1. Kidz First Hospital, Counties Manukau District Health Board, Auckland
  2. Paediatric Infectious Diseases, Starship Children's Hospital, Auckland District Health Board, Auckland
  3. Department of Paediatrics, University of Auckland,
  4. Department of Infectious Diseases and Immunology, Auckland City Hospital, Auckland, New Zealand
  5. Medical Research Institute of New Zealand, Wellington, New Zealand
  6. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
  7. Menzies School of Health Research, Darwin, Australia
  8. Paediatric and Congenital Cardiac Services, Auckland District Health Board, Auckland , New Zealand

Background

There is no evidence-based anti-inflammatory treatment for ARF and no published randomized trial evidence since 20011,2, highlighting evidence gaps and underfunding of ARF research relative to global burden. Hydroxychloroquine has been used for decades to treat autoimmune disorders, is inexpensive with well-established safety. In vitro data suggests disease-modifying potential in ARF.3

 

Methods

We conducted a non-randomized, open-label feasibility and safety pilot of hydroxychloroquine 5-7mg/kg/day, maximum 400mg, for 4-6 weeks in Auckland, NZ, 2021-2023. Children with ARF and carditis were recruited. Standard management included benzathine penicillin and non-steroidal anti-inflammatory drugs. Primary outcome was hydroxychloroquine discontinuation due to QTc prolongation or arrhythmia. Secondary outcomes included carditis grade at 6 months, left ventricular ejection fraction, need for surgery.

 

Results

22 children (6-15yrs) were enrolled: carditis grade mild (8), moderate (6), severe (8). All received hydroxychloroquine. There was no ventricular tachycardia or significant QTc prolongation >500ms and no myocardial depression.

 

Conclusion

Recruitment into an ARF intervention trial is feasible in NZ. Findings will inform a future adaptive platform trial, with planned Australian and global collaboration. Advantages of an adaptive platform design include ability to evaluate multiple new and repurposed immunomodulators in different domains and combinations. Interventions and outcomes will be informed by recent ARF cohort studies. Hydroxychloroquine, steroids and tocilizumab are proposed initial interventions. Ordinal (graded) echocardiographic outcome measures will be assessed. The enduring platform infrastructure, flexibility for sites to choose which domains they participate in, and a web-based software platform will foster global participation, and we invite interested colleagues to collaborate.  

  1. Voss LM, Wilson NJ, Neutze JM, Whitlock RM, Ameratunga RV, Cairns LM, Lennon DR. Intravenous immunoglobulin in acute rheumatic fever: a randomized controlled trial. Circulation. 2001 Jan 23;103(3):401-6.
  2. Cilliers A, Adler AJ, Saloojee H. Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database Syst Rev. 2015 May 28;(5):CD003176.
  3. Kim ML, et al. Dysregulated IL-1β-GM-CSF Axis in Acute Rheumatic Fever That Is Limited by Hydroxychloroquine. Circulation. 2018 Dec 4;138(23):2648-2661