ACT4RHD is an Open-label, Randomised, Adaptive Platform Trial to Evaluate Novel and Repurposed Clinical Interventions for Patients With Acute Rheumatic Fever and Carditis. ACT4RHD Seeks to Determine Whether These Interventions Reduce RHD Severity at 6 Months.

Background: Acute rheumatic fever (ARF) is a major health priority in lower-middle income countries (LMIC) and for Indigenous and underserved populations in high income countries including Australia and New Zealand. It is an autoimmune condition of childhood triggered by Strep A infection, leading to rheumatic heart disease (RHD). RHD affects more than 40 million people globally, resulting in approximately 310,000 deaths each year. There are currently no proven anti-inflammatory or immune modulating therapies to limit cardiac damage during ARF to prevent RHD. The only treatment is antibiotics (penicillin) given after ARF is diagnosed, to prevent recurrent streptococcal infections that drive ARF recurrences and progression of RHD.

Design: ACT4RHD is a randomized, multifactorial, open label adaptive platform trial with blinded end- point assessment. At trial launch, domains will comprise a Corticosteroid domain and an Immunomodulatory Domain. The treatment intervention in the Corticosteroid domain will include 4 to 6 weeks of corticosteroids or a no-corticosteroid control.

Treatment for the Immunomodulatory domain includes hydroxychloroquine for 12 weeks compared to a no-hydroxychloroquine control.

These are interventions are prescribed open label in addition to standard care. The primary endpoint is a 6-point ordinal scale which comprises RHD severity (measured by echocardiography), need for rheumatic cardiac surgery or death at 6 months.

Aims: The overarching aim of ACT4RHD is to alleviate suffering from ARF and reduce the prevalence and severity of RHD which arises from ARF. Trial hypotheses at launch:

• That corticosteroids administered to children and young adults with ARF affecting the mitral and/or aortic valve will be safe and will reduce valve inflammation (that is, carditis) in rheumatic fever;
• That hydroxychloroquine treatment administered to children and young adults with ARF affecting the mitral and/or aortic valve will be safe and will reduce valve inflammation in rheumatic fever;
• That reduction in carditis severity and/or duration, will be associated with reduction in valve scarring and dysfunction, measured by an echocardiographic RHD severity grade at 6 months;
• That reduction in carditis will be associated with lower RHD severity at 12 months, and with improved patient-centered outcomes;
• That the development of a durable ARF platform trial will allow several investigational products and management approaches to be tested in a robust and rigorous fashion over the coming years.

Inclusion criteria

• Aged ≥4 and ≤25 years old
• Currently admitted to hospital, or hospital like setting, with the primary diagnosis of Definite or Possible Acute Rheumatic Fever (diagnosed according to the 2015 Jones Criteria)
• Echocardiographic confirmed valvulitis during the current admission
• If previous participation in the randomised ACT4RHD platform, then meets pre-specified criteria for re-enrolment
• Patient expected to be able to complete protocol-required follow up assessments to 6 months post-enrolment

Exclusion criteria

• Presentation to current hospital was more than 10 days prior to randomisation
• Cardiac surgery (or anticipated interhospital transfer for cardiac surgery) or death is anticipated within 72 hours from screening
• Patient has had cardiac intervention (surgery or percutaneous) for RHD within the last 6 months
• Previous cardiac intervention /surgery for RHD more than 6months ago, but patient has not had at least 2 post-intervention echocardiograms, including at least 1 echocardiogram more than 6months after the intervention.

Each domain will have additional eligibility criteria. Refer to the appliable Domain Specific Appendix (DSA).