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. (ACT4RHD)

October 5, 2026 updated by: Starship Child Health, Te Toka Tumai Auckland

ACT4RHD: Adaptive Collaborative Trial for Rheumatic Heart Disease

The ACT4RHD trial is a multicentre, pragmatic, multi-arm, open-label adaptive platform trial addressing multiple therapeutic questions in patients with ARF and carditis. ACT4RHD aims to improve health outcomes for children and young people affected by ARF by finding treatments to reduce heart damage. The trial's Bayesian adaptive design enables multiple promising treatments to be tested at the same time. The trial will adapt by stopping treatments that are not effective sooner than traditional trials, adding new treatments as they become available, and answering research questions as soon as enough evidence has been collected. This flexibility allows researchers to identify the most effective treatments more quickly than traditional clinical trials.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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:

  1. 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;
  2. 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;
  3. 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;
  4. That reduction in carditis will be associated with lower RHD severity at 12 months, and with improved patient-centered outcomes;
  5. 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.

Study Type

Interventional

Enrollment (Estimated)

600

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years to 25 years (Child, Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Aged ≥4 and ≤25 years old
  2. 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)
  3. Echocardiographic confirmed valvulitis during the current admission
  4. If previous participation in the randomised ACT4RHD platform, then meets pre-specified criteria for re-enrolment
  5. Patient expected to be able to complete protocol-required follow up assessments to 6 months post-enrolment

Exclusion Criteria:

  1. Presentation to current hospital was more than 10 days prior to randomisation
  2. Cardiac surgery (or anticipated interhospital transfer for cardiac surgery) or death is anticipated within 72 hours from screening
  3. Patient has had cardiac intervention (surgery or percutaneous) for RHD within the last 6 months
  4. 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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Immunomodulatory Domain

Hydroxychloroquine (HCQ) as per standardised dosing table for 12 weeks

OR

No hydroxychloroquine (no placebo)
Drug: Hydroxychloroquine (HCQ)

Hydroxychloroquine (HCQ)

Other: No Hydroxychloroquine (HCQ)

No Hydroxychloroquine (HCQ)
Other: Corticosteroid domain

Corticosteroids. Corticosteroid strategy:

Mild carditis:

Prednis(ol)one 2mg/kg once daily for 2 weeks, followed by a taper over 2 weeks according to standard tables

Moderate and severe carditis:

Three days of high-dose, pulsed corticosteroid (IV methylprednisolone or oral dexamethasone), followed by Prednis(ol)one 2mg/kg once daily for 2 weeks, followed by a taper over 4 weeks according to standard tables

OR

No corticosteroid (no placebo)
Drug: Prednisone or Prednisolone

With or without initial pulsed Methylprednisolone / oral dexamethasone

Other: No corticosteroid

No corticosteroid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
6-point ordinal scale
Time Frame: 6 months from enrolment

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.
6 months from enrolment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Starship Child Health, Te Toka Tumai Auckland

Collaborators

Menzies School of Health Research
Berry Consultants

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

December 1, 2026

Primary Completion (Estimated)

December 1, 2034

Study Completion (Estimated)

December 1, 2036

Study Registration Dates

First Submitted

September 15, 2026

First Submitted That Met QC Criteria

September 15, 2026

First Posted (Actual)

September 21, 2026

Study Record Updates

Last Update Posted (Actual)

October 7, 2026

Last Update Submitted That Met QC Criteria

October 5, 2026

Last Verified

October 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 22-442

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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