Background Treatment of tuberculosis infection (TBI) is a cornerstone of the WHO End TB Strategy. Two widely recommended short-course regimens—weekly isoniazid plus rifapentine for 12 weeks (3HP) and daily rifampicin for 16 weeks (4RIF)—have not been directly compared in a randomised trial. This study aimed to compare treatment completion between 3HP and 4RIF among individuals with TBI.

Methods We conducted a multicentre, open-label, parallel-group, randomised controlled trial at seven tuberculosis clinics in Sydney, Australia, between July 1, 2019, and June 30, 2024. Participants of any age with TBI were randomised 1:1 using a computer-generated, site-stratified sequence to receive either 3HP (isoniazid 15 mg/kg [max 900 mg] plus rifapentine 900 mg weekly for 12 weeks) or 4RIF (rifampicin 10 mg/kg [max 600 mg], daily for 16 weeks). All doses were self-administered. Participants in the 3HP group received weekly SMS reminders; both groups received standard clinic follow-up. The primary outcome was treatment completion, defined as ingestion of ≥90% of prescribed doses, assessed at the end of treatment. Analyses followed the intention-to-treat principle, including all randomised participants. The trial is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12618001672246) and is closed to new enrolments.

Findings A total of 210 participants were enrolled (106 assigned to 3HP, 104 to 4RIF; 121 [57.6%] female, 89 [42.4%] male). Completion was higher in the 3HP group (90/106 [84.9%]) than the 4RIF group (68/104 [65.4%]; relative risk 1.30, 95% CI 1.10–1.53; p=0.002). Adverse events of any grade occurred in 26/106 (24.5%) in the 3HP group and 21/104 (20.2%) in the 4RIF group. No treatment-related deaths were reported.

Interpretation The 3HP regimen, supported by SMS reminders, led to significantly higher treatment completion than 4RIF. These findings support broader implementation of 3HP in TBI programs to improve adherence and outcomes.

Funding This study was funded by an Investigator Grant (#2007920) from the Australian National Health and Medical Research Council (NHMRC), with additional in-kind support from Sanofi Pharmaceuticals and the generous assistance of staff at the participating tuberculosis clinics.

This study was funded by an Investigator Grant (#2007920) from the Australian National Health and Medical Research Council (NHMRC).

The trial was registered prospectively with the Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au; ACTRN12618001672246)

This study was funded by an Investigator Grant (#2007920) from the Australian National Health and Medical Research Council (NHMRC), with additional in-kind support from Sanofi Pharmaceuticals and the generous assistance of staff at the participating tuberculosis clinics.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The trial was registered prospectively with the Australian and New Zealand Clinical Trials Registry (www.anzctr.org.au; ACTRN12618001672246). Ethical approval for the study was granted by the Sydney Local Health District Human Research Ethics Committee (HREC/17/RPAH/229). A Clinical Trials Notification from the Therapeutic Goods Administration (TGA) was obtained (CT-2019-CTN-01472-1) to enable the use of rifapentine which was not licensed by the TGA. The study sponsor was Sydney Local Health District.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors.