2R2 Trial: High-Dose, Short-Duration Rifampicin for TB Prevention

Published in: The Lancet
Authors: Ruslami R et al.
Publication Year: 2024
Source: The Lancet, DOI: 10.1016/S2213-2600(24)00076-6


Objective of the Study:
The 2R2 Trial was conducted to compare the safety and treatment completion rates of different doses and durations of rifampicin in patients who were recommended tuberculosis preventive treatment (TPT). The trial was designed to evaluate whether a higher dose of rifampicin given over a shorter duration could achieve similar or better outcomes compared to the standard treatment.

Study Design:

  • Type: Partially blinded, 3-arm, randomized, controlled trial
  • Patients Enrolled: 1368
  • Inclusion Criteria:
    • Aged 10 years or older
    • Weight of at least 25 kg
    • Evidence of latent TB infection
    • Eligible for latent TB treatment per Canadian and WHO guidelines
  • Exclusion Criteria:
    • Pregnancy
    • Baseline AST or ALT levels more than 3 times the upper limit of normal
    • Grade 3-4 hematological abnormalities

Treatment Groups:

  1. Standard-Dose Group (n = 454): 10 mg/kg of rifampicin for 4 months.
  2. 20 mg/kg Group (n = 461): Higher dose of 20 mg/kg for 2 months.
  3. 30 mg/kg Group (n = 453): Highest dose of 30 mg/kg for 2 months.

Primary Outcomes:

  1. Treatment Completion in the mITT Population:
    • Standard-Dose Group (A) vs 20 mg/kg Group (B):
      • Standard group (A): 82%
      • 20 mg/kg group (B): 82%
    • Standard-Dose Group (A) vs 30 mg/kg Group (C):
      • Standard group (A): 82%
      • 30 mg/kg group (C): 71%
  2. Completion in A vs C:
    • Completion in the highest dose group (30 mg/kg) was lower at 65%.

Secondary Outcomes:

  1. Safety Outcome (Grade 3 Hepatotoxicity):
    • Standard-Dose Group (A) vs 20 mg/kg Group (B):
      • Both groups had 0% incidence of Grade 3 hepatotoxicity.
    • Standard-Dose Group (A) vs 30 mg/kg Group (C):
      • Standard group (A): 0%
      • 30 mg/kg group (C): 1% incidence of Grade 3 hepatotoxicity.

Conclusion:

In this study, a 2-month regimen of 30 mg/kg daily rifampicin was found to have significantly worse safety and completion rates compared to the standard regimen of 10 mg/kg daily for 4 months. The intermediate dose of 20 mg/kg daily for 2 months was found to be as safe as the standard treatment but resulted in lower completion rates. The 2R2 trial suggests that while shortening the treatment duration is possible, higher doses come with increased risks and challenges in treatment adherence.

Clinical Implications:

This trial provides essential insights for TB preventive treatment protocols. While shorter treatment durations are appealing, the increased risk of adverse events and reduced completion rates with higher doses warrant careful consideration. Clinicians must balance the potential benefits of shortened regimens against patient safety and adherence, particularly in resource-limited settings where TB burden remains high.


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