Finding the right dose of rifampicin, and the right dose of optimism
Authors: Rovina Ruslami, Dick Menzies
Journal: The Lancet Infectious Diseases (2016)

After the widespread introduction of rifampicin in the early 1970s, it took another two decades, and more than 50 randomised trials with more than 20 000 participants1Menzies D Benedetti A Paydar A et al.Effect of duration and intermittency of Rifampin on Tuberculosis treatment outcomes: a systematic review and meta-analysis.PLoS Med. 2009; 6: e1000146Crossref PubMed Scopus (165) Google Scholar to finalise the drugs, doses, and schedule for the currently recommended regimen for newly diagnosed patients with active tuberculosis. Yet this regimen has important drawbacks, most notably the 6 months duration, and frequent toxicity. These limitations have stimulated considerable research interest to find shorter and better-tolerated regimens. New drug development is expensive, and progress in the past 20 years has been very slow. Investigators have re-examined current drugs and doses, including the dose of rifampicin, which was initially selected as the lowest effective dose because this drug was very expensive when first introduced. Bacterial clearance in mice,2Rosenthal IM Tasneen R Peloquin C Dose-ranging comparison of rifampin and rifapentine in two pathologically distinct murine models of tuberculosis.Antimicrob Agents Chemoth. 2006; 56: 4331-4340Crossref Scopus (121) Google Scholar extended early bactericidal activity in patients with pulmonary tuberculosis,3Boeree M Diacon AH Dawson R A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis.Am J Resp Crit Care Med. 2015; 191: 1058-1065Crossref PubMed Scopus (209) Google Scholar and 6-month survival in patients with tuberculosis meningitis4Ruslami R Ganeim AR Dian S et al.Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trail.Lancet Infect Dis. 2013; 13: 27-35Summary Full Text Full Text PDF PubMed Scopus (245) Google Scholar have all been improved with higher doses of rifampicin. In patients with tuberculosis, meningitis survival was closely related to serum concentrations.5te Brake L Dian S Ganiem AR et al.Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis.Int J Antimicrob Agents. 2015; 45: 1-10Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar In The Lancet Infectious Diseases, Martin Boeree and colleagues6Boeree M Heinrich N Aarnoutse R et al.High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial.Lancet Infect Dis. 2016; (published online Oct 26.)http://dx.doi.org/10.1016/S1473-3099(16)30274-2PubMed Google Scholar report findings of a randomised controlled phase 2B trial of patients with drug-sensitive pulmonary tuberculosis. The trial assessed four experimental regimens given for 12 weeks followed by 14 weeks of isoniazid and rifampicin. The regimen with rifampicin dosage of 35 mg/kg (RIF35) resulted in faster time to culture conversion compared with the standard regimen. This difference was not seen with the other experimental regimens (including two with rifampicin dose of 20 mg/kg), and was seen only with liquid culture media, but not solid cultures. Compared with the standard regimen, serious adverse events including hepatitis were not significantly higher with any experimental regimen, although the study was underpowered for this outcome, and the occurrence of hepatitis with RIF35 was more than twice as high as with standard rifampicin doses. There are two important methodological issues to consider when interpreting this interesting and well executed study; use of the innovative multi-arm, multi-stage (MAMS) design, and time to culture conversion as the primary outcome. The MAMS trial design has been used successfully in phase 2 cancer trials to select regimens for phase 3 trials, and to minimise enrolment to regimens with inadequate efficacy or excessive toxicity.7Parmar MKB Barthel FM-S Sydes M et al.Speeding up the evaluation of new agents in cancer.J Natl Cancer Inst. 2008; 100: 120-214Crossref Scopus (105) Google Scholar, 8James ND Sydes MR Clarke NW et al.Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.Lancet. 2016; 387: 1163-1177Summary Full Text Full Text PDF PubMed Scopus (1354) Google Scholar However, to successfully reduce the number of participants enrolled to worse regimens, the time from enrolment to outcome in participants included in the interim analyses must be substantially shorter than the total time to enrol all participants. In this trial, 117 participants were randomly assigned to the arms that were stopped early, compared with 127 randomly assigned to the experimental arms that were continued—the difference represented a 3% reduction of overall enrolment—a rather modest benefit. The other consideration is the critical importance in phase 2 trials of the predictive accuracy of the intermediate outcome,7Parmar MKB Barthel FM-S Sydes M et al.Speeding up the evaluation of new agents in cancer.J Natl Cancer Inst. 2008; 100: 120-214Crossref Scopus (105) Google Scholar and a high negative predictive value is essential to avoid falsely concluding that a regimen is inadequate. In this trial, enrolment was stopped for two regimens containing SQ109, based on the time to culture conversion. But, before concluding that SQ109 should not be considered for phase 3 trials, what is the accuracy of this outcome? Using meta-regression techniques, Wallis and colleagues9Wallis RS Doherty T M Onyebujoh P et al.Biomarkers for tuberculosis disease activity, cure, and relapse.Lancet. 2009; 9: 162-172Summary Full Text Full Text PDF PubMed Scopus (132) Google Scholar found a relationship between 2-month culture conversion (a dichotomous outcome) and relapse. This spurred highly optimistic thinking about the value of phase 2b trials, since dampened by the failure of 4-month fluoroquinolone-containing regimens to achieve relapse free cure in three independent trials,10Gajalakshmi V Peto R Kanaka T Jha P Smoking and mortality from tuberculosis and other diseases in India: retrospective study of 43000 adult male deaths and 35000 controls.Lancet. 2003; 362: 507Summary Full Text Full Text PDF PubMed Scopus (367) Google Scholar, 11Jindani A Harrison TS Nunn AJ et al.High-dose rifapentine with moxifloxacin for pulmonary tuberculosis.N Engl J Med. 2014; 371: 1599-1608Crossref PubMed Scopus (313) Google Scholar, 12Gillespie S H Crook AM McHugh TD et al.Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis.N Eng J Med. 2014; 371: 1577-1587Crossref PubMed Scopus (443) Google Scholar despite promising culture conversion data.13Conde MB Efron A Carla Loredo et al.Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: a double-blinded, randomised, controlled phase II trial.Lancet. 2009; 373: 1183-1189Summary Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 14Rustomjee R Lienhardt C Kanyok T Davies GR A phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.Int J Tuberc Lung Dis. 2014; 12: 128-138Google Scholar We advocate for continued study of SQ109, since Wallis and colleagues9Wallis RS Doherty T M Onyebujoh P et al.Biomarkers for tuberculosis disease activity, cure, and relapse.Lancet. 2009; 9: 162-172Summary Full Text Full Text PDF PubMed Scopus (132) Google Scholar did not estimate negative (or positive) predictive values, nor did they examine the relationship of relapse free cure with time to culture conversion, the outcome used in this trial. We believe that a shorter regimen for active tuberculosis that is also safe and well tolerated is urgently needed. Phase 2 trials can be helpful to identify promising regimens, but the intermediate outcome of 2 or 3 months culture conversion requires further validation work, before we can confidently use this outcome to plan phase 3 trials. This work would also allow use of the more efficient MAMS design. Boeree and colleagues are very optimistic that high dose rifampicin might be useful in shortening current treatment for drug sensitive tuberculosis; we share their optimism, but in a more limited dose. RR reports that one of the authors of the paper, Rob Aarnoutse, was a former PhD supervisor and continues to be a collaborator. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trialA dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. Full-Text PDF Open Access