[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]
High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial
Martin J Boeree, PhD†, Norbert Heinrich, MD†, Rob Aarnoutse, PhD, Andreas H Diacon, PhD, Rodney Dawson, PhD, Sunita Rehal, MSc, Prof Gibson S Kibiki, PhD, Prof Gavin Churchyard, FRCP, Ian Sanne, FRCP, Nyanda E Ntinginya, MD, Lilian T Minja, MD, Robert D Hunt, BSc, Salome Charalambous, PhD, Madeleine Hanekom, PhD, Hadija H Semvua, PhD, Stellah G Mpagama, PhD, Christina Manyama, MD, Bariki Mtafya, MSc, Klaus Reither, MD, Prof Robert S Wallis, MD, Amour Venter, NatDipMicr, Kim Narunsky, MD, Anka Mekota, PhD, Sonja Henne, MSc, Angela Colbers, PhD, Georgette Plemper van Balen, PhD, Prof Stephen H Gillespie, DSc, Patrick P J Phillips, PhD, Prof Michael Hoelscher, FRCP on behalf of the PanACEA consortium‡
*These authors contributed equally
†For a complete list of the investigators in the PanACEA MAMS trial see the appendix.
Published: 26 October 2016 / Open Access / Article has an altmetric score of 7 / DOI: http://dx.doi.org/10.1016/S1473-3099(16)30274-2
User License: Creative Commons Attribution (CC BY 4.0)
© 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.
Tuberculosis is the world’s leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis.
We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186).
Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm.
A 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.
The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).
Research in context
- Evidence before this study
- We did literature searches in PubMed, applying the Medical Subject Heading (MeSH) terms “tuberculosis’ and “rifampicin AND dose”, “moxifloxacin”, or “SQ109”. Publications on pulmonary tuberculosis listed not later than April 30, 2016, in English, German, French, and Italian language were considered.
- Pharmacokinetic studies indicate that standard dose (1 0mg/kg) of rifampicin often did not achieve effective plasma concentrations in patients. Enhanced efficacy of higher doses of rifampicin was reported in a number of animal studies. A systematic review on elevated doses of rifampicin published before 2008 identified 14 studies testing up to 1200 mg of rifampicin. Despite difficulties comparing efficacy outcomes across trials, there was an indication that higher doses were beneficial. Among 339 articles published after 2008, a single 14-day dose-ranging study of up to 35 mg/kg reported a supra-proportional increase in pharmacokinetic parameters and good tolerability, with a suggestion of enhanced early bactericidal activity. 43 publications on SQ109 were identified. A mouse study reported improved efficacy when SQ109 replaced ethambutol, but with a delayed onset of several weeks in reduction of lung and spleen colony-forming units. One 14-day phase 1 and one phase 2a study reported good tolerability, but absence of early bactericidal activity during the 14-day phase 2a study duration. A meta-analysis of moxifloxacin trials concluded that this drug added to the bactericidal activity of the regimen when it replaced ethambutol or isoniazid, but this was not enough to shorten treatment duration from 6 to 4 months.
- Added value of this study
- This study showed that 35 mg/kg rifampicin given over 12 weeks was safe and shortened the time to stable culture conversion from 62 to 48 days, showing the potential for an enhanced regimen. The other experimental arms, including various combinations of 10 mg/kg or 20 mg/kg of rifampicin, moxifloxacin, and SQ109, did not achieve significant improvements over the control arm. Taking all the data into consideration, this study supports that rifampicin given at 35 mg/kg is likely to improve treatment outcome. To our knowledge, this is the first time that a multi-arm adaptive trial design was successfully implemented in a multi-centre study in a high tuberculosis burden setting. This approach might accelerate tuberculosis regimen development at a reduced cost.
- Implications of all the available evidence
- Our study substantiated that an increase in rifampicin dose could improve the clearance of bacteria in patients with pulmonary tuberculosis without an increase in associated adverse events. The scale of the improvement shown in this study of 35 mg/kg rifampicin administered orally could translate to improved clinical outcomes. Smaller increases in rifampicin doses did not have this effect and suggest that future pivotal phase 3 studies should be done with at least 35 mg/kg. The combination of moxifloxacin and 20 mg/kg rifampicin had a modest effect on bacterial clearance. This combination could be improved by increasing the dose of moxifloxacin to overcome induction of its metabolism by rifampicin.
Keywords: Tuberculosis; Rifampicin; moxifloxacin.