title: High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial.
abstract: 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).
authors.affiliation: Department of Lung Diseases, Radboud University Medical Center, Nijmegen, Netherlands. Electronic address: martin.boeree@radboudumc.nl.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Boeree
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich, Munich, Germany; German Center for Infection Research, Partner Site Munich, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Heinrich
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Aarnoutse
authors.affiliation: Centre for Clinical Tuberculosis Research, Department of Science and Technology and National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.affiliation: Centre for Tuberculosis Research Innovation, University of Cape Town, Grote Schuur, South Africa.
authors.forename: Rodney
authors.initials: R
authors.lastname: Dawson
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Sunita
authors.initials: S
authors.lastname: Rehal
authors.affiliation: Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical Centre, Tumaini University, Moshi, Tanzania.
authors.forename: Gibson S
authors.initials: GS
authors.lastname: Kibiki
authors.affiliation: Aurum Institute, Johannesburg, South Africa; School of Public Health, University of Witwatersrand, Johannesburg, South Africa; Department of Infectious Diseases, London School of Hygiene & Tropical Medicine, London, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Churchyard
authors.affiliation: Helen Joseph Hospital, Johannesburg, South Africa.
authors.forename: Ian
authors.initials: I
authors.lastname: Sanne
authors.affiliation: National Institute for Medical Research, Mbeya Medical Research Centre, Mbeya, Tanzania.
authors.forename: Nyanda E
authors.initials: NE
authors.lastname: Ntinginya
authors.affiliation: Ifakara Health Institute, Bagamoyo, Tanzania.
authors.forename: Lilian T
authors.initials: LT
authors.lastname: Minja
authors.affiliation: Division of Infection and Immunity, Centre for Clinical Microbiology, University College London, UK.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Hunt
authors.affiliation: Aurum Institute, Johannesburg, South Africa.
authors.forename: Salome
authors.initials: S
authors.lastname: Charalambous
authors.affiliation: Centre for Clinical Tuberculosis Research, Department of Science and Technology and National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Hanekom
authors.affiliation: Kilimanjaro Clinical Research Institute, Kilimanjaro Christian Medical Centre, Tumaini University, Moshi, Tanzania.
authors.forename: Hadija H
authors.initials: HH
authors.lastname: Semvua
authors.affiliation: Kibong'oto National Tuberculosis Hospital, Tanzania.
authors.forename: Stellah G
authors.initials: SG
authors.lastname: Mpagama
authors.affiliation: National Institute for Medical Research, Mbeya Medical Research Centre, Mbeya, Tanzania.
authors.forename: Christina
authors.initials: C
authors.lastname: Manyama
authors.affiliation: National Institute for Medical Research, Mbeya Medical Research Centre, Mbeya, Tanzania.
authors.forename: Bariki
authors.initials: B
authors.lastname: Mtafya
authors.affiliation: Swiss Tropical and Public Health Institute, Basel, Switzerland; University of Basel, Basel, Switzerland.
authors.forename: Klaus
authors.initials: K
authors.lastname: Reither
authors.affiliation: Aurum Institute, Johannesburg, South Africa.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wallis
authors.affiliation: MRC Centre for Tuberculosis Research, University of Stellenbosch, Tygerberg, South Africa.
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
authors.affiliation: Centre for Tuberculosis Research Innovation, University of Cape Town, Grote Schuur, South Africa.
authors.forename: Kim
authors.initials: K
authors.lastname: Narunsky
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich, Munich, Germany.
authors.forename: Anka
authors.initials: A
authors.lastname: Mekota
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich, Munich, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Henne
authors.affiliation: Department of Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Colbers
authors.affiliation: Department of Lung Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Georgette Plemper
authors.initials: GP
authors.lastname: van Balen
authors.affiliation: Medical School University of St Andrews, North Haugh, St Andrews, UK.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gillespie
authors.affiliation: MRC Clinical Trials Unit at UCL, London, UK.
authors.forename: Patrick P J
authors.initials: PPJ
authors.lastname: Phillips
authors.affiliation: Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich, Munich, Germany; German Center for Infection Research, Partner Site Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoelscher
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000627:therapeutic use; D005029:Ethylenediamines / Q000627:therapeutic use*; D005260:Female; D024841:Fluoroquinolones / Q000627:therapeutic use*; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D000077266:Moxifloxacin; D011718:Pyrazinamide / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use*; D013019:South Africa; D013636:Tanzania; D014397:Tuberculosis, Pulmonary / Q000175:diagnosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D005029:Ethylenediamines; D024841:Fluoroquinolones; C506841:N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine; D011718:Pyrazinamide; D004977:Ethambutol; D000218:Adamantane; D000077266:Moxifloxacin; D007538:Isoniazid; D012293:Rifampin