High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial

Abstract

SummaryBackgroundTuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis.MethodsWe 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).FindingsBetween 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.Interpr...

Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis

“…Here, rifampin doses of up to 20 mg/kg/day produced toxicity comparable to that of standard doses while generating slightly more-than-proportional C max and AUC 0 -6 increases (4-6, 18, 19). This is the first such evidence from a controlled study in South America; while the magnitude increase is smaller than that reported in studies in Africa and Asia (19,20), a supraproportional increase is still observed. The AUC 0 -6 is a preliminary exposure estimate calculated by using observed concentrations in all participants.…”

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

“…Arms containing SQ109 and moxifloxacin failed to show superiority to the standard of care. 30 Rifapentine, is being tested as a flat, not weight-based, dose of 1200 mg daily in a phase 3 study TBTC S31/ACTG A5349 as part of two four-month regimens for shortened treatment of DS-TB enrolling to date more than 1,400 of a target of 2,500 participants. 31 The first experimental regimen in this trial replaces rifampin with rifapentine and reduces the continuation phase to two months.…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…383 A key lesson that has been learned is that defining optimal drug doses is a necessary step in optimising regimen efficacy and preventing the emergence of resistance. [384][385][386][387] Astonishingly, 50 years has passed since the introduction of rifampicin into clinical use, and the optimal dose of this key sterilising drug has yet to be established. Some data suggest that dose optimisation of rifampicin or rifapentine alone might deliver a 4-month regimen that is less likely to select for isoniazid-resistant and MDR disease than the 6-month regimen.…”

“…Some data suggest that dose optimisation of rifampicin or rifapentine alone might deliver a 4-month regimen that is less likely to select for isoniazid-resistant and MDR disease than the 6-month regimen. [384][385][386][387] Repetition of the mistake of underdosing with new drugs should be avoided in drug-resistant tuberculosis regimens, because resistance could rapidly emerge. For repurposed drugs, doses used to treat other infections should not be assumed to be optimal for drug-resistant tuberculosis treatment, in which disease-specific pharmacokineticpharmacodynamic associations, longer treatment durations, overlapping toxicities, and drug-drug interactions associated with combin ation therapy are important factors in establishing optimal doses.…”