A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis

Abstract

BackgroundThe combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment.MethodsAdults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment.Results121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450–600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm).ConclusionFor intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin.Trial Registrationwww.ClinicalTrials.gov NCT00728507

A Review of Moxifloxacin for the Treatment of Drug‐Susceptible Tuberculosis

“…A drug safety review of clinical data comparing safety and risk of adverse events in patients on moxifloxacin with similar comparator drugs found no significantly increased risk of adverse events with moxifloxacin . Phase 2 or 3 studies conducted in patients with tuberculosis (Table ) did not report any significant difference in the incidence of grade 3 or 4 adverse events between moxifloxacin‐containing arms of the study and standard treatment regimens . In keeping with other non‐TB studies, moxifloxacin significantly increased rates of nausea and GI upset and arthralgia compared to standard TB therapy .…”

“…The pharmacokinetic parameters of moxifloxacin from clinical trials done in patients with tuberculosis or healthy individuals using tuberculosis drug regimens is summarized in Table . The range of values for C max , AUC, and time to C max for moxifloxacin are in keeping with data from studies in healthy individuals, although the ranges were wide and more variable (Table ) .…”

“…The pharmacokinetic parameters of moxifloxacin from clinical trials done in patients with tuberculosis or healthy individuals using tuberculosis drug regimens is summarized in Table 1. [37][38][39][40][41][43][44][45]67,68,[72][73][74][75][76][77] The range of values for C max , AUC, and time to C max for moxifloxacin are in keeping with data from studies in healthy individuals, although the ranges were wide and more variable (Table 1). 59,70,71 Importantly, moxifloxacin concentrations are consistently lower when the drug is coadministered with rifamycins.…”

“…Drug regimens used in these studies either replaced ethambutol or isoniazid with moxifloxacin, or added moxifloxacin to, the standard first line drug regimen or tested novel drugs, bedaquiline, or pretomanid with moxifloxacin and pyrazinamide. All studies included patients with sputum smear‐positive TB, mainly HIV uninfected, and most studies reported 60% to 70% or greater cavitation at baseline …”

“…In studies in which moxifloxacin replaced ethambutol or isoniazid in the standard drug regimen, no statistically significant difference was found in sputum culture conversion at 8 weeks of treatment except in 2 studies conducted in Brazil and India, which reported favorable activity for the moxifloxacin‐containing regimens . However, moxifloxacin‐containing regimens resulted in significantly higher proportions of sputum culture conversion at time points earlier than 8 weeks . A Cochrane review and meta‐analysis assessing the use of fluoroquinolones in drug‐susceptible tuberculosis, including these earlier studies, found insufficient evidence on whether addition or substitution of the fluoroquinolones (moxifloxacin, gatifloxacin, and levofloxacin) for ethambutol or isoniazid in the first‐line regimen reduces death or relapse, or increases culture conversion at 8 weeks.…”