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

Marcus B Conde, Fernanda C Q Mello, Rafael Silva Duarte, Solange C Cavalcante, Valeria Rolla, Margareth Dalcolmo, Carla Loredo, Betina Durovni, Derek T Armstrong, Anne Efron, Grace L Barnes, Mark A Marzinke, Radojka M Savic, Kelly E Dooley, Silvia Cohn, Lawrence H Moulton, Richard E Chaisson, Susan E Dorman, Marcus B Conde, Fernanda C Q Mello, Rafael Silva Duarte, Solange C Cavalcante, Valeria Rolla, Margareth Dalcolmo, Carla Loredo, Betina Durovni, Derek T Armstrong, Anne Efron, Grace L Barnes, Mark A Marzinke, Radojka M Savic, Kelly E Dooley, Silvia Cohn, Lawrence H Moulton, Richard E Chaisson, Susan E Dorman

Abstract

Background: The 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.

Methods: Adults 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.

Results: 121 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).

Conclusion: For 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 registration: www.ClinicalTrials.gov NCT00728507.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Enrollment and disposition of study…
Fig 1. Enrollment and disposition of study participants.
Abbreviations: PMHZ, investigational regimen comprised of rifapentine/moxifloxacin/isoniazid/pyrazinamide; REHZ, control regimen comprised of rifampin/ethambutol/isoniazid/pyrazinamide; LJ, Löwenstein-Jensen culture; MGIT, Mycobacterial Growth Indicator Tube culture; MITT, modified intention-to-treat analysis population; PP, per-protocol analysis population; DST, drug susceptibility testing; Mtb, Mycobacterium tuberculosis.
Fig 2. Kaplan-Meier time to stable culture…
Fig 2. Kaplan-Meier time to stable culture conversion, per-protocol analysis population.
Solid lines, control REHZ regimen comprised of rifampin/ethambutol/isoniazid/pyrazinamide. Dashed lines, investigational PMHZ regimen comprised of rifapentine/moxifloxacin/isoniazid/pyrazinamide. (A) Löwenstein-Jensen (LJ) solid culture medium (p = 0.67 for comparing equality of the survival curves), and (B) Mycobacterial Growth Indicator Tube (MGIT) liquid culture medium (p = 0.03).

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