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Clinical Trial
, 371 (17), 1599-608

High-dose Rifapentine With Moxifloxacin for Pulmonary Tuberculosis

Collaborators, Affiliations
Clinical Trial

High-dose Rifapentine With Moxifloxacin for Pulmonary Tuberculosis

Amina Jindani et al. N Engl J Med.

Abstract

Background: Tuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed.

Methods: We randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin; a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.

Results: We enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).

Conclusions: The 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

Figures

Figure 1
Figure 1. Screening, Randomization, and Analysis of the Study Populations
Among the patients who did not undergo randomization, there were 17 patients who did not do so for other reasons: 4 patients had a history of seizures, 4 did not return in order to undergo randomization, 3 weighed less than 35 kg, 1 had extra-pulmonary tuberculosis, 1 had no firm address, 1 was younger than 18 years of age, 1 was receiving antiretroviral therapy, and 1 had tachycardia. In addition, there was 1 patient in whom attempts to draw blood were unsuccessful. MIRU–VNTRS denotes mycobacterial interspersed repetitive unit–variable-number tandem repeats, and TB tuberculosis.
Figure 2
Figure 2. Differences from the Control Regimen in Unfavorable Outcome Rates (90% Confidence Intervals)
The dashed line represents the 6 percentage-point margin of noninferiority for the modified intention-to-treat population and the per-protocol population as compared with the control.
Figure 3
Figure 3. Kaplan–Meier Failure Estimates of the Time to a Favorable Outcome in the Per-Protocol Population
The inset shows the same data on an enlarged y axis.

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