New anti-tuberculosis (TB) regimens are needed to treat drug sensitive (DS) and multi-drug resistant (MDR) TB. NC-005 is an ongoing Phase 2b open-label, partly randomized trial investigating the bactericidal activity of combinations of bedaquiline (Bloading dose/tiw or B200mg), pretomanid (Pa200mg), moxifloxacin (M400mg) and pyrazinamide (Z1500mg) in the first 8 weeks of treatment of DS-TB or MDR-TB.
Newly diagnosed patients with DS or MDR, smear positive pulmonary TB were enrolled. DS-TB patients were randomized to receive either B[sub]loading dose/tiw[/sub]PaZ, B[sub]200mg[/sub]PaZ or HRZE. MDR-TB patients received B[sub]200mg[/sub]PaMZ (BPaMZ). The primary outcome was bactericidal activity measured by the rate of change in time to sputum culture positivity (TTP) over 8 weeks of treatment. Upon treatment completion, all patients were referred to the local community TB clinic for treatment according to National TB Guidelines, and were scheduled to attend regular follow-up visits for 24 months. Safety was assessed by monitoring the incidence and severity of treatment emergent adverse events (TEAEs).
Between 23 October 2014 and 6 May 2016, 180 subjects with DS-TB and 60 subjects with MDR-TB were enrolled at ten sites in South Africa, Tanzania and Uganda. 218 subjects completed treatment and were followed through the Day 140 follow-up visit. Among all treatment arms, BPaMZ showed the highest bactericidal activity as assessed by TTP for Days 0-56 (5.302, 95% BCI [4.518-6.157]), followed by that of B200mgPaZ (5.223, 95% BCI [4.526;5.947]), Bloading dose/t.i.wPaZ (4.906, 95% BCI [4.274; 5.585]) and HRZE (4.016, 95% BCI [3.520; 4.499]). The differences in bactericidal activity of BPaMZ, B200mgPaZ and Bloading dose/t.i.wPaZ treatment arms versus HRZE were statistically significant. While 81.7% of patients had at least one TEAE, only 5 patients (2.1%) had a serious drug-related TEAE (2 in Bloading dose/t.i.wPaZ, 2 in BPaMZ, and 1 in HRZE). Long-term safety follow-up out to 24 months post-treatment completion is ongoing.
The BPaMZ regimen in MDR-TB patients resulted in the highest level of bactericidal activity among all treatment arms. The BPaZ regimen was well tolerated and showed significantly higher bactericidal activity in DS-TB patients compared to HRZE. BPaZ and BPaMZ represent promising, simplified regimens to treat both DS-TB and MDR-TB.