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EFFICACY OF BEDAQUILINE, PRETOMANID, MOXIFLOXACIN & PZA (BPAMZ) AGAINST DS- & MDR-TB
Rodney Dawson1, Kendra Harris2, Almari Conradie2, Divan Burger3, Stephen Murray4, Carl Mendel2, Mel Spigelman2
1Univ of Cape Town, Mowbray, South Africa,2Global Alliance for TB Drug Development, New York, NY, USA,3QuintilesIMS, Bloemfontein, South Africa,4Mallinckrodt Pharmaceuticals, Bedminster, NJ, USA
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.