A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB
METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.
RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI –2.2% to 15.4%) difference per protocol and 9.9% (95%CI –4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.
CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.
Keywords: TB treatment; TB-HIV; drug resistance; tuberculosis
Document Type: Research Article
Affiliations: 1: Medical Research Council Clinical Trials Unit, University College London (UCL), London, UK 2: Centre for Respiratory Disease Research, Kenya Medical Research Institute (KEMRI), Kenyatta National Hospital, Nairobi, Kenya 3: Lung Center of the Philippines, National Centre for Pulmonary Research, Quezon City, The Philippines 4: Pusat Perubatan Universiti Kebangsaan, Kuala Lumpur, Malaysia 5: Centre for Clinical Microbiology, UCL, London, UK 6: Global Alliance for TB Drug Development, New York, NY, USA 7: Aurum Institute, Rustenburg, South Africa 8: Tropical Disease Foundation, Makati Medical Centre, Makati City, Phillippines 9: School of Medicine, Johns Hopkins University, Baltimore, MD, USA 10: Medical School, University of St Andrews, St Andrews, UK 11: University of the Witwatersrand, Clinical HIV Research Unit, Johannesburg 12: University of Cape Town Lung Institute, Cape Town 13: TASK Applied Science, Bellville, South Africa & Division of Physiology, Department of Medical Biochemistry, University of Stellenbosch, Tygerberg, South Africa 14: Universiti Teknologi MARA, Selangor, Malaysia 15: Enhancing Care Foundation, Durban International Clinical Research Site, Wentworth Hospital, Durban 16: Madibeng Centre for Research, Brits, & Department of Family Medicine, University of Pretoria, Pretoria 17: Setshaba Research Centre, Soshanguve, South Africa 18: Ifakara Health Institute (IHI), Dar es Salaam, Tanzania 19: THINK (Tuberculosis and HIV Investigative Network), Durban, South Africa 20: KEMRI, Nairobi, Kenya 21: Mbeya Medical Research Center, National Institute for Medical Research, Mbeya, Tanzania 22: The Aurum Institute, Tembisa Clinical Research Centre, Tembisa 23: The Aurum Institute, Klerksdorp, South Africa 24: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA 25: Global Alliance for TB Drug Development, Pretoria 26: Klerksdorp Tshepong Hospital, Klerksdorp, South Africa
Publication date: April 1, 2021
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