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A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB

Tweed CD 1 , Wills GH 1 , Crook AM 1 , Amukoye E 2 , Balanag V 3 , Ban AYL 4 Show all authors , Bateson ALC 5 , Betteridge MC 6 , Brumskine W 7 , Caoili J 8 , Chaisson RE 9 , Cevik M 10 , Conradie F 11 , Dawson R 12 , Del Parigi A 6 , Diacon A 13 , Everitt DE 6 , Fabiane SM 1 , Hunt R 5 , Ismail AI 14 , Lalloo U 15 , Lombard L 6 , Louw C 16 , Malahleha M 17 , McHugh TD 5 , Mendel CM 6 , Mhimbira F 18 , Moodliar RN 19 , Nduba V 20 , Nunn AJ 1 , Sabi I 21 , Sebe MA 22 , Selepe RAP 23 , Staples S 19 , Swindells S 24 , van Niekerk CH 25 , Variava E 26 , Spigelman M 6 , Gillespie SH 10

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
Int J Tuberc Lung Dis, 2021 Apr 01;25(4):305-314.
PMID: 33762075 DOI: 10.5588/ijtld.20.0513

Abstract

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.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.

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