Andrew J Nunn1, Patrick P J Phillips1, Sarah K Meredith1, Chen-Yuan Chiang1, Francesca Conradie1, Doljinsuren Dalai1, Armand van Deun1, Phan-Thuong Dat1, Ngoc Lan1, Iqbal Master1, Tesfamarium Mebrahtu1, Daniel Meressa1, Ronelle Moodliar1, Nosipho Ngubane1, Karen Sanders1, Stephen Bertel Squire1, Gabriela Torrea1, Bazarragchaa Tsogt1, I D Rusen1. 1. From the Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL), London (A.J.N, P.P.J.P., S.K.M., K.S.), and the Liverpool School of Tropical Medicine, Liverpool (S.B.S.) - both in the United Kingdom; International Union against Tuberculosis and Lung Disease (the Union), Paris (C.-Y.C., A.D., I.D.R.); the Department of Internal Medicine, Wanfang Hospital, and School of Medicine, Taipei Medical University (C.-Y.C.) - both in Taipei, Taiwan; the University of Witwatersrand, Faculty of Health Sciences, Johannesburg (F.C.), King Dinizulu Hospital Complex, Kwazulu Natal (I.M., N.N.), and Think TB and HIV Investigative Network, Durban (R.M.) - all in South Africa; National Center for Communicable Diseases (D.D.) and the Mongolian Tuberculosis Coalition (B.T.) - both in Ulaanbaatar, Mongolia; the Institute of Tropical Medicine, Antwerp, Belgium (A.D., G.T.); Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam (P.-T.D., N.L.); Armauer Hansen Research Institute (T.M.), and St. Peter's Tuberculosis Specialized Hospital and Global Health Committee (D.M.) - all in Addis Ababa, Ethiopia; the Division of Research and Development, Vital Strategies, New York (I.D.R.); and the Dalla Lana School of Public Health, University of Toronto, Toronto (I.D.R.).
Abstract
BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011. METHODS: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority. RESULTS: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).
RCT Entities:
BACKGROUND: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011. METHODS: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority. RESULTS: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P = 0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P = 0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively. CONCLUSIONS: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety. (Funded by the U.S. Agency for International Development and others; Current Controlled Trials number, ISRCTN78372190; ClinicalTrials.gov number, NCT02409290.).
Authors: Bertin C Bisimwa; Jean B Nachega; Robin M Warren; Grant Theron; John Z Metcalfe; Maunank Shah; Andreas H Diacon; Nadia A Sam-Agudu; Marcel Yotebieng; André N H Bulabula; Patrick D M C Katoto; Jean-Paul Chirambiza; Rosette Nyota; Freddy M Birembano; Eric M Musafiri; Sifa Byadunia; Esto Bahizire; Michel K Kaswa; Steven Callens; Zacharie M Kashongwe Journal: Clin Infect Dis Date: 2021-07-15 Impact factor: 9.079
Authors: Hyejeong Hong; David W Dowdy; Kelly E Dooley; Howard W Francis; Chakra Budhathoki; Hae-Ra Han; Jason E Farley Journal: Clin Infect Dis Date: 2020-02-14 Impact factor: 9.079
Authors: Susan E Dorman; Payam Nahid; Ekaterina V Kurbatova; Stefan V Goldberg; Lorna Bozeman; William J Burman; Kwok-Chiu Chang; Michael Chen; Mark Cotton; Kelly E Dooley; Melissa Engle; Pei-Jean Feng; Courtney V Fletcher; Phan Ha; Charles M Heilig; John L Johnson; Erica Lessem; Beverly Metchock; Jose M Miro; Nguyen Viet Nhung; April C Pettit; Patrick P J Phillips; Anthony T Podany; Anne E Purfield; Kathleen Robergeau; Wadzanai Samaneka; Nigel A Scott; Erin Sizemore; Andrew Vernon; Marc Weiner; Susan Swindells; Richard E Chaisson Journal: Contemp Clin Trials Date: 2020-01-22 Impact factor: 2.226
Authors: Francesca Conradie; Andreas H Diacon; Nosipho Ngubane; Pauline Howell; Daniel Everitt; Angela M Crook; Carl M Mendel; Erica Egizi; Joanna Moreira; Juliano Timm; Timothy D McHugh; Genevieve H Wills; Anna Bateson; Robert Hunt; Christo Van Niekerk; Mengchun Li; Morounfolu Olugbosi; Melvin Spigelman Journal: N Engl J Med Date: 2020-03-05 Impact factor: 91.245
Authors: Emily A Kendall; Shelly Malhotra; Sarah Cook-Scalise; David W Dowdy; Claudia M Denkinger Journal: Clin Infect Dis Date: 2020-12-31 Impact factor: 9.079
Authors: S D Masuku; R Berhanu; C Van Rensburg; N Ndjeka; S Rosen; L Long; D Evans; B E Nichols Journal: Int J Tuberc Lung Dis Date: 2020-04-01 Impact factor: 2.373
Authors: Payam Nahid; Sundari R Mase; Giovanni Battista Migliori; Giovanni Sotgiu; Graham H Bothamley; Jan L Brozek; Adithya Cattamanchi; J Peter Cegielski; Lisa Chen; Charles L Daley; Tracy L Dalton; Raquel Duarte; Federica Fregonese; C Robert Horsburgh; Faiz Ahmad Khan; Fayez Kheir; Zhiyi Lan; Alfred Lardizabal; Michael Lauzardo; Joan M Mangan; Suzanne M Marks; Lindsay McKenna; Dick Menzies; Carole D Mitnick; Diana M Nilsen; Farah Parvez; Charles A Peloquin; Ann Raftery; H Simon Schaaf; Neha S Shah; Jeffrey R Starke; John W Wilson; Jonathan M Wortham; Terence Chorba; Barbara Seaworth Journal: Am J Respir Crit Care Med Date: 2019-11-15 Impact factor: 21.405