Corinne S Merle1, Katherine Fielding, Omou Bah Sow, Martin Gninafon, Mame B Lo, Thuli Mthiyane, Joseph Odhiambo, Evans Amukoye, Boubacar Bah, Ferdinand Kassa, Alimatou N'Diaye, Roxana Rustomjee, Bouke C de Jong, John Horton, Christian Perronne, Charalambos Sismanidis, Olivier Lapujade, Piero L Olliaro, Christian Lienhardt. 1. From the London School of Hygiene and Tropical Medicine, London (C.S.M., K.F., C.S.), and Tropical Projects, Hitchin (J.H.) - both in the United Kingdom; Service de Pneumo-phtisiologie, Hôpital Ignace Deen, Conakry, Guinea (O.B.S., B.B.); Centre National Hospitalier de Pneumo-phtisiologie, Cotonou, Benin (M.G., F.K.); Programme National de Lutte contre la Tuberculose, Dakar, Senegal (M.B.L., A.N.); Medical Research Council, Durban, South Africa (T.M., R.R.); Kenya Medical Research Institute, Nairobi (J.O., E.A.); Institute of Tropical Medicine, Antwerp, Belgium (B.C.J.); Hôpitaux Universitaires Paris Ile-de-France Ouest, Assistance Publique-Hôpitaux de Paris, Paris (C.P.), and Institut de Recherche pour le Développement, Marseille (O.L., C.L.) - both in France; and Special Program for Research and Training in Tropical Diseases, World Health Organization, Geneva (P.L.O.).
Abstract
BACKGROUND: Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS: We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS: A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS: Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).
BACKGROUND: Shortening the course of treatment for tuberculosis would be a major improvement for case management and disease control. This phase 3 trial assessed the efficacy and safety of a 4-month gatifloxacin-containing regimen for treating rifampin-sensitive pulmonary tuberculosis. METHODS: We conducted a noninferiority, randomized, open-label, controlled trial involving patients 18 to 65 years of age with smear-positive, rifampin-sensitive, newly diagnosed pulmonary tuberculosis in five sub-Saharan African countries. A standard 6-month regimen that included ethambutol during the 2-month intensive phase was compared with a 4-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The primary efficacy end point was an unfavorable outcome (treatment failure, recurrence, or death or study dropout during treatment) measured 24 months after the end of treatment, with a noninferiority margin of 6 percentage points, adjusted for country. RESULTS: A total of 1836 patients were assigned to the 4-month regimen (experimental group) or the standard regimen (control group). Baseline characteristics were well balanced between the groups. At 24 months after the end of treatment, the adjusted difference in the risk of an unfavorable outcome (experimental group [21.0%] minus control group [17.2%]) in the modified intention-to-treat population (1356 patients) was 3.5 percentage points (95% confidence interval, -0.7 to 7.7). There was heterogeneity across countries (P=0.02 for interaction, with differences in the rate of an unfavorable outcome ranging from -5.4 percentage points in Guinea to 12.3 percentage points in Senegal) and in baseline cavitary status (P=0.04 for interaction) and body-mass index (P=0.10 for interaction). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%). There was no evidence of increased risks of prolongation of the QT interval or dysglycemia with the 4-month regimen. CONCLUSIONS: Noninferiority of the 4-month regimen to the standard regimen with respect to the primary efficacy end point was not shown. (Funded by the Special Program for Research and Training in Tropical Diseases and others; ClinicalTrials.gov number, NCT00216385.).
Authors: Gustavo E Velásquez; Meredith B Brooks; Julia M Coit; Henry Pertinez; Dante Vargas Vásquez; Epifanio Sánchez Garavito; Roger I Calderón; Judith Jiménez; Karen Tintaya; Charles A Peloquin; Elna Osso; Dylan B Tierney; Kwonjune J Seung; Leonid Lecca; Geraint R Davies; Carole D Mitnick Journal: Am J Respir Crit Care Med Date: 2018-09-01 Impact factor: 21.405
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: Danfeng Zhang; James E Gomez; Jung-Yien Chien; Nathan Haseley; Christopher A Desjardins; Ashlee M Earl; Po-Ren Hsueh; Deborah T Hung Journal: Antimicrob Agents Chemother Date: 2016-10-21 Impact factor: 5.191
Authors: Susan E Dorman; Radojka M Savic; Stefan Goldberg; Jason E Stout; Neil Schluger; Grace Muzanyi; John L Johnson; Payam Nahid; Emily J Hecker; Charles M Heilig; Lorna Bozeman; Pei-Jean I Feng; Ruth N Moro; William MacKenzie; Kelly E Dooley; Eric L Nuermberger; Andrew Vernon; Marc Weiner Journal: Am J Respir Crit Care Med Date: 2015-02-01 Impact factor: 21.405