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N Engl J Med. 2019 Mar 13. doi: 10.1056/NEJMoa1811867. [Epub ahead of print]

A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis.

Author information

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.).

PMID:
30865791
DOI:
10.1056/NEJMoa1811867

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