Delamanid for Multidrug-Resistant Pulmonary Tuberculosis

Maria Tarcela Gler, M.D., Vija Skripconoka, M.D., Epifanio Sanchez-Garavito, M.D., Heping Xiao, M.D., Jose L. Cabrera-Rivero, M.D., Dante E. Vargas-Vasquez, M.D., Mengqiu Gao, M.D., Ph.D., Mohamed Awad, M.B., B.Ch., M.D., Seung-Kyu Park, M.D., Ph.D., Tae Sun Shim, M.D., Ph.D., Gee Young Suh, M.D., Manfred Danilovits, M.D., Hideo Ogata, M.D., Anu Kurve, M.D., Joon Chang, M.D., Ph.D., Katsuhiro Suzuki, M.D., Thelma Tupasi, M.D., Won-Jung Koh, M.D., Barbara Seaworth, M.D., Lawrence J. Geiter, Ph.D., and Charles D. Wells, M.D.

N Engl J Med 2012; 366:2151-2160June 7, 2012

BACKGROUND

Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis.

METHODS

In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months.

RESULTS

Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid.

CONCLUSIONS

Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.)

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the members of the data and safety monitoring committee — Drs. Charles Daley, Thomas Fleming, Martin Keane, and Tom Shinnick — for their close monitoring of patient safety and their expert guidance during the conduct of this trial.