Delamanid for multidrug-resistant pulmonary tuberculosis.
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.).
Makati Medical Center, Manila, Philippines.
Maria Tarcela
MT
Gler
Vija
V
Skripconoka
Epifanio
E
Sanchez-Garavito
Heping
H
Xiao
Jose L
JL
Cabrera-Rivero
Dante E
DE
Vargas-Vasquez
Mengqiu
M
Gao
Mohamed
M
Awad
Seung-Kyu
SK
Park
Tae Sun
TS
Shim
Gee Young
GY
Suh
Manfred
M
Danilovits
Hideo
H
Ogata
Anu
A
Kurve
Joon
J
Chang
Katsuhiro
K
Suzuki
Thelma
T
Tupasi
Won-Jung
WJ
Koh
Barbara
B
Seaworth
Lawrence J
LJ
Geiter
Charles D
CD
Wells
D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000302:isolation & purification; D009593:Nitroimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010080:Oxazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013183:Sputum / Q000382:microbiology; D016019:Survival Analysis; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
D000995:Antitubercular Agents; D009593:Nitroimidazoles; C516022:OPC-67683; D010080:Oxazoles