Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study

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• 作者：Prof Alejandro Llanos-Cuentas ; MD^a ; Prof Marcus V Lacerda ; MD^b ; Ronnatrai Rueangweerayut ; MD^c ; Prof Srivicha Krudsood ; MD^d ; Sandeep K Gupta ; MD^e ; Sanjay K Kochar ; MD^f ; Preetam Arthur ; MD^g ; Nuttagarn Chuenchom ; MD^c ; Jö ; rg J Mö ; hrle ; PhD^h ; Stephan Duparc ; MD^h ; Cletus Ugwuegbulam ; PhDⁱ ; Jö ; rg-Peter Kleim ; PhDⁱ ; Nick Carter ; MScⁱ ; Justin A Green ; MDⁱ ; Lynda Kellam ; MScⁱ ; ^{lynda.m.kellam@gsk.com" class="auth_mail}
• 刊名：The Lancet
• 出版年：22-28 March, 2014
• 年：2014
• 卷：383
• 期：9922
• 页码：1049-1058
• 全文大小：309 K

文摘

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Summary

Background

Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose-response, safety, and tolerability of single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure.

Methods

In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged 鈮?6 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100鈥?00 per 渭L blood) were enrolled from community health centres and hospitals across seven sites in Brazil, Peru, India, and Thailand. Patients with glucose-6-phosphate dehydrogenase enzyme activity of less than 70% were excluded. Eligible patients received chloroquine (days 1-3) and were randomly assigned (1:1:1:1:1:1) by a computer-generated randomisation schedule to receive single-dose tafenoquine 50 mg, 100 mg, 300 mg, or 600 mg, primaquine 15 mg for 14 days, or chloroquine alone. Randomisation was stratified by baseline parasite count (鈮?500 and >7500 per 渭L blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with , number .

Findings

Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 57路7% (95% CI 43-70) with tafenoquine 50 mg, 54路1% (40-66) with tafenoquine 100 mg, 89路2% (77-95) with tafenoquine 300 mg, 91路9% (80-97) with tafenoquine 600 mg, 77路3% (63-87) with primaquine, and 37路5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51路7% [95% CI 35-69], p<0路0001, with tafenoquine 300 mg and 54路5% [38-71], p<0路0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39路9% [21-59], p=0路0004). Adverse events were similar between treatments. 29 serious adverse events occurred in 26 (8%) of 329 patients; QT prolongation was the most common serious adverse event (11 [3%] of 329), occurring in five (2%) of 225 patients receiving tafenoquine, four (8%) of 50 patients receiving primaquine, and two (4%) of 54 patients receiving chloroquine alone, with no evidence of an additional effect on QT of chloroquine plus tafenoquine coadministration.

Interpretation

Single-dose tafenoquine 300 mg coadministered with chloroquine for P vivax malaria relapse prevention was more efficacious than chloroquine alone, with a similar safety profile. As a result, it has been selected for further clinical assessment in phase 3.

Funding

GlaxoSmithKline, Medicines for Malaria Venture.