title: Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study.
abstract: 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 ≥16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100,000 per μL 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 (≤7500 and >7500 per μL 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 ClinicalTrials.gov, number NCT01376167.
  
  
  RESULTS
  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 57·7% (95% CI 43-70) with tafenoquine 50 mg, 54·1% (40-66) with tafenoquine 100 mg, 89·2% (77-95) with tafenoquine 300 mg, 91·9% (80-97) with tafenoquine 600 mg, 77·3% (63-87) with primaquine, and 37·5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51·7% [95% CI 35-69], p<0·0001, with tafenoquine 300 mg and 54·5% [38-71], p<0·0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39·9% [21-59], p=0·0004). 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  GlaxoSmithKline, Medicines for Malaria Venture.
authors.affiliation: Instituto de Medicina Tropical, Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Peru.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Llanos-Cuentas
authors.affiliation: Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas, Brazil.
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Lacerda
authors.affiliation: Mae Sot Hospital, Mae Sot, Tak Province, Thailand.
authors.forename: Ronnatrai
authors.initials: R
authors.lastname: Rueangweerayut
authors.affiliation: Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Srivicha
authors.initials: S
authors.lastname: Krudsood
authors.affiliation: MV Hospital and Research Centre, Lucknow, Uttar Pradesh, India.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Sardar Patel Medical College, Bikaner, Rajasthan, India.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Kochar
authors.affiliation: Sri Ramchandra Medical College and Research Institute, Department of Medicine, Porur, Chennai, Tamil Nadu, India.
authors.forename: Preetam
authors.initials: P
authors.lastname: Arthur
authors.affiliation: Mae Sot Hospital, Mae Sot, Tak Province, Thailand.
authors.forename: Nuttagarn
authors.initials: N
authors.lastname: Chuenchom
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Möhrle
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Duparc
authors.affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK.
authors.forename: Cletus
authors.initials: C
authors.lastname: Ugwuegbulam
authors.affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK.
authors.forename: Jörg-Peter
authors.initials: JP
authors.lastname: Kleim
authors.affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Carter
authors.affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Green
authors.affiliation: GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK. Electronic address: lynda.m.kellam@gsk.com.
authors.forename: Lynda
authors.initials: L
authors.lastname: Kellam
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000008:administration & dosage*; D000962:Antimalarials / Q000008:administration & dosage*; D001938:Brazil; D002738:Chloroquine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007194:India; D016780:Malaria, Vivax / Q000188:drug therapy* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D010568:Peru; D011319:Primaquine / Q000627:therapeutic use; D055502:Secondary Prevention; D013785:Thailand; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; C055852:tafenoquine; D002738:Chloroquine; D011319:Primaquine