title: Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial.
abstract: BACKGROUND
  Chloroquine has in-vitro activity against influenza and could be an ideal candidate for worldwide prevention of influenza in the period between onset of a pandemic with a virulent influenza strain and the development and widespread dissemination of an effective vaccine. We aimed to assess the efficacy of such an intervention.
  
  
  METHODS
  In this randomised, double-blind, placebo-controlled trial done at a single centre in Singapore, we randomly assigned (1:1) healthy adults to receive chloroquine phosphate (500 mg/day for 1 week, then once a week to complete 12 weeks) or matching placebo by use of a computer-generated randomisation list. Participants filled an online symptom diary every week, supplemented by daily diaries and self-administered nasal swabs when unwell. Haemagglutination-inhibition assays for influenza A (H1N1, H3N2) and B were done on blood samples taken at baseline and after 12 weeks. The primary outcome was laboratory-confirmed clinical influenza defined by specific symptoms accompanied by influenza RNA on nasal swabs or a four-fold increase in haemagglutination-inhibition titres over the 12-week study period. Analysis was by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01078779.
  
  
  RESULTS
  From November, 2009, to February, 2010, we recruited 1516 eligible participants. 1496 (96%) returned at week 12 and were included in the efficacy analysis. Adherence to study intervention was 97%, and 94% of the scheduled weekly diaries were completed. Eight (1%) of 738 participants had laboratory-confirmed clinical influenza in the placebo group and 12 (2%) of 724 in the chloroquine group (relative risk 1·53, 95% CI 0·63-3·72; p=0·376). 29 (4%) of 738 had laboratory-confirmed influenza infection (symptomatic or asymptomatic) in the placebo group and 38 (5%) of 724 in the chloroquine group (1·34, 0·83-2·14; p=0·261). 249 (33%) of 759 participants reported adverse events (mostly mild) in the placebo group and 341 (45%) of 757 in chloroquine group (p<0·0001). Headache, dizziness, nausea, diarrhoea, and blurred vision were more common in the chloroquine group, but rarely resulted in treatment discontinuation. One serious adverse event (hepatitis) was possibly related to chloroquine.
  
  
  CONCLUSIONS
  Although generally well tolerated by a healthy community population, chloroquine does not prevent infection with influenza. Alternative drugs are needed for large-scale prevention of influenza.
  
  
  BACKGROUND
  National Medical Research Council, Singapore.
authors.affiliation: Yong Loo Lin School of Medicine, National University of Singapore, Singapore. nick.paton@ctu.mrc.ac.uk
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Paton
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lee
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.forename: Yin Bun
authors.initials: YB
authors.lastname: Cheung
authors.forename: Sophia
authors.initials: S
authors.lastname: Archuleta
authors.forename: Gerard
authors.initials: G
authors.lastname: Wong
authors.forename: Annelies
authors.initials: A
authors.lastname: Wilder-Smith
authors.forename: Annelies Wilder
authors.initials: AW
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002738:Chloroquine / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D009981:Influenza B virus; D007251:Influenza, Human / Q000517:prevention & control*; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D009296:Nasal Cavity / Q000821:virology; D012367:RNA, Viral / Q000302:isolation & purification*; D057566:Self Report; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D002738:Chloroquine