Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial.

Author(s): Paton NI, Lee L, Xu Y, Ooi EE, Cheung YB, Archuleta S, Wong G, Wilder-Smith A

Affiliation(s): Yong Loo Lin School of Medicine, National University of Singapore, Singapore. nick.paton@ctu.mrc.ac.uk

Publication date & source: 2011-09, Lancet Infect Dis., 11(9):677-83. Epub 2011 May 5.

Publication type: Randomized Controlled Trial; Research Support, Non-U.S. Gov't

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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: National Medical Research Council, Singapore. Copyright (c) 2011 Elsevier Ltd. All rights reserved.