title: Efficacy of topical mosquito repellent (picaridin) plus long-lasting insecticidal nets versus long-lasting insecticidal nets alone for control of malaria: a cluster randomised controlled trial.
abstract: BACKGROUND
  Although effective topical repellents provide personal protection against malaria, whether mass use of topical repellents in addition to long-lasting insecticidal nets can contribute to a further decline of malaria is not known, particularly in areas where outdoor transmission occurs. We aimed to assess the epidemiological efficacy of a highly effective topical repellent in addition to long-lasting insecticidal nets in reducing malaria prevalence in this setting.
  
  
  METHODS
  A cluster randomised controlled trial was done in the 117 most endemic villages in Ratanakiri province, Cambodia, to assess the efficacy of topical repellents in addition to long-lasting insecticidal nets in controlling malaria in a low-endemic setting. We did a pre-trial assessment of village accessibility and excluded four villages because of their inaccessibility during the rainy season. Another 25 villages were grouped because of their proximity to each other, resulting in 98 study clusters (comprising either a single village or multiple neighbouring villages). Clusters were randomly assigned (1:1) to either a control (long-lasting insecticidal nets) or intervention (long-lasting insecticidal nets plus topical repellent) study group after a restricted randomisation. All clusters received one long-lasting insecticidal net per individual, whereas those in the intervention group also received safe and effective topical repellents (picaridin KBR3023, SC Johnson, Racine, WI, USA), along with instruction and promotion of its daily use. Cross-sectional surveys of 65 randomly selected individuals per cluster were done at the beginning and end of the malaria transmission season in 2012 and 2013. The primary outcome was Plasmodium species-specific prevalence in participants obtained by real-time PCR, assessed in the intention-to-treat population. Complete safety analysis data will be published seperately; any ad-hoc adverse events are reported here. This trial is registered with ClinicalTrials.gov, number NCT01663831.
  
  
  RESULTS
  Of the 98 clusters that villages were split into, 49 were assigned to the control group and 49 were assigned to the intervention group. Despite having a successful distribution system, the daily use of repellents was suboptimum. No post-intervention differences in PCR plasmodium prevalence were observed between study groups in 2012 (4·91% in the control group vs 4·86% in the intervention group; adjusted odds ratio [aOR] 1·01 [95% CI 0·60-1·70]; p=0·975) or in 2013 (2·96% in the control group vs 3·85% in the intervention group; aOR 1·31 [0·81-2·11]; p=0·266). Similar results were obtained according to Plasmodium species (1·33% of participants in the intervention group vs 1·10% in the intervention group were infected with Plasmodium falciparum; aOR 0·83 [0·44-1·56]; p=0·561; and 1·85% in the control group vs 2·67% in the intervention group were infected with Plasmodium vivax; aOR 1·51 [0·88-2·57]; p=0·133). 41 adverse event notifications from nine villages were received, of which 33 were classified as adverse reactions (11 of these 33 were cases of repellent abuse through oral ingestion, either accidental or not). All participants with adverse reactions fully recovered and 17 were advised to permanently stop using the repellent.
  
  
  CONCLUSIONS
  Mass distribution of highly effective topical repellents in resource-sufficient conditions did not contribute to a further decline in malaria endemicity in a pre-elimination setting in the Greater Mekong subregion. Daily compliance and appropriate use of the repellents remains the main obstacle.
  
  
  BACKGROUND
  Bill & Melinda Gates Foundation.
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Department of Biology, University of Antwerp, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sluydts
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Lies
authors.initials: L
authors.lastname: Durnez
authors.affiliation: Department of Biomedical Sciences, University of Antwerp, Belgium; National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Somony
authors.initials: S
authors.lastname: Heng
authors.affiliation: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium; Amsterdam Institute of Social Science Research, University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gryseels
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Lydie
authors.initials: L
authors.lastname: Canier
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Saorin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Van Roey
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Karen
authors.initials: K
authors.lastname: Kerkhof
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Nimol
authors.initials: N
authors.lastname: Khim
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Sokny
authors.initials: S
authors.lastname: Mao
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Sambunny
authors.initials: S
authors.lastname: Uk
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Siv
authors.initials: S
authors.lastname: Sovannaroth
authors.affiliation: Department of Public Health, Institute of Tropical Medicine, Antwerp, Belgium; School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan; Partners for Applied Social Sciences, PASS-international, Tessenderlo, Belgium.
authors.forename: Koen Peeters
authors.initials: KP
authors.lastname: Grietens
authors.affiliation: National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia.
authors.forename: Tho
authors.initials: T
authors.lastname: Sochantha
authors.affiliation: Institut Pasteur du Cambodge, Phnom Penh, Cambodia.
authors.forename: Didier
authors.initials: D
authors.lastname: Menard
authors.affiliation: Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Belgium. Electronic address: mcoosemans@itg.be.
authors.forename: Marc
authors.initials: M
authors.lastname: Coosemans
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002160:Cambodia / Q000453:epidemiology; D002648:Child; D016000:Cluster Analysis; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007302:Insect Repellents / Q000494:pharmacology*; D007303:Insect Vectors / Q000187:drug effects; D057148:Insecticide-Treated Bednets; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000517:prevention & control*; D016780:Malaria, Vivax / Q000453:epidemiology / Q000517:prevention & control*; D008297:Male; D009032:Mosquito Control / Q000379:methods*; D010880:Piperidines / Q000494:pharmacology*; D015995:Prevalence
chemical_list: D007302:Insect Repellents; D010880:Piperidines; C483506:picaridin