A cluster-randomized controlled trial to assess the effectiveness of using 15% DEET topical repellent with long-lasting insecticidal nets (LLINs) compared to a placebo lotion on malaria transmission

Abstract

BackgroundLong-lasting insecticidal nets (LLINs) have limited effect on malaria transmitted outside of sleeping hours. Topical repellents have demonstrated reduction in the incidence of malaria transmitted in the early evening. This study assessed whether 15% DEET topical repellent used in combination with LLINs can prevent greater malaria transmission than placebo and LLINs, in rural Tanzania.MethodsA cluster-randomized, placebo-controlled trial was conducted between July 2009 and August 2010 in a rural Tanzanian village. Sample size calculation determined that 10 clusters of 47 households with five people/household were needed to observe a 24% treatment effect at the two-tailed 5% significance level, with 90% power, assuming a baseline malaria incidence of one case/person/year. Ten clusters each were randomly assigned to repellent and control groups by lottery. A total of 4,426 individuals older than six months were enrolled. All households in the village were provided with an LLIN per sleeping space. Repellent and placebo lotion was replaced monthly. The main outcome was rapid diagnostic test (RDT)-confirmed malaria measured by passive case detection (PCD). Incidence rate ratios were estimated from a Poisson model, with adjustment for potential confounders, determined a priori. According-to-protocol approach was used for all primary analyses.ResultsThe placebo group comprised 1972.3 person-years with 68.29 (95% C.I 37.05-99.53) malaria cases/1,000 person-years. The repellent group comprised 1,952.8 person-years with 60.45 (95% C.I 48.30-72.60) cases/1,000 person-years, demonstrating a non-significant 11.44% reduction in malaria incidence rate in this group, (Wilcoxon rank sum z = 0.529, p = 0.596). Principal components analysis (PCA) of the socio-economic status (SES) of the two groups demonstrated that the control group had a higher SES (Pearson’s chi square = 13.38, p = 0.004).ConclusionsLack of an intervention effect was likely a result of lack of statistical power, poor capture of malaria events or bias caused by imbalance in the SES of the two groups. Low malaria transmission during the study period could have masked the intervention effect and a larger study size was needed to increase discriminatory power. Alternatively, topical repellents may have no impact on malaria transmission in this scenario. Design and implementation of repellent intervention studies is discussed.Trial registrationThe trial was registered ISRCTN92202008 - http://www.controlled-trials.com/ISRCTN92202008Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-324) contains supplementary material, which is available to authorized users.

Evidence-based vector control? Improving the quality of vector control trials

“…This technique has been used to estimate the size of area-wide effects in studies of LLINs for malaria control [61]. Unintended consequences of topical repellents can be avoided by randomising only a relatively low proportion of individuals or households in a village to receive the intervention [31,62,63]. Tackling the problem of human movement in dengue studies is more difficult because Aedes aegypti feeds during the day when people are engaged in their daily activities.…”

Mosquito repellents for malaria prevention

“…The true effect may be substantially different from the estimation of the effect.Parasitaemia: P. vivax 18 per 1000 19 per 1000 (14 to 25) RR 1.07 (0.80 to 1.41)9434(3 studies)⊕⊕⊖⊖LOW 7,8 Due to risk of bias and imprecisionTopical repellents may or may not have a protective effect against P. vivax parasitaemia Our confidence in the effect estimation is limited. The true effect may be substantially different from the estimation of the effect.* The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; RR: risk ratio; OR: odds ratio. GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. 1 Downgraded by 1 for risk of bias: Sangoro 2014a used alternate allocation and reported a baseline imbalance; random sequence generation and allocation concealment were not described by Rowland 2004; and Sluydts 2016 did not have a placebo so the intervention was not blinded. 2 Downgraded by 1 because of the large heterogeneity between the 3 trials. The I² statistic, which quantifies the proportion of the variation in the point estimates due to among-study differences, was considered substantial at 50%.…”

“…The I² statistic, which quantifies the proportion of the variation in the point estimates due to among-study differences, was considered substantial at 50%. The subgroup analysis to some extent explained the heterogeneity but we do not believe that there is enough evidence to suggest there is a true subgroup effect given that there is no heterogeneity in the outcome parasitaemia caused by P. falciparum where studies with and without LLINs were also analysed. 3 Downgraded by 1 for imprecision because the sample size is too small, the CIs are wide, the pooled effect (0.40 to 1.07) overlaps a risk ratio (RR) of 1.0 (no effect) and presents an estimate of effect ranging between beneficial and harmful. 4 Downgraded by 1 for risk of bias: Hill 2007 used alternate allocation and reported a baseline imbalance; random sequence generation and allocation concealment were not described by McGready 2001. 5 Downgraded by 1 for imprecision because the sample size is too small, the CIs are very wide, the pooled effect (0.62 to 1.12) overlaps a risk ratio (RR) of 1.0 (no effect) and presents an estimate of effect ranging between beneficial and harmful. 6 Downgraded by 1 for risk of bias: random sequence generation and allocation concealment were not described by Rowland 2004; Sluydts 2016 was not placebo-controlled and intervention was not blinded. 7 Downgraded by 1 for imprecision because the CIs are very wide, the pooled effect (0.80 to 1.41) overlaps a risk ratio (RR) of 1.0 (no effect) and presents an estimate of effect ranging between beneficial and harmful. 8 Downgraded by 1 for risk of bias: random sequence generation and allocation concealment were not described by McGready 2001.…”

“… 1 Downgraded by 1 for risk of bias: Sangoro 2014a used alternate allocation and reported a baseline imbalance; random sequence generation and allocation concealment were not described by Rowland 2004; and Sluydts 2016 did not have a placebo so the intervention was not blinded. 2 Downgraded by 1 because of the large heterogeneity between the 3 trials. The I² statistic, which quantifies the proportion of the variation in the point estimates due to among-study differences, was considered substantial at 50%.…”

“… 1 Downgraded by 1 for risk of bias: Sangoro 2014a used alternate allocation and reported a baseline imbalance; random sequence generation and allocation concealment were not described by Rowland 2004; and Sluydts 2016 did not have a placebo so the intervention was not blinded.…”