Early trials on the mg

Early trials on the 0.75mg/kg dose reported variable reductions in gametocyte carriage (El-Sayed et al., 2007; Shekalaghe et al., 2011; von Seidlein et al., 2003) and a dose-ranging trial in clinically ill patients showed efficacy at doses as low as 0.40mg/kg (Eziefula et al., 2014a); however, non-inferiority of the 0·1mg/kg dose was inconclusive (Eziefula et al., 2014a). More recent studies in high transmission areas and high-density gametocyte carriage confirm that gli protein PQ reduces gametocyte carriage and infectiousness to mosquitoes over a range of doses that includes the currently recommended 0.25mg/kg (Dicko et al., 2016; Goncalves et al., 2016). There are indications that the added value of PQ in reducing post-treatment infectivity may differ between symptomatic and asymptomatic infections (El-Sayed et al., 2007; Shekalaghe et al., 2007) and the dynamics of asymptomatic low-density parasite carriage may be markedly different (WWARN Gametocyte Study Group, 2016), perhaps due to longer periods of infection in asymptomatic infections and hence more circulating mature gametocytes (Price et al., 1999; Stepniewska et al., 2008). Therefore, there is the need for evidence on the efficacy and safety of these PQ doses in asymptomatic individuals with low-density malaria infections and their impact on infectiousness to mosquitoes. This study compared the gametocytocidal efficacy of three different single doses of PQ combined with dihydroartemisinin-piperaquine (DHAP) on gametocyte carriage in asymptomatic, malaria-infected, G6PD-normal individuals in The Gambia. Infectivity to Anopheles coluzzii mosquitoes was measured in a subset of enrolled participants.
Method
Data Management
Statistical Analysis Descriptive statistics are presented by treatment arm at baseline and gametocyte carriage compared using one way Analysis of Variance (ANOVA) on log-transformed gametocyte densities at analyzed visits. We determined the odds of gametocytemia on days 7, 10 and 14 in a multivariable logistic regression model using a generalized estimating equation with exchangeable correlation structure to control for potential confounding/effect modification due to age, gender, baseline hemoglobin level and asexual parasite count. We fitted a Cox proportional hazard model to determine the effect of PQ dose on gametocyte clearance compared to the control adjusted for baseline asexual parasite density and hemoglobin in those with gametocytemia on enrolment. For this specific analysis only, baseline gametocytemia was defined as all QT-NASBA positive samples on either day 0 or day 3 (one day post-PQ dose) to adjust for fluctuation in gametocyte densities around the threshold of detection of the QT-NASBA and hence gametocytemia as changes during this period is most likely be due to the effect of the ACT. A Kaplan Meier estimator survival plot was used to show probabilities of gametocyte carriage over time in the study arms. The change in hemoglobin levels from baseline was calculated as the difference between the reference visit and baseline. All analyses were restricted to gametocyte results between day 0 and 14 to minimize bias from possible new asexual infections that lead to de novo gametocyte production, as DHAP concentrations beyond this time may no longer prevent the emergence of new infections (Bousema et al., 2010). Analyses were done using Stata 13.1 (Stata Corp, College Station, TX, USA) and based on an intention-to-treat principle.
Ethics, Approvals and Trial Management An independent Trial Steering Committee and a Data Safety and Management Board reviewed the trial conduct. The trial was approved by The Gambia Government/MRC Joint Ethics Committee (SCC 1321, 13 March 2013) and the London School of Hygiene and Tropical Medicine Research Ethics Committee (ref 6412). A signed informed consent was obtained from all participants; consent for children was provided by the caregiver and an assent obtained from children between 12 and 17years. The trial was conducted in conformity with the principles of good clinical practice and the Helsinki Declaration.