Protocol for a cluster randomised placebo-controlled trial of adjunctive ivermectin mass drug administration for malaria control on the Bijagós Archipelago of Guinea-Bissau: the MATAMAL trial

Abstract

Introduction: As malaria declines, innovative tools are required to further reduce transmission and achieve elimination. Mass drug administration (MDA) of artemisinin-based combination therapy (ACT) is capable of reducing malaria transmission where coverage of control interventions is already high, though the impact is short-lived. Combining ACT with ivermectin, an oral endectocide shown to reduce vector survival, may increase its impact, while also treating ivermectin-sensitive co-endemic diseases and minimising the potential impact of ACT resistance in this context.

Methods and analysis: MATAMAL is a cluster-randomised placebo-controlled trial. The trial is being conducted in 24 clusters on the Bijagós Archipelago, Guinea-Bissau, where the peak prevalence of Plasmodium falciparum (Pf) parasitaemia is approximately 15%. Clusters have been randomly allocated to receive MDA with dihydroartemisinin-piperaquine and either ivermectin or placebo. The primary objective is to determine whether the addition of ivermectin MDA is more effective than dihydroartemisinin-piperaquine MDA alone in reducing the prevalence of P. falciparum parasitaemia, measured during peak transmission season after 2 years of seasonal MDA. Secondary objectives include assessing prevalence after 1 year of MDA; malaria incidence monitored through active and passive surveillance; age-adjusted prevalence of serological markers indicating exposure to P. falciparum and anopheline mosquitoes; vector parous rates, species composition, population density and sporozoite rates; prevalence of vector pyrethroid resistance; prevalence of artemisinin resistance in P. falciparum using genomic markers; ivermectin's impact on co-endemic diseases; coverage estimates; and the safety of combined MDA.

Ethics and dissemination: The trial has been approved by the London School of Hygiene and Tropical Medicine's Ethics Committee (UK) (19156) and the Comite Nacional de Eticas de Saude (Guinea-Bissau) (084/CNES/INASA/2020). Results will be disseminated in peer-reviewed publications and in discussion with the Bissau-Guinean Ministry of Public Health and participating communities.

Trial registration number: NCT04844905.

Keywords: clinical trials; epidemiologic studies; guinea-bissau; ivermectin; malaria; mass drug administration.

Figure 1

Timeline of the MATAMAL clinical trial showing months of MDA, cohort surveys, Ento, Survey and NTD survey. Rainy season months indicated in dark colour. Ento, entomological surveys; MDA, mass drug administration; NTD, neglected tropical disease; Survey, major cross-sectional surveys.

Figure 2

Map of Guinea-Bissau showing the Bijagós Archipelago off the south-west coast.74]

Figure 3

Map of the Bijagós Archipelago. MATAMAL clusters marked by stars and separated by lines where sharing a landmass.

Figure 4

Design elements of the MATAMAL clinical trial. DP, dihydroartemisinin–piperaquine; IVM, ivermectin.

Figure 5

Graph showing modelled qPCR prevalence of malaria over time, assuming 70% coverage and 75% DP efficacy. Green dots: MDA rounds. Green bars: survey periods. Dashed line: no intervention. Blue line: MDA with DP only. Pink line: MDA with DP and IVM at 300 µg/Kg. DP, dihydroartemisinin–piperaquine; IVM, ivermectin; MDA, mass drug administration.