Adjunctive Ivermectin Mass Drug Administration for Malaria Elimination: A cluster randomized trial

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

This trial will be the first to investigate the impact of adding ivermectin (IVM) to mass drug administration (MDA) with an efficacious antimalarial (eg dihydroartemisinin-piperaquine (DP)) to reduce malaria transmission in a seasonal low-transmission setting. Additive IVM MDA will be compared to DP-only MDA (with treatment daily for three days during the three months of peak malaria transmission (July-September)) in combination with standard programmatic interventions for malaria control (long-lasting insecticidal nets (LLIN) and intermittent preventative treatment in pregnancy (IPTp)) in a cluster-randomized community-based trial. Primary outcome measures will be population-based Plasmodium falciparum (malaria infection) prevalence (estimated using ultra-sensitive PCR tests) and Anopheles gambiae (malaria vector) survival (measured using parity estimated by dissection of Anopheles ovaries). Data on MDA coverage, acceptability and feasibility of the intervention and a cost-effectiveness analysis will be included. We have established field infrastructure on the Bijagós Archipelago (including trained field entomologists and field laboratory technicians) and have detailed recent baseline data on the burden of disease caused by malaria and other neglected tropical diseases (NTDs) and vector populations on the islands. This 'natural laboratory' island setting provides an unparalleled opportunity to understand transmission and its interruption using a combined MDA strategy through investigating the impact of imported infections (through an expanded community-based CDSAT (case detection screen and treat) intervention which we will include in both arms), using serological (immune) markers in the blood to define transmission dynamics and estimate entomological inoculation rate (EIR) and monitoring the effect of IVM MDA on confined vector populations over time.

Technical Summary

This trial will be the first to investigate the impact of adjunctive IVM MDA to reduce malaria transmission in a seasonal low-transmission setting. Adjunctive IVM MDA will be compared to DP-only MDA (with treatment daily for three days during the three months of peak malaria transmission (July-September)) in combination with standard programmatic interventions (long-lasting insecticidal nets (LLIN) and intermittent preventative treatment in pregnancy (IPTp)) in a cluster-randomized community-based trial. Primary outcome measures will be population-based Pf prevalence (estimated using ultra-sensitive PCR) and Anopheles gambiae survival (measured using parity). Data on MDA coverage, acceptability and feasibility of the intervention and a cost-effectiveness analysis will be included. We have established field infrastructure on the Bijagós Archipelago (including trained field entomologists and field laboratory technicians) and have detailed recent baseline data on malaria and NTD epidemiology and vector populations on the islands. This island setting provides an unparalleled opportunity to understand transmission and its interruption using a combined MDA strategy through investigating the impact of imported infections (through an expanded community-based CDSAT (case detection screen and treat) intervention in both arms), using serological markers to define transmission dynamics and estimate entomological inoculation rate (EIR) and monitoring the effect of IVM MDA on confined vector populations over time (parity, sporozoite rate, resistance to pyrethroids and IVM and population genomic diversity).

Planned Impact

There is increasing interest in the potential of ivermectin (IVM) mass drug administration (MDA) tailored to local transmission patterns to complement vector control strategies, particularly where existing strategies such as long lasting insecticidal nets (LLIN) and indoor residual spraying (IRS) have been maximized. Moreover, new tools for reduction in malaria transmission are required as both pyrethroid and antimalarial resistance emerges. There is growing evidence that adjunctive IVM MDA used in this context will be a useful new tool in reducing malaria transmission, and even eliminating malaria in some settings, but there is currently a lack of cluster randomized trials investigating its utility and efficacy. The public health impact of adjunctive IVM MDA to MDA with an efficacious antimalarial is not known and there have not been any trials to date designed to answer this research question specifically. Results from the proposed trial will be important in addressing some of the outstanding questions. The design of the trial will allow us to quantify the impact of adjunctive IVM MDA as a malaria control strategy. The confined nature of the islands will allow us to estimate the impact on vector density and survival and measure the effect of imported infection and population movement on MDA strategies for malaria control and elimination. The results will be generalizable in other settings of similar endemicity in Africa.

The results of this trial will contribute to information relevant to malaria control programmes of the efficacy of IVM MDA in in combination with dihydroartemesinin-piperaquine (DP) MDA as part of a community-based intervention strategy for malaria elimination. If DP+IVM MDA is shown to be feasible and cost-effective this strategy may be important in the acceleration of elimination of malaria which would have a significant beneficial impact on health. The results of this trial may also contribute knowledge towards the integrated elimination of IVM-susceptible Neglected Tropical Diseases (NTDs) such as lymphatic filariasis (LF), soil-transmitted helminths (STH) (such as Strongyloides) and scabies alongside malaria elimination in co-endemic settings. This study will enhance our knowledge of sustainable surveillance and feasible and equitable access to MDA. The results of this study will inform malaria (and NTD) control policies in Guinea Bissau and elsewhere in Africa with similar geography or malaria endemicity and could have a major impact on the burden of these diseases in West Africa and beyond. The Bissau-Guinean Ministry of Public Health (MoPH) (including the National Malaria Control Programme (PNLCP) and the National Programme for Neglected Tropical Diseases (PNDTN)) and the National Institute for Public Health (INASA) in Bissau will be able to use these data to define and implement these strategies on the islands. This trial is complementary to the MASSIV trial, currently underway, which is investigating a similar strategy for malaria transmission reduction in The Gambia. The combined data from both of these trials will be a powerful data set that will enhance the knowledge of these interventions and their implementation.

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