Adjunctive Ivermectin Mass Drug Administration for Malaria Control (MATAMAL)

Adjunctive Ivermectin Mass Drug Administration for Malaria Control on the Bijagos Archipelago of Guinea Bissau: A Cluster-randomized Placebo-controlled Trial

Medical Research Council Unit, The Gambia, Ministerio de Saude Publica, Guinee-Bissau, Bandim Health Project, Instituto Nacional de Estudos e Pesquisas, Guinee-Bissau

This is a cluster-randomized placebo-controlled clinical trial to evaluate the additive benefit of Ivermectin (IVM) (or Placebo) mass drug administration (MDA) to dihydroartemisinin-piperaquine (DP) MDA for malaria control in a moderate to low malaria-endemic setting as an adjunctive strategy to existing programmatic malaria control measures. The regime of DP and IVM will target both human reservoirs of Plasmodium falciparum and the Anopheles gambiae vector respectively, with the aim of interrupting transmission. The trial will be conducted on the Bijagos Archipelago, where islands (clusters) will be randomised to receive seasonal DP and IVM or DP and Placebo MDA. The primary outcome will be the prevalence of infection with Plasmodium falciparum in all age groups detected by nucleic acid amplification testing during the peak malaria transmission season after two years of intervention.

The objectives of this trial are To evaluate the impact of adjunctive IVM to DP MDA on malaria transmission in communities with high ITN coverage. To evaluate the impact of IVM MDA on An. gambiae population density and age-structure. To evaluate the impact of IVM MDA on the prevalence of co-endemic IVM-susceptible Neglected Tropical Diseases (lymphatic filariasis, soil transmitted helminths and scabies) To evaluate acceptability, feasibility and access to MDA as a strategy for malaria control and to identify the most acceptable way of achieving and sustaining high coverage MDA with IVM and DP. This cluster-randomized placebo-controlled trial has two arms. A total of 24 clusters will be randomly assigned to receive DP + IVM MDA or DP+ Placebo MDA using computer-generated random numbers. To mitigate against contamination effects, the majority of clusters will be separate islands and will be separated by distances greater than 2km. On the two islands that are divided (each into two clusters), a buffer zone of 2km between each cluster will be ensured. The total population of the archipelago is 24,000. The investigators will ensure balance between trial arms with respect to population size, baseline Plasmodium falciparum prevalence and access to health care. All clusters will receive the standard programmatic malaria control interventions implemented by the National Malaria Control Programme which includes insecticide-treated nets (ITN), intermittent preventative treatment in pregnancy (IPTp), seasonal malarial chemoprophylaxis (SMC) for children aged 3-59 months and case diagnosis and treatment (CDT) with Artemether-lumefantrine.

Malaria,Falciparum, Neglected Tropical Diseases, Strongyloidiasis, Lymphatic Filariasis, Scabies, Hook Worm, Soil Transmitted Helminths

Vector Control, Mass Drug Administration, Integrated Disease Control, Malaria, Guinea Bissau, West Africa, Antimalarials, Ivermectin, Dihydroartemisinin, Piperaquine

An independent statistician will randomize the clusters to DP+IVM or DP+Placebo. The Placebo is identical in size, shape and colour and packaging. An independent pharmacist at Medical Research Council Unit The Gambia @ London School of Hygiene and Tropical Medicine will label the IVM and Placebo according to the statistician's designation and maintain the masking from all other investigators. Specifically generated masking codes will be generated and saved in three separate encrypted locations securely. Only the statistician and the pharmacist will have access to the encryption key.

Ivermectin and Dihydroartemisinin-piperaquine MDA will be given to all eligible participants in each cluster (island) in addition to the standard national malaria control programme interventions.

Placebo and Dihydroartemisinin-piperaquine MDA will be given to all eligible participants in each cluster (island) in addition to the standard national malaria control programme interventions.

Ivermectin will be given as tablets of 3 or 6mg. It will be given at 300-400μg/kg/day for 3 days (to the nearest whole tablet) each month for 3 months. It will be taken on an empty stomach with water.

Placebo will be given as tablets of 3 or 6mg (identical to Ivermectin in colour, size, shape and packaging). It will be given at 300-400μg/kg/day for 3 days (to the nearest whole tablet) each month for 3 months. It will be taken by mouth with water and without food.

Dihydroartemisinin-piperaquine will be given as tablets of 320/40mg (adult) and 160/20mg (child) piperaquine/dihydroartemisinin per tablet. Administration of a full course of dihydroartemisinin-piperaquine will be given in accordance with the manufacturer's guidelines once daily for 3 days each month for 3 months according to body weight. Dihydroartemisinin-piperaquine will be taken by mouth with water and without food.

Prevalence of infection with Plasmodium falciparum in all age groups estimated using a cross-sectional survey sample conducted during peak transmission season after 2 years of intervention

Vector parous rate will be determined by assessment of mosquitoes trapped 7-14 days following MDA. Vector parity will be used to determine Anopheles gambiae age structure to estimate vector survival between arms.

Prevalence of infection with Plasmodium falciparum in all age groups estimated using a cross-sectional survey sample conducted after the first year of intervention

Incidence of clinical malaria diagnosed at health facilities confirmed by malaria Rapid Diagnostic Test

Incidence of clinical malaria confirmed by malaria Rapid Diagnostic Test in a cohort of 50 children per cluster aged 5-14 years

Mean Median Fluorescence Intensity of serological markers associated with recent exposure to Plasmodium falciparum in all age groups estimated using a cross-sectional survey sample during peak transmission season after each year of intervention

Species characterisation using nucleic acid amplification tests as a proportion of total mosquitoes caught in traps

Mean Median Fluorescence Intensity of serological markers associated with exposure to Anopheles salivary antigen in all age groups estimated using a cross-sectional survey sample

Proportion of Plasmodium falciparum circumsporozoite antibody (CSP) positive mosquitoes caught in traps

Prevalence of IVM-susceptible NTDs (scabies, strongyloides, other soil-transmitted helminths and lymphatic filariasis) and head lice using clinical and serological parameters estimated using a cross-sectional survey sample during the dry season after two years of intervention.

Prevalence of resistance to artemisinin and partner drugs in humans using molecular markers of resistance in all age groups estimated using a cross-sectional survey sample

Inclusion Criteria: Age over six months to receive dihydroartemisinin-piperaquine Height over 90cm or weight over 15kg to receive ivermectin or placebo Willingness to adhere to trial procedures Individual written, informed consent from the participant or parent/guardian in the case of participants below the age of 18 years (and assent in young people between the ages of 12 and 17 years of age) Exclusion Criteria: Known severe chronic illness (AIDS, Tuberculosis, chronic malnutrition) Known hypersensitivity to either dihydroartemisinin-piperaquine or ivermectin Pregnancy (any trimester) and breastfeeding (for ivermectin (or placebo)) and pregnancy (first trimester only) (for dihydroartemisinin-piperaquine) Travel to a Loa loa endemic country (eg Central African Republic) (for ivermectin (or placebo)) Concomitant drugs that influence cardiac function or affect the corrected QT interval (for dihydroartemisinin-piperaquine)

There is a manuscript in preparation detailing the study protocol and statistical analysis plan. The participant information and and informed consent form may be requested from the trial research team. Results and a clinical study report will be made available within six months of completion of the trial. Analytic code will be made available under a Creative Commons license. Publication of results will be open-access and available in pre-print on MedRxiv (The Preprint Server for Health Sciences).

The study protocol and Statistical Analysis Plan (SAP) will be made available on acceptance of the manuscript for publication. Participant information and Informed Consent Form (ICF) will be made available from recruitment. Results (including Clinical Study Report (CSR)) will be made available within six months of completion of the trial.

Study Protocol and Statistical Analysis Plan (SAP) will be published in an Open Access peer-reviewed journal. The participant information and and informed consent form may be requested from the trial research team. Results and a clinical study report will be made available within six months of completion of the trial. Analytic code will be made available under a Creative Commons license. Publication of results will be Open-Access and available in pre-print on MedRxiv (The Preprint Server for Health Sciences).