P. Falciparum Infection Dynamics and Transmission to Inform Elimination (INDIE-1a)

Centre national de recherche et de formation sur le paludisme, Radboud University Medical Center, Institute for Disease Modeling, Bellevue, US

In the current randomized trial, the investigators will test the ability of two experimental approaches to malaria infection management to reduce malaria transmission potential. Compounds in Saponé, Burkina Faso, will be randomized to 1 of 3 study arms: arm 1 - current standard of care with passively monitored malaria infections; arm 2 - standard of care plus enhanced community case management (CCM), comprising active weekly screening for fever, and detection and treatment of infections in fever positive individuals using conventional rapid diagnostic tests (RDTs); or arm 3 - standard of care and enhanced CCM, plus monthly screening and treatment (MSAT) using RDTs. The study will be conducted over approximately 18 months covering two high transmission seasons and the intervening dry season

Standard of care with passively monitored malaria incidence at health centers that receive appropriate diagnostic and clinical supplies and Seasonal Malaria Chemoprevention (SMC) for children less than 5 years of age

Standard of care supplemented with enhanced Community Case Management for malaria (CCM) involving weekly active screening for fever using a research-grade thermometer by a trained health worker. A measured temperature ≥37.5°C or reported fever in the last 24 hours will prompt screening with a conventional rapid diagnostic test (RDT). RDT positive individuals will be treated with artemether-lumefantrine (AL) according to national guidelines

Standard of Care supplemented with CCM and Monthly Screening and Treatment (MSAT) regardless of symptoms with a conventional RDT. Screening will be performed by research staff with 25-35 days between screening rounds; RDT positive individuals will be treated with AL according to national guidelines.

Enhanced Community Case Management for malaria (CCM) involving weekly active screening for fever using a research-grade thermometer by a trained health worker. A measured temperature ≥37.5°C or reported fever in the last 24 hours will prompt screening with a conventional rapid diagnostic test (RDT). RDT positive individuals will be treated with AL according to national guidelines

Monthly Screening and Treatment (MSAT) regardless of symptoms with a conventional RDT. Screening will be performed by research staff with 25-35 days between screening rounds; RDT positive individuals will be treated with AL according to national guidelines.

The primary outcome measure is parasite prevalence in the cross-sectional survey conducted at the end of the transmission season of year 2. If CCM and MSAT result in the early detection of infections, parasite prevalence at the end of the study will be lower in these arms compared to the control arm.

Parasite prevalence and density in the cross-sectional survey conducted at the end of the transmission season of year 1. If CCM and MSAT result in the early detection of infections, parasite prevalence will be lower in these arms compared to the control arm.

Parasite prevalence and density by molecular detection at the end of dry season cross-sectional survey.

Parasite prevalence and density in the cross-sectional survey conducted at the end of the dry season. If CCM and MSAT result in the early detection of infections, parasite prevalence will be lower in these arms compared to the control arm.

Gametocyte prevalence and or density in P. falciparum infections at the end of study cross-sectional survey

Gametocyte prevalence in qPCR detected infections is assessed by molecular methods and compared between study arms.

Gametocyte prevalence and or density in P. falciparum infections at the end of year 1 cross-sectional survey

Gametocyte density of male and female gametocytes will be assessed by molecular methods and compared between study arms.

Gametocyte prevalence and or density in P. falciparum infections at the end of dry season cross-sectional survey

Gametocyte density of male and female gametocytes will be assessed by molecular methods and compared between study arms.

Gametocyte density of male and female gametocytes will be assessed by molecular methods and compared between study arms.

Regular visits by CCM and MSAT will result in the identification of malaria infections that are not detected during passive case detection. The numbers of infections that are detected in each arm are quantified and compared between arms.

For a selection of samples, the detectability of infections is assessed by conventional rapid diagnostic test and by highly sensitive rapid diagnostic tests and related to i. histidine rich protein-2 (HRP2) concentrations; ii. duration of infection; iii. parasite density by molecular diagnostics.

Gametocyte density and sex ratio will be assessed by molecular methods and associated with the proportion of infected mosquitoes and the burden of infection in mosquitoes

Under this outcome, we aim to determine the impact of gametocyte sex-ratio, other gametocyte characteristics, duration of infection and clonal complexity of malaria infections on the transmissibility of infections to mosquitoes

Under this outcome, we aim to determine the impact of red blood cell haemoglobinopathies, haemoglobin concentration, inflammatory markers, naturally acquired antibody responses to gametocyte antigens and other host characteristics on the transmissibility of infections to mosquitoes

Under this outcome, we aim to evaluate the relationship between asexual parasite density and gametocyte density in P. falciparum infections

Under this outcome, we aim to determine malaria transmission potential of infections based on the gametocyte density

Under this outcome, we aim to examine the complexity of P. falciparum infection by measuring the number of clones present in infections

Month 6-12, between end of season survey January/February 2019 and end of dry season survey June 2019

Under this outcome, we aim to quantify mosquito exposure and relate this to number of incident infections

Inclusion Criteria: Participants should be permanent residents of the compound Participants should be willing to participate in repeated assessments of health and infection status and willing to donate a maximum of 37mL of blood (children <10 years of age) or 52mL of blood (older individuals) during an 18-month period Exclusion Criteria: Any (chronic) illness that would affect with study participation Pre-existing severe chronic health conditions Current participation in malaria vaccine trials or participation in such trials in the last 2 years History of intolerance to artemether-lumefantrine

London School of Hygiene and Tropical Medicine, Faculty of Infectious and Tropical Diseases, London, United Kingdom

Anonymised individual participant data may be shared on a digital repository or upon reasonable request.

Collins KA, Ouedraogo A, Guelbeogo WM, Awandu SS, Stone W, Soulama I, Ouattara MS, Nombre A, Diarra A, Bradley J, Selvaraj P, Gerardin J, Drakeley C, Bousema T, Tiono A. Investigating the impact of enhanced community case management and monthly screening and treatment on the transmissibility of malaria infections in Burkina Faso: study protocol for a cluster-randomised trial. BMJ Open. 2019 Sep 13;9(9):e030598. doi: 10.1136/bmjopen-2019-030598.