P. Falciparum Infection Dynamics and Transmission to Inform Elimination

Study Overview
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Brief Summary
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In the current study, three experimental approaches aiming at reducing malaria transmission will be tested. The study will cover two transmission season (2019 and 2020) and the interventions will vary by season. More specifically, in the 2019 transmission season (June-December) (Year 1), community case management of malaria (CCM) will be implemented in all eight villages as improved standard of care; in the 2020 transmission season (Year 2), the eight study villages will be divided into 4 study arms. CCM will continue in all villages; two villages will continue with CCM only (Arm 1, control); the three other pairs of villages will receive active fever screening and treatment (Arm 2); monthly mass screening and treatment (MSAT) (Arm 3); and mass drug administration (MDA) during the last 3 months of the dry season (April-June) (Arm 4). For MDA, the whole population (except for those not fulfilling the entry criteria) will be treated with a full course of dihydroartemisinin-piperaquine (DP) (320/40mg and 160/20mg piperaquine/ dihydroartemisinin per tablet) per manufacturer's guidelines (once daily for 3 days and according to body weight). The MDA treatment will be repeated 3 times at monthly intervals.

Detailed Description
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In the current study, the investigators will first improve access to care in all villages by implementing community-based clinical case management (CCM) (year 1). In this year, the investigators will quantify gametocyte carriage and transmission from clinical cases passively recruited by CCM, and gametocyte carriage and transmission from asymptomatic infections detected in community surveys. These data will support the interpretation of the main study outcomes in year 2 when the investigators will directly compare the effect of CCM on the human reservoir of infection as compared to three different approaches, namely i) active fever screening and treatment that should detect symptomatic infections for early treatment; ii) Mass Screening and Treatment (MSAT) that will systematically screen, using point-of-care diagnostics, the whole population, with infected individuals immediately treated; and iii) mass drug administration (MDA) that will treat the whole population with a full course of an antimalarial treatment.

Official Title
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P. Falciparum Infection Dynamics and Transmission to Inform Elimination

Conditions
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Malaria

Intervention / Treatment
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* Other: Community Case Management
* Other: Weekly fever screening and treatment
* Other: Monthly malaria screening
* Other: MDA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Resident in the village. Willingness to participate in repeated assessments of health and infection status and to donate a maximum of 30 mL (milliliter) of blood (children <5 years of age), 37 mL (milliliter) of blood (children <10 years of age) or 52 mL (milliliter) of blood (older individuals) during an 18-month period. Exclusion Criteria: Any chronic illness that would affect study participation. Pre-existing severe chronic health conditions History of intolerance to artemether-lumefantrine. Participants < 6months old and pregnant women in the first trimester (only for Arm with MDA-DP treatment). Hypersensitivity to DP (only for Arm with MDA-DP treatment). Taking drugs that influence cardiac function or prolong QTcorrected interval (only for Arm with MDA-DP treatment).

Ages Eligible for Study
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Minimum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: CCM:Standard of Care<br>Community Case Management (CCM), with passively monitored malaria incidence by community health workers using standard RDTs and artemisinin-based combination therapy (ACT), artemether-lumefantrine (AL) according to national guidelines. | |
| Experimental: CCM plus weekly fever screening and treatment<br>CCM plus active case detection (ACD) by fever screening and treatment if positive. Trained village health workers (VHW) recruited for this study will carry out weekly visits of all residents and screen for fever using research-grade thermometers. A standard RDT will be performed in all individuals with a body temperature ≥37.5°C or with reported fever in the last 24 hours. RDT positive individuals will be treated with AL according to national guidelines. | Other: Community Case Management<br>* Community Case Management (CCM), consisting of community health workers able to diagnose malaria by standard RDTs and treating positive individuals with artemether-lumefantrine (AL), according to national guidelines.<br>Other: Weekly fever screening and treatment<br>* Consists of weekly visits by trained VHW who will screen for fever by taking the axillary temperature. If the body temperature is ≥37.5°C, a standard RDT will be performed and, if positive, the individual will be treated with AL, according to national guidelines.<br>|
| Experimental: CCM plus MSAT<br>CCM plus monthly screening for malaria infection and treatment of positive individuals, regardless of symptoms. Screening will be performed by research staff and timed to ensure a gap of 25-35 days between screening rounds; Positive individuals will be treated with AL, according to national guidelines. | Other: Community Case Management<br>* Community Case Management (CCM), consisting of community health workers able to diagnose malaria by standard RDTs and treating positive individuals with artemether-lumefantrine (AL), according to national guidelines.<br>Other: Monthly malaria screening<br>* CCM plus monthly screening of the whole population with high sensitive RDT (HS-RDT); positive individuals will be treated with AL regardless of symptoms (MSAT).<br>|
| Experimental: CCM plus dry season MDA<br>CCM plus plus 3 monthly rounds of MDA with a long-acting ACT (dihydroartemisinin-piperaquine, DP) starting in the dry season (April, May, June) (tablets of 320/40mg and 160/20mg piperaquine/ dihydroartemisinin per tablet. Administration of a full course of DP will be done as per manufacturer's guidelines once daily for 3 days and according to body weight). | Other: Community Case Management<br>* Community Case Management (CCM), consisting of community health workers able to diagnose malaria by standard RDTs and treating positive individuals with artemether-lumefantrine (AL), according to national guidelines.<br>Other: MDA<br>* CCM plus 3 monthly rounds of MDA with dihydroartemisinin-piperaquine (DP) starting during the dry season, before the malaria transmission season starts.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parasite prevalence by molecular detection at the end of study (cross-sectional survey). | The primary outcome measure is parasite prevalence in the cross-sectional survey conducted at the end of the transmission season of year 2. | 16 weeks | 
| Parasite density by molecular detection at the end of study (cross-sectional survey). | The primary outcome measure is parasite density (parasite/µL) in the cross-sectional survey conducted at the end of the transmission season of year 2. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gametocyte prevalence by molecular methods at the end of study (cross-sectional survey). | Gametocyte prevalence in quantitative polymerase chain reaction (qPCR) detected infections is assessed by molecular methods and compared between arms. | 16 weeks | 
| Gametocyte density by molecular methods at the end of study (cross-sectional survey). | Gametocyte density (gametocytes/µL) in qPCR detected infections is assessed by molecular methods and compared between arms. | 16 weeks | 
| Gametocyte prevalence of male and female gametocytes by molecular methods among P. falciparum infections at all study visits. | Gametocyte prevalence of male and female gametocytes will be assessed by molecular methods and compared between study arms. | Throughout study, an average of 18 months | 
| Gametocyte density of male and female gametocytes by molecular methods among P. falciparum infections at all study visits. | Gametocyte density of male and female gametocytes will be assessed by molecular methods and compared between study arms. | Throughout study, an average of 18 months | 
| Incidence of malaria infections | Regular visits by weekly active case detection and monthly screening will result in the identification of malaria infections that are not detected during CCM. Number of infections detected in each arm will be quantified and compared between arms. | Throughout study, an average of 18 months | 
| Infectivity of P. falciparum infections to mosquitoes | For a selection of infections, infectiousness to mosquitoes is assessed by membrane feeding assays. | Throughout study, an average of 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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falciparum, gametocyte, elimination, anopheles, transmission, diagnostic