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

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.

Study Overview

• Status: Recruiting
• Conditions: Malaria
• Intervention / Treatment: Other: Community Case Management; Other: Weekly fever screening and treatment; Other: Monthly malaria screening; Other: MDA

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 4000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chris Drakeley, PhD; Phone Number: +44 (0)20 7927 2289; Email: Chris.drakeley@lshtm.ac.uk
• Study Contact Backup: Name: Umberto D'Alessandro, PhD, MD; Phone Number: +220 4495442/6; Email: udalessandro@mrc.gm

Study Locations

• Gambia
  • Basse Santa Su, Gambia
    • Recruiting
    • Medical research Council Unit The Gambia at LSHTM
    • Contact: Umberto D'Alessandro, PhD, MD; Phone Number: (+220) 449-5442; Email: udalessandro@mrc.gm

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Resident in the village.
2. 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:

1. Any chronic illness that would affect study participation.
2. Pre-existing severe chronic health conditions
3. History of intolerance to artemether-lumefantrine.
4. Participants < 6months old and pregnant women in the first trimester (only for Arm with MDA-DP treatment).
5. Hypersensitivity to DP (only for Arm with MDA-DP treatment).
6. Taking drugs that influence cardiac function or prolong QTcorrected interval (only for Arm with MDA-DP treatment).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: CCM:Standard of Care; 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; 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; 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.; Other: Weekly fever screening and treatment; 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.
Experimental: CCM plus MSAT; 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; 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.; Other: Monthly malaria screening; 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).
Experimental: CCM plus dry season MDA; 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; 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.; Other: MDA; CCM plus 3 monthly rounds of MDA with dihydroartemisinin-piperaquine (DP) starting during the dry season, before the malaria transmission season starts.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The detectability of infections by highly-sensitive rapid diagnostic tests related to histidine rich protein-2 (HRP2) concentrations.	For a selection of samples, the detectability of infections is assessed by highly sensitive rapid diagnostic tests related to histidine rich protein-2 (HRP2) concentrations.	Throughout study, an average of 18 months
The detectability of infections by highly-sensitive rapid diagnostic tests related to duration of infection.	For a selection of samples, the detectability of infections is assessed by highly sensitive rapid diagnostic test and related to duration of infection.	Throughout study, an average of 18 months
The detectability of infections by rapid diagnostic tests related to duration of infection.	For a selection of samples, the detectability of infections is assessed by conventional rapid diagnostic tests and related to duration of infection.	Throughout study, an average of 18 months
The detectability of infections by highly-sensitive rapid diagnostic tests related to parasite density by molecular diagnostics.	The detectability of infections is assessed by highly sensitive rapid diagnostic test and related to parasite density by molecular diagnostics.	Throughout study, an average of 18 months
The detectability of infections by rapid diagnostic tests related to parasite density by molecular diagnostics.	For a selection of samples, the detectability of infections is assessed by conventional rapid diagnostic test and related to parasite density by molecular diagnostics.	Throughout study, an average of 18 months
The relationship between the proportion of infected mosquitoes (Direct Membrane Feeding Assay) and gametocyte density.	Gametocyte density will be assessed by molecular methods and associated with infectivity mosquitoes.	Throughout study, an average of 18 months
The relationship between the proportion of infected mosquitoes (Direct Membrane Feeding Assay) and gametocyte sex-ratio.	Sex-ratio gametocytemia of P. falciparum will be assessed by molecular methods and associated with infectivity in mosquitoes.	Throughout study, an average of 18 months
The effect of infection characteristics (clonal parasite infection) on the transmissibility of infections to mosquitoes.	To determine the impact of duration and complexity of malaria infections on the transmissibility of infections to mosquitoes	Throughout study, an average of 18 months
Gametocyte sex-ratio on the transmissibility of infections to mosquitoes.	To determine the impact of gametocyte sex-ratio on the transmissibility of infections to mosquitoes	Throughout study, an average of 18 months
The impact of human haemoglobinopathies on the transmissibility of infections to mosquitoes.	To determine the impact of red blood cell haemoglobinopathies and haemoglobin concentration on the transmissibility of infections to mosquitoes.	Throughout study, an average of 18 months
Mean fluorescence intensity (MFI) to inflammatory markers and naturally acquired antibody responses to gametocyte antigens on the transmissibility of infections to mosquitoes.	To determine the impact of inflammatory markers and naturally acquired antibody responses to gametocyte antigens and other host characteristics on the transmissibility of infections to mosquitoes.	Throughout study, an average of 18 months
Relationship between total parasite density (parasite/µL) and gametocyte density (gametocytes/µL)	To assess the relationship between asexual parasite density and gametocyte density in P. falciparum infections	Throughout study, an average of 18 months
Malaria transmission potential based on measured gametocyte densities (gametocytes/µL).	To determine malaria transmission potential of infections based on the gametocyte density	Throughout study, an average of 18 months
Number of acquired parasite clones based on genotyping.	Under this outcome, we aim to examine the complexity of P. falciparum infection by measuring the number of clones present in infections	Throughout study, an average of 18 months
Number of days that P. falciparum infections last in the dry season.	To evaluate the duration of P. falciparum carriage during the dry season, routine follow-up will be performed.	Up to 6 months
Mosquito exposure monitored by monthly CDC-light traps (CDC-LT) and Human landing catches (HLC) mosquito collections	For the quantification of the mosquito exposure, indoor and outdoor mosquito collections will be performed monthly during transmission and dry season.	Throughout study, an average of 18 months
Mean fluorescence intensity (MFI) antibody responses to mosquito saliva proteins during high and low transmission season.	To determine the exposure to Anopheles bites with serological markers of malaria infection.	Throughout study, an average of 18 months
Number of infections in community surveys that can be linked to a symptomatic or asymptomatic parent infection.	This outcome allow bridging mosquito feeding studies with actual transmission events in communities and at the same time quantify the relevance of infections associated with movement.	Throughout study, an average of 18 months
Number of human host from mosquito blood meal source.	To quantify the transmission potential of individuals by identification of human blood source by molecular typing.	Up to 12 months

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: Radboud University Medical Center; University of California, San Francisco; Medical Research Council Unit, The Gambia; National Malaria Control Programme, The Gambia; Institute for Disease Modeling
• Investigators: Principal Investigator: Teun Bousema, PhD, Radboud University Medical Centre, Nijmegen, The Netherlands; Principal Investigator: Chris Drakeley, PhD, London School Hygiene and Tropical medicine; Principal Investigator: Umberto D'Alessandro, PhD, MD, MRC Unit The Gambia @ LSHTM

Study record dates

Study Major Dates

• Study Start (Actual): August 15, 2019
• Primary Completion (Anticipated): May 31, 2022
• Study Completion (Anticipated): May 31, 2022

Study Registration Dates

• First Submitted: July 29, 2019
• First Submitted That Met QC Criteria: August 8, 2019
• First Posted (Actual): August 13, 2019

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 25, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: diagnostic; falciparum; transmission; elimination; gametocyte; anopheles
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Malaria
• Other Study ID Numbers: 16642; OPP1173572 (Other Grant/Funding Number: Bill and Melinda Gates Foundation (BMGF))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Anonymised individual participant data may be shared on a digital repository or upon reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No