Evaluating ATSBs for Malaria Reduction in Kenya

Study Overview
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Brief Summary
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The effectiveness of long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) in western Kenya are threatened by insecticide resistance and vector behaviour changes toward early evening and outdoor biting malaria vectors. New tools to control malaria are needed to reduce and even interrupt malaria transmission. Attractive Targeted Sugar Bait (ATSB) is a promising new intervention designed to attract and kill mosquitoes, including those that IRS and LLINs do not effectively target. The ATSB 'bait stations' are A4-sized panels containing thickened fruit syrup laced with a neonicotinoid insecticide, dinotefuran, to attract and kill the foraging vectors. Entomological field trials in western Mali showed that ATSBs successfully reduce mosquito densities and longevity and thus have the potential to reduce malaria transmission. In Kenya, the investigators will conduct an open-label cluster-randomized controlled trial in 80 village clusters (40 per arm) to evaluate the effect of ATSBs on the burden of malaria. During two years, households in half of these village clusters will receive two or three ATSB bait stations per household structure on exterior walls approximately 1.8 meters above the ground. ATSBs will be replaced every six months. The primary outcome will be the incidence of clinical malaria in children aged 1-<15 years enrolled in a prospective cohort followed monthly for about six months each during a 2-year period. Secondary outcomes include malaria infection prevalence assessed by rapid diagnostic tests through household surveys and the case burden of clinical malaria assessed by passive facility-based and community-based surveillance. The study includes entomological monitoring and nested acceptability, feasibility, and health economics studies. The stand-alone trial in western Kenya is a part of a multi-country ATSB consortium conducting similar trials in Zambia and Mali.

Detailed Description
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The current malaria vector control tools, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) are critically important and have saved many lives. However, their effectiveness in western Kenya is threatened by insecticide resistance and vector behaviour changes toward more early evening and outdoor biting malaria vectors. LLINs and IRS specifically target indoor-biting and indoor-resting mosquitoes. Malaria vectors exhibit different behavioural characteristics that mitigate the effectiveness of vector control strategies. For example, traditionally, An. gambiae s.s. has been regarded as human-biting with late-night indoor-feeding and indoor-resting behaviours, while An. Arabiensis is found more often in drier environments and is more zoophagic with outdoor biting and resting behaviours. Following LLINs and IRS's widespread scale-up, the dominant African vectors' distributions and behaviours changed with An. gambiae s.s. and An. Funestus (also an indoor human biter) diminishing in abundance relative to An. arabiensis. Subsequently, shifts towards earlier evening biting by An. Gambiae s.s. (before people enter houses to sleep under LLINs) and later biting by An. Funestus (biting in the morning after sunrise) are examples of behavioural plasticity enabling these species to avoid contact with the LLIN and IRS insecticides. There is a need for interventions that supplement and complement LLINs and IRS by killing mosquitoes outside houses using other biologic mechanisms (e.g., targeting sugar feeding behaviour). Furthermore, insecticides are required with novel modes of action that may restore sensitivity to pyrethroids by killing both pyrethroid-resistant and sensitive mosquitoes. Attractive Targeted Sugar Bait (ATSB) (the name was recently changed from Attractive Toxic Sugar Bait to highlight that it targets malaria vectors) is a promising new intervention that potentially fills the need for outdoor interventions with novel killing effects. ATSB 'bait stations' are A4-sized panels containing thickened fruit syrup laced with a neonicotinoid insecticide (dinotefuran) to attract and kill the foraging vectors. Entomological field trials in Mali showed that ATSBs successfully reduce mosquito densities and longevity and thus have the potential to reduce malaria transmission. Large scale efficacy studies are now needed to establish the efficacy of ATSB for controlling malaria transmission.

Official Title
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Phase III, Open-label, Community-based, Cluster Randomised Controlled Trial to Evaluate the Efficacy, Cost-effectiveness, and Acceptability of Attractive Targeted Sugar Baits (ATSB) for Malaria Burden Reduction in Western Kenya

Conditions
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Malaria

Intervention / Treatment
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* Device: Attractive Targeted Sugar Bait (ATSB)


Participation Criteria
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Eligibility Criteria
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Eligibility criteria for clusters: Inclusion criteria A grouping of contiguous rural villages in Alego-Usonga and Rarieda sub-counties of Siaya County A minimum of 200 households Eligibility criteria for clusters: Exclusion criteria Hard to reach in the rainy season Refusal to participate by village elders Eligibility criteria for participants in the cohort study: Inclusion criteria A resident of a household within the core area of a study cluster, defined as living in the household in the recent four months and planning to live in the same household for the next 6.5 months Aged ≥ 1 year and < 15 years at the time of enrollment Written informed consent and/or assent Eligibility criteria for participants in the cohort study: Exclusion criteria A confirmed or suspected pregnancy. Pregnant women are excluded because they are eligible for intermittent preventive treatment of malaria in pregnancy (IPTp). Taking daily cotrimoxazole prophylaxis (because this has antimalarial effects) Known sickle cell disease (because they received antimalarial prophylaxis) Contraindication to artemether-lumefantrine, the medication used for parasite clearance Eligibility criteria for households for ATSB deployment: Inclusion criteria --Households located within one of the 40 clusters (core or buffer area) randomly allocated to the trial intervention arm with a least one permanent resident Eligibility criteria for households for ATSB deployment: Exclusion criteria Refusal of consent by the head-of-household to deploy ATSB on the outer walls (intervention villages only) Vacated compounds Eligibility criteria for households for entomological monitoring: Inclusion criteria Household located within the core area of the cluster Head of household or his/her representative is at least 18 years of age Written informed consent for the collection of entomological data by the head of household or representative Eligibility criteria for households for entomological monitoring: Exclusion criteria --No residents sleeping in the household during the planned night of monitoring Eligibility criteria for human landing catches: Inclusion criteria Men aged 18 to 49 years Willingness and ability to work late at night for up to 7 hours at a time Willingness to take and tolerate a treatment regimen of the appropriate Kenya Ministry of Health (MoH) recommended antimalarial and chemoprophylaxis with 250 mg of mefloquine weekly to prevent malaria starting two weeks before the start of and until four weeks after completing HLCs Written informed consent Eligibility criteria for human landing catches: Exclusion criteria Refusal/inability to work late at night for up to 7 hours at a time Unwillingness to take or intolerance/allergy to appropriate MoH treatment regimen or chemoprophylaxis Eligibility criteria for participants in rapid ethnographic methods evaluation (community members): Inclusion criteria A resident of a household within an intervention area defined as an ATSB area during the main trial or an ASB area during any preliminary studies Resides in a household at the time of ASB/ATSB deployment, where the ASB/ATSB was installed for at least one month. 18 years of age or older if participating in focus group discussions; 15 years of age or older if participating in in-depth interviews Eligibility criteria for participants in rapid ethnographic methods evaluation (community members): Exclusion criteria --Unable to provide consent Eligibility criteria for participants in rapid ethnographic methods evaluation (ATSB monitoring assistants): Inclusion criteria Inclusion criteria ethnographic evaluation (ATSB monitoring assistants) Serving as an ATSB monitoring assistant with experience installing ATSBs and monitoring the deployment Eighteen years of age or older Eligibility criteria for participants in rapid ethnographic methods evaluation (ATSB monitoring assistants): Exclusion criteria Less than one month experience (i.e. is new to the job) Unable to provide consent

Ages Eligible for Study
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Minimum Age: 1 Year

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Using restricted randomization criteria, eighty clusters will be randomized 1:1 to either the intervention arm (ATSBs deployed throughout the cluster) or the control arm. The clusters will be followed in parallel for two years.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Attractive Targeted Sugar Bait (ATSB)<br>Clusters within the ATSB arm will have 2 to 3 ATSBs hung on all eligible structures in the cluster where consent from the corresponding compound has been given. | Device: Attractive Targeted Sugar Bait (ATSB)<br>* An ATSB is a A4-sized panel containing thickened fruit syrup laced with a neonicotinoid insecticide, dinotefuran. The syrup-insecticide mixture is covered with a protective membrane that allows mosquitoes to feed through the membrane while preventing non-target organisms from feeding. This device is designed to attract and kill mosquitoes.<br>* Other names: Attractive Toxic Sugar Bait;|
| No Intervention: Control<br>Clusters within the control arm will not receive ATSBs. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical malaria | The incidence rate of clinical malaria defined as current fever (axillary temperature of ≥37.5°C) or history of fever in last 48 hours and a positive rapid diagnostic test (RDT, pLDH or HRP2), in children aged 1-<15 years enrolled in the cohort study | Two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first malaria infection by PCR | The time to first malaria infection assessed by PCR in children aged 1-<15 years enrolled in a cohort study | Two years | 
| Malaria infection incidence by RDT (pLDH) | The incidence rate of malaria infection detected by RDT (pLDH) in children aged 1-<15 years enrolled in a cohort study | Two years | 
| Malaria infection prevalence by RDT (pLDH) | The prevalence of malaria infection detected by RDT (pLDH) in cross-sectional household surveys | Two years | 
| Incidence of malaria illness (passive surveillance) | The incidence rate of malaria illness (sick-visit with a positive malaria rapid diagnostic test or microscopy) assessed by health-facility and community-based surveillance | Two years | 
| Incidence of non-malaria illness (cohort) | The incidence rate of non-malaria illness in children aged 1-<15 years enrolled in a cohort study | Two years | 
| Incidence of non-malaria illness (passive surveillance) | The incidence rate of non-malaria illness assessed by health-facility and community-based surveillance | Two years | 
| Prevalence of non-malaria illness | The prevalence of non-malaria illness in cross-sectional household surveys | Two years | 
| Malaria vector density | Entomological outcome: Malaria vector densities | Two years | 
| Proportion of female anopheles mosquitoes older than three gonotrophic cycles, | Entomological outcome: The proportion of female anopheles mosquitoes older than three gonotrophic cycles. | Two years | 
| Sporozoite rate | Entomological outcomes: Sporozoite rate | Two years | 
| Entomological Inoculation Rate (EIR) | Entomological outcome: Entomological Inoculation Rate (EIR) | Two years | 
| Non-Target Organisms (NTOs) attracted to ATSBs | Entomological outcome: Proportion of monitoring visits where NTOs were observed on bait stations | Two years | 
| Markers of insecticide resistance (dinotefuran) | Entomological outcome: Proportion of mosquitoes with resistance to dinotefuran among total mosquitoes collected in 4 WHO mosquito tubes in the trial area | Two years | 
| Markers of insecticide resistance (permethrin) | Entomological outcome: Proportion of mosquitoes with resistance to permethrin among total mosquitoes collected in 4 WHO mosquito tubes in the trial area | Two years | 
| Markers of insecticide resistance (deltamethrin) | Entomological outcome: Proportion of mosquitoes with resistance to deltamethrin among total mosquitoes collected in 4 WHO mosquito tubes in the trial area | Two years | 
| Antibody concentrations against malaria antigen MSP-1 | Antibody concentration against merozoite surface protein-1 (MSP-1) among cohort participants | Two years | 
| Antibody concentrations against malaria antigen CSP | Antibody concentration against circumsporozoite proteins (CSP) among cohort participants | Two years | 
| Complexity of infection (COI) | The complexity of (malaria) infection assessed by molecular markers, including, but not limited to, 24-single-nucleotide polymorphisms (24-SNP) barcodes | Two years | 
| Mosquito salivary antigens | Presence of mosquito salivary antigens in human blood as a measure for mosquito biting rates among cohort participants | Two years | 
| AEs | Number of adverse events associated with misuse of ATSBs. | Two years | 
| ATSB removal rate | The proportion of ATSBs that have been moved/removed | Two years | 
| Perceptions of ATSBs | The proportion of household heads who perceive ATSBs as safe and effective out of all household head who consented to ATSB deployment on their household structures. | Two years | 
| Household use of LLINs in the setting of ATSBs | The proportion of children aged 1-<15 years enrolled in a cohort study who used an LLIN the night prior | Two years | 
| Household care seeking behavior in the setting of ATSBs | The proportion of children aged 1-<15 years enrolled in a cohort study who sought care for febrile illness | Two years | 
| Cost-effectiveness | Incremental cost-effectiveness of ATSB above the standard of care measured through costing of intervention and efficacy outcomes | Two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ATSB, Malaria, Kenya