Clinical trial NCT05219565: Evaluating ATSBs for Malaria Reduction in Kenya
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Malaria
Keywords: ATSB
Malaria
Kenya
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
Collaborators: name: Kenya Medical Research Institute
name: Centers for Disease Control and Prevention
name: PATH
name: Kenya Ministry of Health
First posted: 2022-02-02
Enrollment: 2962
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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. In year one the first and second cohort were enrolled and followed up over 6 months each. In year 2, the third cohort was enrolled and followed up over 1 year.
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Clinical malaria
timeFrame: Two years
Secondary outcomes:
measure: Time to first malaria infection by PCR
timeFrame: Two years
measure: Malaria infection incidence by RDT (pLDH)
timeFrame: Two years
measure: Malaria infection prevalence by RDT (pLDH)
timeFrame: Two years
measure: Incidence of malaria illness (passive surveillance)
timeFrame: Two years
measure: Incidence of non-malaria illness (cohort)
timeFrame: Two years
measure: Incidence of non-malaria illness (passive surveillance)
timeFrame: Two years
measure: Prevalence of non-malaria illness
timeFrame: Two years
measure: Malaria vector density
timeFrame: Two years
measure: Proportion of female anopheles mosquitoes older than three gonotrophic cycles,
timeFrame: Two years
measure: Sporozoite rate
timeFrame: Two years
measure: Entomological Inoculation Rate (EIR)
timeFrame: Two years
measure: Non-Target Organisms (NTOs) attracted to ATSBs
timeFrame: Two years
measure: Markers of insecticide resistance (dinotefuran)
timeFrame: Two years
measure: Markers of insecticide resistance (permethrin)
timeFrame: Two years
measure: Markers of insecticide resistance (deltamethrin)
timeFrame: Two years
measure: Antibody concentrations against malaria antigen MSP-1
timeFrame: Two years
measure: Antibody concentrations against malaria antigen CSP
timeFrame: Two years
measure: Complexity of infection (COI)
timeFrame: Two years
measure: Mosquito salivary antigens
timeFrame: Two years
measure: AEs
timeFrame: Two years
measure: ATSB removal rate
timeFrame: Two years
measure: Perceptions of ATSBs
timeFrame: Two years
measure: Household use of LLINs in the setting of ATSBs
timeFrame: Two years
measure: Household care seeking behavior in the setting of ATSBs
timeFrame: Two years
measure: Cost-effectiveness
timeFrame: Two years
Other outcomes:
Locations:
city: Siaya
country: Kenya
facility: Naya Health Centre
state: Siaya County
city: Siaya
country: Kenya
facility: Benga Dispensary
state: Siaya County
city: Siaya
country: Kenya
facility: Boro Dispensary
state: Siaya County
city: Siaya
country: Kenya
facility: Manyuanda Health Centre
state: Siaya County
city: Siaya
country: Kenya
facility: Nyadhi Dispensary
state: Siaya County
city: Siaya
country: Kenya
facility: Ong'ielo Model Health Centre
state: Siaya County
city: Siaya
country: Kenya
facility: Rabar Dispensary
state: Siaya County
city: Siaya
country: Kenya
facility: Rageng'ni Dispensary
state: Siaya County
city: Siaya
country: Kenya
facility: Rambugu Dispensary
state: Siaya County
Study officials:
affiliation: Centers for Disease Control and Prevention
name: Aaron Samuels, MD, MHS
role: PRINCIPAL_INVESTIGATOR
affiliation: Kenya Medical Research Institute
name: Eric Ochomo
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huho B, Briet O, Seyoum A, Sikaala C, Bayoh N, Gimnig J, Okumu F, Diallo D, Abdulla S, Smith T, Killeen G. Consistently high estimates for the proportion of human exposure to malaria vector populations occurring indoors in rural Africa. Int J Epidemiol. 2013 Feb;42(1):235-47. doi: 10.1093/ije/dys214. Epub 2013 Feb 9.
citation: Amek N, Bayoh N, Hamel M, Lindblade KA, Gimnig JE, Odhiambo F, Laserson KF, Slutsker L, Smith T, Vounatsou P. Spatial and temporal dynamics of malaria transmission in rural Western Kenya. Parasit Vectors. 2012 Apr 28;5:86. doi: 10.1186/1756-3305-5-86.
citation: Moiroux N, Damien GB, Egrot M, Djenontin A, Chandre F, Corbel V, Killeen GF, Pennetier C. Human exposure to early morning Anopheles funestus biting behavior and personal protection provided by long-lasting insecticidal nets. PLoS One. 2014 Aug 12;9(8):e104967. doi: 10.1371/journal.pone.0104967. eCollection 2014.
citation: Sougoufara S, Diedhiou SM, Doucoure S, Diagne N, Sembene PM, Harry M, Trape JF, Sokhna C, Ndiath MO. Biting by Anopheles funestus in broad daylight after use of long-lasting insecticidal nets: a new challenge to malaria elimination. Malar J. 2014 Mar 28;13:125. doi: 10.1186/1475-2875-13-125.
citation: Killeen GF. Characterizing, controlling and eliminating residual malaria transmission. Malar J. 2014 Aug 23;13:330. doi: 10.1186/1475-2875-13-330.
citation: Killeen GF, Marshall JM, Kiware SS, South AB, Tusting LS, Chaki PP, Govella NJ. Measuring, manipulating and exploiting behaviours of adult mosquitoes to optimise malaria vector control impact. BMJ Glob Health. 2017 Apr 26;2(2):e000212. doi: 10.1136/bmjgh-2016-000212. eCollection 2017.
citation: Zhu L, Muller GC, Marshall JM, Arheart KL, Qualls WA, Hlaing WM, Schlein Y, Traore SF, Doumbia S, Beier JC. Is outdoor vector control needed for malaria elimination? An individual-based modelling study. Malar J. 2017 Jul 3;16(1):266. doi: 10.1186/s12936-017-1920-y.
citation: Traore MM, Junnila A, Traore SF, Doumbia S, Revay EE, Kravchenko VD, Schlein Y, Arheart KL, Gergely P, Xue RD, Hausmann A, Beck R, Prozorov A, Diarra RA, Kone AS, Majambere S, Bradley J, Vontas J, Beier JC, Muller GC. Large-scale field trial of attractive toxic sugar baits (ATSB) for the control of malaria vector mosquitoes in Mali, West Africa. Malar J. 2020 Feb 14;19(1):72. doi: 10.1186/s12936-020-3132-0.
citation: Beier JC, Muller GC, Gu W, Arheart KL, Schlein Y. Attractive toxic sugar bait (ATSB) methods decimate populations of Anopheles malaria vectors in arid environments regardless of the local availability of favoured sugar-source blossoms. Malar J. 2012 Feb 1;11:31. doi: 10.1186/1475-2875-11-31.
citation: Fiorenzano JM, Koehler PG, Xue RD. Attractive Toxic Sugar Bait (ATSB) For Control of Mosquitoes and Its Impact on Non-Target Organisms: A Review. Int J Environ Res Public Health. 2017 Apr 10;14(4):398. doi: 10.3390/ijerph14040398.
citation: Marshall JM, White MT, Ghani AC, Schlein Y, Muller GC, Beier JC. Quantifying the mosquito's sweet tooth: modelling the effectiveness of attractive toxic sugar baits (ATSB) for malaria vector control. Malar J. 2013 Aug 23;12:291. doi: 10.1186/1475-2875-12-291.
citation: Pocock SJ. When (not) to stop a clinical trial for benefit. JAMA. 2005 Nov 2;294(17):2228-30. doi: 10.1001/jama.294.17.2228. No abstract available.
citation: Protopopoff N, Mosha JF, Lukole E, Charlwood JD, Wright A, Mwalimu CD, Manjurano A, Mosha FW, Kisinza W, Kleinschmidt I, Rowland M. Effectiveness of a long-lasting piperonyl butoxide-treated insecticidal net and indoor residual spray interventions, separately and together, against malaria transmitted by pyrethroid-resistant mosquitoes: a cluster, randomised controlled, two-by-two factorial design trial. Lancet. 2018 Apr 21;391(10130):1577-1588. doi: 10.1016/S0140-6736(18)30427-6. Epub 2018 Apr 11.
citation: Gimnig JE, Walker ED, Otieno P, Kosgei J, Olang G, Ombok M, Williamson J, Marwanga D, Abong'o D, Desai M, Kariuki S, Hamel MJ, Lobo NF, Vulule J, Bayoh MN. Incidence of malaria among mosquito collectors conducting human landing catches in western Kenya. Am J Trop Med Hyg. 2013 Feb;88(2):301-8. doi: 10.4269/ajtmh.2012.12-0209. Epub 2012 Dec 18.
citation: Attractive Targeted Sugar Bait Phase III Trial Group. Attractive targeted sugar bait phase III trials in Kenya, Mali, and Zambia. Trials. 2022 Aug 9;23(1):640. doi: 10.1186/s13063-022-06555-8.