Clinical trial NCT04149119: Attractive Targeted Sugar Bait Trial in Mali
Official title: Attractive Targeted Sugar Bait Phase III Trial in Mali
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Vector Transmission
Keywords: Malaria
Vector control
ATSB
Transmission
Mali
Lead sponsor: University Clinical Research Center, Mali
Sponsor class: OTHER
First posted: 2019-11-04
Enrollment: 2100
Sex: ALL
Minimum age (years): 5
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: An open-label two-arm cluster randomized controlled trial (CRCT) design will be used comparing ATSB + LLINS vs LLINS alone (standard of care). A cluster trial design is indicated given the intended community-level effect of ATSBs on malaria transmission. Universal LLIN coverage will be ensured in both arms prior to start of the study and will serve as the standard of care. Arm 1 will receive ATSBs for two years. Arm 2 will receive the standard of care of universal LLIN coverage.

The incidence cohorts will be powered to detect a 30% reduction in incidence assuming follow-up over a two year period (see sample size section). Prevalence of infection will be powered to detect a 30% lower prevalence in the treatment arm of of the trial during each of the two post randomisation cross sectional surveys.
Primary purpose: PREVENTION

Brief summary: Globally, the female mosquitoes to be effective at transmitting malaria parasites, must have a number of characteristics including: abundance, longevity (individual mosquitoes must survive long enough after feeding on infected blood to allow the parasite time to develop and travel to the mosquito's salivary glands), capacity (each female mosquito must be both susceptible to infection with Plasmodium and able to carry enough malaria parasites in the salivary glands), contact with humans (frequently feed on humans).

Vectors in SSA are often anthropophagic and anthropophilic, and exhibit indoor biting and indoor resting behavior. Highly effective interventions against vectors have been developed and implemented at scale (e.g., indoor Residual Spraying of Insecticides \[IRS\] and Long Lasting Insecticide-treated Nets \[LLINs\]). While these interventions have contributed importantly to the reduction of malaria transmission and disease (68% and 11% respectively), none of them target outdoor-biting g and outdoor-resting mosquitoes. Given the increase in resistance to current generation of insecticides and the behavioral plasticity of vectors that results in continued malaria transmission despite high coverage of LLINs or IRS, there is a need for interventions that can supplement and complement LLINs and IRS by killing mosquitoes outside houses using other biologic mechanisms (e.g., targeting sugar feeding behavior). Finally, insecticides with novel modes of action that may be capable of restoring sensitivity to pyrethroids by killing both pyrethroid resistant and sensitive mosquitoes are required. Attractive Target Sugar Baits (ATSBs) that kill mosquitoes through the ingestion of the toxicant dinotefuran (and possibly by other ingestion toxicants that are effective when ingested) potentially fill the need for outdoor interventions with novel killing effects. This study aims to establish the efficacy and contribution of the ATSBs for controlling malaria transmission where An. gambiae s.l. and An. Funestus are the major vectors for malaria.

Detailed description: The current dominant malaria vector control tools remain critically important and have saved many lives. Yet, they are not well-suited for malaria vectors that avoid contact with indoor insecticides by predominantly biting outdoors, by frequently biting animals, and by resting outdoors or remaining within houses only briefly when they do enter. These behaviors allow residual populations of vector mosquitoes to survive, expand, and to increasingly contribute to malaria transmission, despite high coverage. These vectors can sustain endemic transmission even if they rarely bite humans. An. arabiensis is a particularly important source of persistent residual transmission despite Long Lasting Insecticide-treated Net (LLIN) scale-up; this mosquito prefers to feed on animals, and, often bites and rests outside, and has limited indoor exposure. There is need for new vector control tools to target residual outdoor transmission.

In addition to the biological need for female Anopheles species to take a blood meal to obtain protein necessary for egg production, all Anopheles must feed regularly and frequently on liquid and carbohydrates (sugars) to survive. Common sources of liquid and sugar meals include plant tissue and floral nectar. Mosquitoes are guided to sugar sources by chemical attractants. The Attractive Target Sugar Baits (ATSBs) is designed specifically to attract the mosquito with a source of liquid and sugar and include an ingestion toxicant to then kill the mosquito. Using sugar sources to attract mosquitoes to an ingestion toxicant is a relatively simple and inexpensive, strategy that has been shown to be highly efficacious for mosquito control in a limited number of trials. Limited data suggest efficacy, even in sugar-rich environments, due to the high frequency of sugar feeding.

Early studies examined the effect of spraying ingestion toxicants on attractive flowers to use their scent as bait. While these flowers effectively attract the target mosquitoes, the impact on non-target insects, especially pollinators, can be devastating. Furthermore, this approach is not suitable where there is a lack of flowering vegetation. Subsequent studies evaluated locally available plants and fruits as attractants. While such attractants can be sprayed onto non-flowering green vegetation, further studies evaluated products (bait stations) that could be used across a wide variety of settings including indoors and in areas without suitable vegetation.

Westham Compagny recently developed a bait station that contains a plant-based mosquito attractant, sugar as a feeding stimulant, and an active ingredient (the neonicotinoid, dinotefuran) to kill the foraging vectors. The bait station has a protective membrane that covers and protects the bait from rain and dust, but that allows mosquitoes to feed through it. The Westham ATSB can remain effective in the field for at least six months and has a shelf life of greater than three years with no specific requirements for storage. This Attractive Target Sugar Bait (ATSB) is now being produced at an industrial scale, uses simple and widely available ingredients, and is environmentally friendly. The bait station was designed to have the lowest practicable material content with a high proportion of the mass being fully biodegradable. The protective membrane allows mosquitoes to feed, but it serves as a barrier to pollinators. Field studies to-date have also shown that the ATSB has a minimal impact on non-target organisms. This includes evidence specifically for the toxicant that will be used, dinotefuran. Initial environmental assessment and subsequent field trials in Mali have demonstrated that when deployed within the ATSB, the toxicant does not pose safety risks to non-target organisms, including pollinators and humans.

ATSBs may be a particularly important vector control tool in the context of insecticide resistance. Insecticide resistance for the six insecticide classes currently used in LLINs and IRS threatens malaria prevention efforts. Resistance to pyrethroids (used in LLINs and IRS) is commonly reported. If pyrethroids lose most of their efficacy, more than 55% of the benefits of vector control could be lost. ATSBs can help mitigate insecticide resistance to these contact insecticides because they can use ingestion toxicants from very different chemical classes. There are many existing ingestion toxicants that may be used in a bait station, which could facilitate resistance prevention strategies, such as rotation or combination approaches.

Eligibility criteria: Inclusion criteria

* . Household resident of the selected villages
* Aged 5 to 14 years of age at the time of enrollment
* All parents or guardians provide consent for their child's participant (5-14 years old)
* If age 12 - 14 years, the child also provides assent for participation
* Absence of pregnancy

Exclusion criteria

* Not resident of any household within the selected villages
* Children below 5 years old
* Aged 15 years and older
* Pregnancy
* Do not consent or assent (14 years old)

Primary outcomes:
measure: Malaria incidence per person times
timeFrame: Through study completion (average 2 years
Secondary outcomes:
measure: Incidence of malaria per person times using molecular analysis tools
timeFrame: Through study completion (average 2 years
Other outcomes:
measure: Community acceptance of ATSBs in intervention area
timeFrame: Through study completion (average 2 years
Locations:
city: Bamako
country: Mali
facility: University Clinical Research Center
Study officials:
affiliation: University Clinical Research Center - USTTB - Mali
name: Seydou Doumbia, PhD
role: STUDY_DIRECTOR
References:
citation: Sinka ME, Bangs MJ, Manguin S, Rubio-Palis Y, Chareonviriyaphap T, Coetzee M, Mbogo CM, Hemingway J, Patil AP, Temperley WH, Gething PW, Kabaria CW, Burkot TR, Harbach RE, Hay SI. A global map of dominant malaria vectors. Parasit Vectors. 2012 Apr 4;5:69. doi: 10.1186/1756-3305-5-69.
citation: Bhatt S, Weiss DJ, Cameron E, Bisanzio D, Mappin B, Dalrymple U, Battle K, Moyes CL, Henry A, Eckhoff PA, Wenger EA, Briet O, Penny MA, Smith TA, Bennett A, Yukich J, Eisele TP, Griffin JT, Fergus CA, Lynch M, Lindgren F, Cohen JM, Murray CLJ, Smith DL, Hay SI, Cibulskis RE, Gething PW. The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature. 2015 Oct 8;526(7572):207-211. doi: 10.1038/nature15535. Epub 2015 Sep 16.
citation: Ranson H, Lissenden N. Insecticide Resistance in African Anopheles Mosquitoes: A Worsening Situation that Needs Urgent Action to Maintain Malaria Control. Trends Parasitol. 2016 Mar;32(3):187-196. doi: 10.1016/j.pt.2015.11.010. Epub 2016 Jan 27.
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: 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: 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: Muller GC and Galili A. (2016). Attractive toxic sugar baits (ATSB): from basic science to product- a new paradigm for vector control. Roll Back Malaria, Vector Control Working Group meeting presentation.
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: Muller GC, Beier JC, Traore SF, Toure MB, Traore MM, Bah S, Doumbia S, Schlein Y. Field experiments of Anopheles gambiae attraction to local fruits/seedpods and flowering plants in Mali to optimize strategies for malaria vector control in Africa using attractive toxic sugar bait methods. Malar J. 2010 Sep 20;9:262. doi: 10.1186/1475-2875-9-262.
citation: Mnzava AP, Knox TB, Temu EA, Trett A, Fornadel C, Hemingway J, Renshaw M. Implementation of the global plan for insecticide resistance management in malaria vectors: progress, challenges and the way forward. Malar J. 2015 Apr 23;14:173. doi: 10.1186/s12936-015-0693-4.
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: WHO. (2017). Malaria vector control policy recommendations and their applicability to product evaluation. Geneva: WHO.
citation: Midega JT, Mbogo CM, Mwnambi H, Wilson MD, Ojwang G, Mwangangi JM, Nzovu JG, Githure JI, Yan G, Beier JC. Estimating dispersal and survival of Anopheles gambiae and Anopheles funestus along the Kenyan coast by using mark-release-recapture methods. J Med Entomol. 2007 Nov;44(6):923-9. doi: 10.1603/0022-2585(2007)44[923:edasoa]2.0.co;2.
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.