Clinical trial NCT04716387: Estimating the Malaria Prevention Impact of New Nets: Observational Analyses to Evaluate the Evidence Generated During Piloted New Net Distributions in Mozambique
Official title: Estimating the Malaria Prevention Impact of New Nets: Observational Analyses to Evaluate the Evidence Generated During Piloted New Net Distributions in Mozambique
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Malaria
Keywords: Long-lasting insecticidal net
LLIN
Insecticide treated net
ITN
Malaria
Epidemiology
Entomology
Anthropology
Durability monitoring
Cost-effectiveness
Lead sponsor: PATH
Sponsor class: OTHER
Collaborators: name: Tropical Health LLP
name: Ministry of Health, Mozambique
name: Instituto Nacional de Saúde, Mozambique
name: Tulane University
name: Liverpool School of Tropical Medicine
First posted: 2021-01-20
Enrollment: 8726
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study districts are located in Niassa and Zambezia provinces of northern Mozambique and Manica, Sofala, and Tete provinces in western Mozambique. The study districts, Mandima, Cuamba, Gurue, Changara, Guro, and Chemba will receive enhanced data collection. In addition, routine entomological and epidemiological data from all districts in these provinces will be used to compare trends. The study districts have similar malaria transmission dynamics. Routine data provided by in-country stakeholders show that these districts are comparable in underlying malaria prevalence, incidence, vector species composition, and insecticide resistance status, as well as general climate and geographic similarities.

Brief summary: The use of insecticide-treated bed nets (ITNs) has contributed to the substantial reduction in malaria cases and deaths. This progress is threatened by increasing resistance to commonly used insecticides in important mosquito vector populations. Newly developed, next-generation ITNs that use two insecticides, or an insecticide synergist and an insecticide, are effective at killing resistant mosquitoes, but large-scale uptake of these nets has been slow due to higher costs and lack of enough evidence to support broad policy recommendations.

This observational study will occur alongside a pilot distribution of next-generation ITNs in two regions of Mozambique. Over three years, data on the entomological and epidemiological impact of the different ITN types will be collected. Data collection will occur in six districts: two districts receiving the dual-active ingredient ITN Interceptor® G2 (BASF: alphacypermethrin + chlorfenapyr); one district that will receive the dual-active ingredient ITN Royal Guard® (Disease Control Technologies: alphacypermethrin + pyriproxyfen); one district receiving an ITN containing an insecticide plus an insecticide synergist , Olyset®Plus (Sumitomo Chemical: permethrin + piperonyl butoxide); and two districts receiving the standard pyrethroid-only ITNs DuraNet® (Shobikaa Impex Private Limited: alphacypermethrin). Data will be collected on malaria vector bionomics, disease epidemiology, and ITN use in order to help better demonstrate the public health value of next-generation ITNs and to support donors, policymakers, and National Malaria Control Programs in their ITN decision-making and planning processes.

Detailed description: The World Health Organization's (WHO) 2018 World Malaria Report estimates that in 2017, 219 million cases of malaria occurred worldwide resulting in 435,000 deaths, 93% of which occurred in Africa (WHO 2018). While this represents a remarkable improvement in comparison with 2000, with malaria deaths having fallen by 40% in Africa, the downward trends in incidence and mortality stalled between 2015 and 2017. This recent failure to maintain the hard-won progress, let alone accelerate progress towards elimination, over the past three years has caused WHO to describe the global fight against malaria as being at a crossroads, calling for increased funding and highlighting the need to develop, optimize, and implement new tools to combat malaria.

Universal coverage of populations at risk with malaria vector control interventions, primarily insecticide treated nets (ITNs) and indoor residual spraying (IRS), in malaria-endemic countries is a global and national priority because of its fundamental importance for malaria control and elimination. Unfortunately, the effectiveness of these tools is threatened by the emergence and spread of pyrethroid resistance in key mosquito populations, which is now reported in more than 85% of all malaria endemic countries and poses significant risk to the future impact of these tools. Emerging evidence suggests, however, that increasing mosquito mortality and thereby continuing to reduce malaria transmission is possible in areas with pyrethroid resistance by introducing new insecticide formulations for IRS and ITNs. For example, Protopopoff et al. showed in Tanzania that the distribution of LLINs with piperonyl butoxide (PBO) plus pyrethroid reduced malaria prevalence by 13% compared to standard pyrethroid-only LLIN distribution (42% vs. 29%; p=0.0011), and Tiono et al., working in Burkina Faso, showed that the distribution of a dual active-ingredient ITN reduced clinical malaria incidence by 22% (Incidence Rate Ratio = 0.88; p=0.04) and potentially infective mosquito bites by 51% (entomological inoculation rate ratio = 0.49; p\<0.0001) compared to the distribution of a standard pyrethroid-only LLIN.

While there is evidence that standard LLINs can continue to provide effective personal protection to regular net users in regions with resistant vector populations, new classes of ITNs developed to perform against pyrethroid-resistant mosquitoes have been developed, with early trials and modelling suggesting that they may provide superior protective efficacy against malaria in areas with pyrethroid-resistant vectors. Access to these new resistance-breaking ITNs is restricted by need for efficacy data for continuing policy recommendations, high prices, lack of evidence of cost effectiveness compared to pyrethroid-only LLINs, and consequent poor demand in an uncertain market. Two types of next-generation ITNs, each utilizing a different mixture of active ingredients from different insecticide classes, have recently received WHO prequalification listing demonstrating that they perform to the thresholds required of pyrethroid-only ITNs and have no known specific side effects: Interceptor G2® (IG2; by BASF SE) and Royal Guard®(RG; by Disease Control Technologies, LLC). The IG2 ITN contains a mixture of a pyrethroid (alpha-cypermethrin) and a pyrrole (chlorfenapyr), while the RG ITN contains a mixture of the same pyrethroid (alpha-cypermethrin) and an insect growth regulator (pyriproxyfen). While both net types have been subsequently registered and approved for use in Mozambique based on this WHO listing, the Roll Back Malaria Vector Control Advisory Group guidance indicates that dual active ingredient ITNs will require further epidemiological evidence before policy recommendations are made for their use in preference to pyrethroid-only ITNs in certain settings.

The Global Fund and Unitaid have developed a market shaping program for next-generation ITNs with novel insecticide formulations. Evidence on the efficacy of IG2 and RG ITNs will be generated by the project through two randomized control trials taking place in Benin and Tanzania. In addition, through this program, these next-generation ITNs will be made available to countries for incorporation into their national distribution programs as pilot distributions with the aim of determining real-world effectiveness and cost-effectiveness in different contexts. In addition to the pilot distribution of IG2s taking place in Mozambique, three other countries will be piloting next-generation ITNs as part of the New Nets project: Burkina Faso, Nigeria, and Rwanda. This research will utilize these pilot distributions to understand the cost-effectiveness of the new ITNs in the chosen settings. The NMCP in Mozambique, in discussion with the Global Fund, chose to incorporate IG2, RG, and PBO ITNs into the 2020 mass distribution campaign. This study will collect information to determine the public health impact of the RG, PBO, and IG2 ITNs in Mozambique, in comparison to two sites that will receive standard pyrethroid-only ITNs. The aim of this research is to better understand the effectiveness and cost effectiveness of IG2 and RG ITNs in Mozambique and to collect data on community uptake of the ITNs.

During the upcoming pilot implementation enhanced entomological, epidemiological, and net use data will be collected in up to six study districts: two districts receiving the dual-active ingredient ITN Interceptor® G2 (BASF: alphacypermethrin + chlorfenapyr); one district that will receive the dual-active ingredient ITN Royal Guard® (Disease Control Technologies: alphacypermethrin + pyriproxyfen); one district receiving an ITN containing an insecticide plus an insecticide synergist, Olyset®Plus (Sumitomo Chemical: permethrin + piperonyl butoxide); and two districts receiving the standard pyrethroid-only ITNs DuraNet® (Shobikaa Impex Private Limited: alphacypermethrin). Data will be analyzed and results disseminated to support the NMCP, donors, policymakers, and other national and regional stakeholders in their ITN decision-making and planning processes. Each component aims specifically to:

* Epidemiological component - measure the epidemiological impact of the new IG2 ITNs, Royal Guard ITNs, PBO ITNs, and standard ITNs in real deployment scenarios through observational studies. These studies will compare trends in (1) malaria case incidence rates passively reported to the national health system (passive case detection (PCD)) and (2) malaria infection prevalence, measured through rapid diagnostic tests (RDTs), in children aged 6 months to 5 years of age from annual cross-sectional surveys during peak transmission periods.
* Entomological component - evaluate the impact of the different net types on vector populations and biting rates, compared to standard ITNs, through mosquito surveillance data that will measure trends in species-specific (1) adult vector densities (2) indoor and outdoor human landing rates (3) estimated entomological inoculation rates and (4) insecticide resistance patterns. These entomological surveillance activities are aligned with NMCP activities and are not part of the human subject research component of this study.
* Anthropological component - map patterns of ITN usage to determine transmission risk defined as the intersection between time at risk of mosquito blood feeding and human activities not under protection of an ITN, through gathering evidence on ITN uptake and usage. The collection of reliable data on such patterns, both indoors and outdoors, becomes thus an essential component of the evaluation of the ITN pilots for both modeling and contextual analysis of impact.
* Durability monitoring - monitoring of standard, IG2, RG and PBO ITNs in one district each, prospectively measuring physical durability, attrition, and chemical durability.
* Costing and cost-effectiveness component - estimate the cost and cost-effectiveness of IG2, RG and PBO ITNs in Mozambique through data on the price of the product, delivery and deployment costs, and product effectiveness based on case incidence rates measured during the epidemiological component of this study. Additionally, mean costs per case averted that might occur in other contexts will be modeled and incorporated into the cost-effectiveness evaluations.

Eligibility criteria: Inclusion Criteria:

* All suspected malaria cases (fevers) that self-present to the national health system and are counted in the district health surveillance systems (Passive data collection)
* Households in the district (Cross-sectional)
* Residents of the household visited (Cross-sectional
* Questionnaire: parent or guardian giving written informed consent (cross-sectional)
* Malaria screening: child aged 6 to 59 months from the above consenting household.

Exclusion Criteria:

* District non-residents
* Malaria screening: history of recent (within one month) malaria infection or treatment with anti-malarial medication (cross-sectional)
* Parents or guardians who have not yet reached age of consent (18 years) and their children will not be included in study activities requiring consent.
* Head of household unwilling and/or unable to give consent

Primary outcomes:
measure: Cumulative malaria incidence
timeFrame: August 2020 to December 2022
Secondary outcomes:
measure: Vectors species composition
timeFrame: August 2020 to December 2022
measure: Species-specific population densities
timeFrame: August 2020 to December 2022
measure: Biting behaviors
timeFrame: August 2020 to December 2022
measure: Estimated entomological inoculation rates
timeFrame: August 2020 to December 2022
measure: Insecticide resistance profile
timeFrame: August 2020 to December 2022
measure: Parasite prevalence in children 6-59 months
timeFrame: August 2020, August 2021, August 2022
measure: Net use characteristics
timeFrame: August 2020 to December 2022
measure: Cost-effectiveness measures
timeFrame: August 2020 to December 2022
measure: Physical durability monitoring
timeFrame: January 2021, July 2021, June 2022
measure: Insecticide durability monitoring
timeFrame: January 2021, July 2021, June 2022
Other outcomes:
Locations:
city: Maputo
country: Mozambique
facility: Programa Nacional de Controle da Malaria, Ministry of Health
Study officials:
affiliation: PATH
name: Joseph Wagman, PhD
role: PRINCIPAL_INVESTIGATOR
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