LLINEUP2 Cluster Randomized Trial

Related studies:

LLINEUP Cluster Randomized Trial

Background: Long-lasting insecticidal nets (LLINs) provide the foundation for vector control in Uganda and elsewhere in Africa. However, the effectiveness of LLINs is threatened by widespread pyrethroid resistance. In the first LLINEUP trial, we found that piperonyl butoxide (PBO) LLINs were superior to conventional LLINs. However, PBO LLINs have several potential limitations. PBO is a synergist, not an insecticide, and can only restore sensitivity of pyrethroid insecticides if resistance is due to specific metabolic mechanisms. Moreover, PBO cannot fully restore susceptibility in all resistant mosquito populations.

Newer dual active-ingredient LLINs treated with a combination of insecticides using different modes of action are attractive alternatives; these LLINs may provide greater protection and delay the spread of insecticide resistance, but like PBO LLINs, they are more expensive than conventional nets. Further evidence of the effectiveness and cost-effectiveness of pyriproxyfen (PPF)-treated LLINs is urgently needed. Royal Guard LLINs, treated with alphacypermethrin and PPF, are one of only two dual active-ingredient LLINs prequalified by the WHO which are available for widescale distribution.

In Uganda, the National Malaria Control Division (NMCD) and implementing partners were planning to deliver LLINs nationwide in 2020, through a mass distribution campaign supported by generous contributions from international donors. LLINs would be distributed free-of-charge to all Ugandan households, aiming to achieve universal coverage. The Against Malaria Foundation had agreed to provide LLINs treated with a pyrethroid insecticide plus PPF (Royal Guard, Disease Control Technology) and LLINs treated with a pyrethroid insecticide plus PBO (PermaNet 3.0, Vestergaard), presenting an opportunity to rigorously evaluate and compare these two LLINs at scale across Uganda. In collaboration with the MOH, a cluster-randomised trial was embedded to compare the impact of LLINs with PPF to LLINs with PBO into Uganda’s 2020 LLIN distribution campaign, as was done successfully for the last LLIN distribution campaign conducted in 2017-18.

A major strength of LLINEUP2 is the use of malaria incidence as the primary outcome measure. Incidence of malaria, defined as the number of symptomatic cases of malaria occurring in a population at risk over time, is the gold standard for assessing malaria burden. However, cluster-randomised trials using malaria incidence as the primary outcome are very expensive and logistically challenging. A novel approach for measuring malaria incidence in this trial is to utilize data collected routinely at health facilities. By defining catchment areas around health facilities and collecting data on the location of residence of patients diagnosed with malaria, we were able to generate longitudinal measures of malaria incidence at an unprecedented scale across Uganda.

Finally, there is an urgent need to better understand the potential impact of the COVID-19 pandemic on malaria in Uganda. To our knowledge, no published studies have evaluated how malaria control and care have evolved in Uganda since the onset of the COVID-19 pandemic. This is partly because of limited testing available for SARS-CoV-2, particularly in rural communities where the burden of malaria is highest. Given the platform provided by the Malaria Reference Center (MRC) surveillance, we were uniquely poised to evaluate the association between malaria and evidence of prior exposure to COVID-19 across Uganda. These results will inform policies and programmes for both malaria and COVID-19 in Uganda.

Objectives: The primary objective was to evaluate the impact of LLINs treated with a pyrethroid insecticide plus pyriproxyfen (PPF LLINs), as compared to LLINs treated with a pyrethroid plus piperonyl butoxide (PBO LLINs), on malaria incidence in Uganda. We will test the hypothesis that malaria incidence will be lower in intervention clusters (randomized to receive PPF LLINs) than in control clusters (randomized to receive PBO LLINs).

Secondary objectives:

To evaluate the impact of PPF LLINs vs PBO LLINs on parasite prevalence, anaemia, and vector density
To estimate the cost-effectiveness of delivering PPF LLINs, as compared to PBO LLINs
To assess net durability, survivorship and use of PPF LLINs vs PBO LLINs
To evaluate the impact of the COVID-19 pandemic on malaria burden and care in Uganda

Methodology:

Geographic Location/Study Sites: With the Ministry of Health, a high-quality malaria surveillance program was established. Health facilities selected for the malaria surveillance network are referred to as Malaria Reference Centers (MRCs). For this study, a cluster has been defined as the target area of an MRC. The study was conducted in 64 clusters within 32 districts in Uganda, covering a wide range of settings with high malaria burden.

Dates of Data Collection: November 2021 to March 2023

Study Design: Cluster Randomized Controlled Trial

Eligibility Criteria:

Inclusion criteria:

At least one adult aged 18 years or older present
Adult is a usual resident who slept in the sampled household on the night before the survey
Agreement of the adult resident to provide informed consent for the household survey

Exclusion criteria:

Dwelling destroyed or not found
Household vacant
No adult resident at home on more than 3 occasions

Study Arms: Intervention clusters were randomized to receive PPF LLINs while control clusters were randomized to receive PBO LLINs.

Data Collection: Households from each of the 64 clusters were randomly selected for participation in each of the community surveys. Within each cluster (MRC catchment area), households were randomly sampled from a list of households enumerated by the study team, until 50 households with children aged 2-10 years are sampled per cluster. Data was collected at 12 months and 24 months after the nets were distributed.

Study Documentation:

Study protocol
Data dictionary
Codebooks:

Health facility codebook
Household codebook - 12 month
Household codebook - 24 month
Bednet codebook - 12 month
Bednet codebook - 24 month
Household member codebook - 12 month
Household member codebook - 24 month

Consent forms

ClinEpiDB Data Integration: Data files were provided to ClinEpiDB as STATA .dta files. All identifying information was removed, including participant names and location data. Datasets were merged by unique ID and redundant or administrative columns were dropped from presentation on ClinEpiDB.org. All dates were obfuscated per participant through the application of a random number algorithm that shifted dates no more than seven days to comply with the ethical conduct of human subjects research.

Acknowledgements: We would like to thank Emmanuel Arinaitwe, James Kapisi, Chris Ebong, Bridget Nzarubara, Faith Kagoya, Emmanuel Bakashaba, Isiko Joseph, Paul Oketch, Benjamin Guma, Jolly Job Odongo, Daniel Ochuli, Geoffrey Omia, Leuben Patrick Okello, Geoff Lavoy, Peter Mutungi, Nicholas Wendo, Yasin Kisambira, Catherine Pitt and the administration of the Infectious Diseases Research Collaboration for all their contributions. We would also like to acknowledge and thank the members of the Uganda National Malaria Control Division and the Liverpool School of Tropical Medicine for logistical and other support rendered as we carried out the data collection and analysis. We are grateful to the district administration, health and political leadership teams for all their support and guidance during community engagement in the 32 districts of the study area.

Financial Support: The study was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID)

Ethics Statement: The study was approved by the Ugandan National Council for Science and Technology (UNCST Ref HS1097ES), Makerere University School of Medicine Research & Ethics Committee (SOMREC Ref 2020–193), London School of Hygiene & Tropical Medicine Ethics Committee (LSHTM Ref 22615–1) and the University of California San Francisco Human Research Protection Program Institutional Review Board (UCSF Ref 289107). Written informed consent to participate in the study was obtained by the head of household (or their designate) for all participating households. Verbal assent was obtained from all participants over the age of 8 years. Ethical approval for study procedures was provided by ethics committee of the School of Medicine College of Health Sciences, Makerere University (#REC P.EF 2019–122), and Uganda National Council of Science and Technology (HS1033ES).

Last Updated: February 2, 2024The LLIN Evaluation in Uganda Project 2 (LLINEUP2), is a pragmatic cluster-randomized trial embedded in the nationwide 2020-2021 long-lasting insecticidal nets (LLINs) distribution campaign in Uganda. LLINs treated with a pyrethroid insecticide plus pyriproxyfen and LLINs treated with a pyrethroid insecticide plus piperonyl butoxide were rigorously evaluated and compared at scale across Uganda. Cross-sectional community surveys were conducted at 12 and 24 months following LLIN distribution in 50 randomly selected households with children aged 2-10 years per cluster.