Reanalysis of cluster randomized trial data to account for exposure misclassification using a per-protocol and complier-restricted approach

The intention-to-treat analysis of a cluster randomized trial of Wolbachia (wMel strain) mosquito releases for control of dengue (the Applying Wolbachia to Eliminate Dengue [AWED] trial) estimated a protective efficacy of 77.1% for participants resident in areas randomized to receive releases of wMel-infected Aedes aegypti mosquitoes. The limiting assumptions of ITT analyses in cluster randomized trials and the mobility of both mosquitoes and humans across cluster boundaries mean that the primary analysis is likely to have underestimated the full public health benefit. Using spatially and temporally resolved data on the distribution of Wolbachia mosquitoes and on trial participants' mobility collected during the AWED trial, this work performs a complier-restricted and per protocol re-examination of the efficacy of the Wolbachia intervention, taking explicitly into account human mobility and the uneven establishment and spillover of wMel mosquitoes. By applying the same estimation procedures as those performed in the primary analysis, we are able to identify the impact of exposure misclassification on estimated efficacy. Increased intervention efficacy was estimated in all analyses by the refined exposure measures. The complier-restricted analysis resulted in an estimated efficacy of 80.7% (95% CI: 65.9, 89.0). The effect of the refined exposure estimation on per-protocol results was even more striking, with an estimated 82.7% (71.7, 88.4) efficacy when comparing participants with an estimated wMel exposure of 80% or higher compared to those with 20% or lower. These reanalyses provide a case study of how human and mosquito movement can lead to underestimation of the intervention effect in trials of vector interventions, and indicate that the protective efficacy of Wolbachia is even higher than reported in the primary trial results. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03055585 ### Funding Statement We gratefully acknowledge the Tahija Foundation as funders of the AWED trial, and the Wellcome Trust and the Bill and Melinda Gates Foundation, which provided financial support to the World Mosquito Program. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The trial protocol for the Applying Wolbachia to Eliminate Dengue (AWED) trial study was approved by the Universitas Gadjah Mada (UGM) ethics committee (approval number KE/FK/105/EC/2016) and Monash University Human Research Ethics Committee (approval number 0960). Written informed consent was obtained from participants (or their guardian where the participant is a minor). In addition, participants between 13 and 17 years of age were invited to sign a consent form indicating that they understood the research and agreed to participate. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Participants' residential address and travel history was collected and stored under the ethical approval of the AWED trial protocol. Because the geolocated data is considered personally identifiable information, individuals seeking access should contact Katherine Anders (katie.anders@worldmosquito.org) to discuss obtaining ethical approval or accessing a deidentified version of the dataset. All analyses were performed with R and the analytical code can be found on GitHub (https://github.com/sdufault15/yogya-wei-spatial).