Dengue Clinical Trial
Official title:
Applying Wolbachia to Eliminate Dengue (AWED): A Non-blinded Cluster Randomised Controlled Trial to Assess the Efficacy of Wolbachia-infected Mosquito Deployments to Reduce Dengue Incidence in Yogyakarta, Indonesia
This cluster randomised trial will evaluate the efficacy of Wolbachia-infected Aedes aegytpi mosquitoes in reducing dengue cases in Yogyakarta City, Indonesia
Primary objective:
To assess the efficacy of community-based deployments of Wolbachia-infected Aedes aegypti
mosquitoes in reducing the incidence of symptomatic, virologically-confirmed dengue cases of
any severity in Yogyakarta residents aged 3-45 years in release areas, relative to
non-release areas.
Secondary objectives:
- To measure the efficacy of the Wolbachia method against each of the four DENV serotypes.
- To measure the efficacy of the Wolbachia method in reducing the incidence of symptomatic
virologically confirmed Zika virus and chikungunya virus infection in release areas,
relative to non-release areas
- To quantify the level of human mobility within Yogyakarta City, and estimate the
proportion of residents' exposure time that they spend outside the treatment arm to
which they were randomised
- To determine whether community-based deployment of Wolbachia-infected Ae. aegypti
mosquitoes reduces the abundance of wild-type Ae. aegypti adults, or alternatively,
alters the abundance of adults from Aedes species other than Ae. aegypti (e.g. Ae.
albopictus)
Study setting:
The study will be conducted in Yogyakarta City and Bantul District, both located in the
province of Yogyakarta Special Region, Indonesia.The study site is 26 km2 in size, including
24 km2 within Yogyakarta City, and 2km2 in the adjacent Bantul District. The total population
of the study area is approximately 350,000.
Study design:
A cluster randomised trial with a test-negative design will be conducted. The study site will
be divided into 24 clusters. The intervention will be allocated using constrained block
randomisation with a parallel 1:1 assignment of intervention and control.
The intervention is the deployment of Wolbachia-infected Aedes aegypti mosquitoes. Wolbachia
deployments will be conducted in intervention clusters with the aim of achieving Wolbachia
establishment (>80% mean Wolbachia prevalence in trapped mosquitoes) throughout intervention
areas within one year.
The impact of Wolbachia deployments on dengue incidence will be assessed by comparing the
exposure distribution (probability of living in a Wolbachia-treated area) among
virologically-confirmed dengue cases presenting to a network of public primary clinics
(Puskesmas), against the exposure distribution among patients with febrile illness of
non-arboviral aetiology presenting to the same network of clinics in the same temporal
windows. Dengue cases and arbovirus-negative controls will be sampled concurrently from
within the population of patients presenting with febrile illness to the study clinic
network, with case or control status classified retrospectively based on the results of
laboratory diagnostic testing.
A re-estimation of sample size requirements was conducted in January 2019 after one year of
recruitment. The initial power calculation used 1000 dengue cases and 4000 non-dengue
controls allocated to each cluster based on historical proportions of dengue cases and other
febrile illnesses, assuming no variation in the proportion of cases by cluster. This method
was found to overestimate power for small samples by not taking into account randomness in
the sampling. The sample size re-estimation included power estimates for 200, 400, 600, 800
and 1000 dengue cases with 4 times as many controls allocated to each cluster by sampling
from a multinomial distribution, which incorporated added randomness by allowing the
proportion of cases allocated to each cluster to vary across simulations. The re-estimation
found that 400 dengue cases plus four times as many controls would be sufficient to detect a
50% reduction in dengue incidence with 80% power.
Participant selection:
Participants will be enrolled from within the population of patients presenting with
undifferentiated fever of 1-4 days duration, to one of the participating local health clinics
(Puskesmas).
All patients meeting the inclusion criteria will be invited to participate in the study. From
baseline historical data we expect approximately 5000 participants per annum to be enrolled.
Enrolment will continue for up to 36 months.
Analysis plan:
Permutation tests and standard regression models will be used to estimate the relative risk
of dengue in Wolbachia-treated versus untreated clusters, accounting for the non-independence
of study participants resident in the same intervention cluster, and temporal matching of
dengue cases and test-negative controls.
The intention-to-treat analysis will consider Wolbachia exposure as binary depending on the
allocation of the cluster of residence.
The per-protocol analysis will consider Wolbachia exposure as a continuous weighted index
based on Wolbachia prevalence in trapped mosquitoes in the cluster of residence, either with
or without weighting for time spent in other clusters visited during the ten days prior to
illness onset.
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