Applying Wolbachia to Eliminate Dengue (AWED)

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ClinicalTrials.gov Identifier: NCT03055585

Recruitment Status : Terminated (Distancing and movement restrictions of the COVID-19 emergency response made continuation of clinic-based and field entomological trial activities infeasible)

First Posted : February 16, 2017

Last Update Posted : June 9, 2020

Sponsor:

Collaborators:

Monash University

The Tahija Foundation

Information provided by (Responsible Party):

Riris Andono Ahmad, Gadjah Mada University

Study Description

Brief Summary:

This cluster randomised trial will evaluate the efficacy of Wolbachia-infected Aedes aegytpi mosquitoes in reducing dengue cases in Yogyakarta City, Indonesia

Condition or disease	Intervention/treatment	Phase
Dengue Zika Virus Infection Chikungunya Fever	Biological: Wolbachia-infected Aedes aegypti mosquitoes Other: standard practice dengue control	Not Applicable

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Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	8173 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
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
Actual Study Start Date :	November 8, 2017
Actual Primary Completion Date :	March 18, 2020
Actual Study Completion Date :	April 8, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dengue Mosquito Bites Zika Virus

Genetic and Rare Diseases Information Center resources: Zika Virus Infection Chikungunya Dengue Fever Viral Hemorrhagic Fever

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intervention arm Deployment of Wolbachia-infected Aedes aegypti mosquitoes	Biological: Wolbachia-infected Aedes aegypti mosquitoes Deployment of Wolbachia-infected Aedes aegypti mosquitoes Other: standard practice dengue control standard practice dengue control activities conducted by dengue control program
Comparison arm Standard practice dengue control activities	Other: standard practice dengue control standard practice dengue control activities conducted by dengue control program

Outcome Measures

Primary Outcome Measures :

Relative risk of dengue in Wolbachia-treated versus untreated clusters [ Time Frame: Up to 36 months participant enrolment ]
Symptomatic, virologically-confirmed dengue virus (DENV) infection of any severity

Secondary Outcome Measures :

Relative risk of serotype-specific dengue in Wolbachia-treated versus untreated clusters [ Time Frame: Up to 36 months participant enrolment ]
Symptomatic, virologically-confirmed serotype-specific DENV infection of any severity.
Relative risk of Zika in Wolbachia-treated versus untreated clusters [ Time Frame: Up to 36 months participant enrolment ]
Symptomatic, virologically-confirmed Zika virus (ZIKV) infection of any severity.
Relative risk of Chikungunya in Wolbachia-treated versus untreated clusters [ Time Frame: Up to 36 months participant enrolment ]
Symptomatic, virologically-confirmed Chikungunya virus (CHIKV) infection of any severity.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	3 Years to 45 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Fever (either self-reported or objectively measured, e.g. (tympanic membrane temperature ≥38oC)) of 1-4 days duration, and where onset was prior to the day of presentation
Aged between 3-45 years old
Resided in the study area every night for the 10 days preceding illness onset

Exclusion Criteria:

Localising features suggestive of a specific diagnosis other than an arboviral infection e.g. severe diarrhea, otitis, pneumonia
Prior enrollment in the study within the previous 4 weeks

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03055585

Locations

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Indonesia
Faculty of Medicine, Universitas Gadjah Mada
Yogyakarta, DIY, Indonesia, 55281

Sponsors and Collaborators

Gadjah Mada University

Monash University

The Tahija Foundation

Investigators

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Principal Investigator:	Adi Utarini, MD, PhD	Faculty of Medicine, Universitas Gadjah Mada

Study Documents (Full-Text)

Documents provided by Riris Andono Ahmad, Gadjah Mada University:

Statistical Analysis Plan [PDF] May 28, 2020

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Utarini A, Indriani C, Ahmad RA, Tantowijoyo W, Arguni E, Ansari MR, Supriyati E, Wardana DS, Meitika Y, Ernesia I, Nurhayati I, Prabowo E, Andari B, Green BR, Hodgson L, Cutcher Z, Rancès E, Ryan PA, O'Neill SL, Dufault SM, Tanamas SK, Jewell NP, Anders KL, Simmons CP; AWED Study Group. Efficacy of Wolbachia-Infected Mosquito Deployments for the Control of Dengue. N Engl J Med. 2021 Jun 10;384(23):2177-2186. doi: 10.1056/NEJMoa2030243.

Anders KL, Indriani C, Ahmad RA, Tantowijoyo W, Arguni E, Andari B, Jewell NP, Dufault SM, Ryan PA, Tanamas SK, Rancès E, O'Neill SL, Simmons CP, Utarini A. Update to the AWED (Applying Wolbachia to Eliminate Dengue) trial study protocol: a cluster randomised controlled trial in Yogyakarta, Indonesia. Trials. 2020 May 25;21(1):429. doi: 10.1186/s13063-020-04367-2.

Anders KL, Indriani C, Ahmad RA, Tantowijoyo W, Arguni E, Andari B, Jewell NP, Rances E, O'Neill SL, Simmons CP, Utarini A. The AWED trial (Applying Wolbachia to Eliminate Dengue) to assess the efficacy of Wolbachia-infected mosquito deployments to reduce dengue incidence in Yogyakarta, Indonesia: study protocol for a cluster randomised controlled trial. Trials. 2018 May 31;19(1):302. doi: 10.1186/s13063-018-2670-z.

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Responsible Party:	Riris Andono Ahmad, Director of Center for Tropical Medicine, Faculty of Medicine, Universitas Gadjah Mada, Gadjah Mada University
ClinicalTrials.gov Identifier:	NCT03055585
Other Study ID Numbers:	UGM_KE/FK/105/EC
First Posted:	February 16, 2017 Key Record Dates
Last Update Posted:	June 9, 2020
Last Verified:	June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by Riris Andono Ahmad, Gadjah Mada University:


Wolbachia; Ae. aegypti; Indonesia; Dengue; Cluster-randomised trial

Additional relevant MeSH terms:

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Dengue Chikungunya Fever Zika Virus Infection Virus Diseases Arbovirus Infections Flavivirus Infections	Flaviviridae Infections RNA Virus Infections Hemorrhagic Fevers, Viral Alphavirus Infections Togaviridae Infections

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