Clinical trial NCT03631719: Impact of Wolbachia Deployment on Arboviral Disease Incidence in Medellin and Bello, Colombia
Official title: World Mosquito Program - Colombia (WMP-COLOMBIA): The Impact of City-wide Deployment of Wolbachia-infected Mosquitoes on Arboviral Disease Incidence in Medellin and Bello, Colombia
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Dengue
Chikungunya Virus Infection
Zika Virus Infection
Keywords: Wolbachia
Colombia
Dengue
Zika
Chikungunya
Arboviral diseases
Disease surveillance
Lead sponsor: Universidad de Antioquia
Sponsor class: OTHER
Collaborators: name: Monash University
name: United States Agency for International Development (USAID)
name: Bill and Melinda Gates Foundation
name: Wellcome Trust
First posted: 2018-08-15
Enrollment: 834
Sex: ALL
Minimum age (years): 3
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The case-control study area as a whole has a population of approximately 564,000, of which approximately half will be resident in areas that receive early Wolbachia deployments ('early-release') and half in areas that will receive late Wolbachia deployments ('late-release').

The study population for measurement of the efficacy endpoint is the population of patients who reside in the study area, presenting to the network of participating primary health care facility with febrile illness, and meeting the eligibility criteria.

Brief summary: Study setting: Medellin and Bello municipalities, Colombia Health condition(s) studied: Dengue, Zika and chikungunya virus infection Intervention: Deployment of Wolbachia-infected Aedes aegypti mosquitoes in Medellin and Bello.

Study design:

1. An interrupted time-series analysis utilising routine disease surveillance data collected by the Medellín and Bello Health Secretariats, which aims to compare incidence of dengue, chikungunya and Zika pre- and post-Wolbachia release.
2. A test-negative study using an incident case-control design, which aims to quantify the reduction in disease incidence among people living within a Wolbachia-treated zone compared with an untreated zone that has a similar dengue risk profile at baseline.

Detailed description: * Selection and enrolment of participants: Enrolment of patients will commence after completion of Wolbachia releases in the early zones. Study processes for enrolling patients presenting with febrile illness will be established at a network of primary health care facilities that serve the population who reside in the study area. Trained research staff will be employed to assist with study processes in each site. Participants will be enrolled from within the population of patients (aged ≥3 years old) presenting with undifferentiated fever of 1-4 days' duration. All patients meeting the inclusion criteria will be eligible for enrolment and will be asked to provide written informed consent before participating in the study.
* Recruitment procedures: All eligible participants meeting study inclusion criteria will be invited to enroll continuously throughout the study period. Recruitment will occur during normal clinic hours. Participants will be managed according to standard clinical practice by the attending physicians. Recruitment rates in each clinic and across the study site as a whole will be monitored weekly, including a review of the screening logs to identify the proportion of eligible participants who did not consent to participate. The field coordinator will make regular visits to low-enrolling clinics to identify clinic-based, patient-based or other causes for low recruitment, and put measures in place to address these.
* Screening: All patients presenting with febrile illness will be screened against the study inclusion criteria by trained staff. All eligible febrile individuals will be recorded in a screening log and invited to participate. Participation status (consent/decline) will be recorded against each participant in the log.
* Informed consent: Written informed consent will be sought from participants (or their guardian where the participant is a minor) by trained local staff, after explaining the study objectives, processes, data, and sample collection, and the participant has had an opportunity to ask questions. A verbal explanation of the written Explanatory Statement will be provided to all participants in the local language. In addition, participants aged between 7 and 17 years will be invited to sign an assent form indicating they understand the research and agree to participate. Data and sample collection procedures
* Data collection: A unique identifier will be assigned to each participant at enrollment. Basic demographic details, eligibility against the inclusion criteria and illness onset date will be recorded in a standardized case report form.

Eligibility criteria: Inclusion Criteria:

* Fever (either self-reported or objectively measured, e.g. axillary temperature ≥38oC, with a date of onset between 1-4 days prior to the day of presentation.
* Aged ≥3 years old.
* Lived (i.e. slept) in the study area every night (or day) for the 10 days preceding illness onset.

Exclusion Criteria:

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

Primary outcomes:
measure: Dengue cases notified to surveillance system
timeFrame: 5 years
measure: Virologically-confirmed dengue
timeFrame: 2 years
Secondary outcomes:
measure: IgM test positive for dengue
timeFrame: 5 years
measure: Severe dengue cases
timeFrame: 5 years
measure: Zika cases notified to surveillance system
timeFrame: 5 years
measure: Chikungunya cases notified to surveillance system
timeFrame: 5 years
measure: Spatial analysis
timeFrame: 5 years
measure: Virologically-confirmed chikungunya infection
timeFrame: 2 years
measure: Virologically-confirmed Zika infection
timeFrame: 2 years
Other outcomes:
Locations:
city: Medellín
country: Colombia
facility: Universidad de Antioquia
state: Antioquia
Study officials:
affiliation: Monash University
name: Cameron Simmons, Prof.
role: STUDY_DIRECTOR
References:
citation: Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, Moyes CL, Farlow AW, Scott TW, Hay SI. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Negl Trop Dis. 2012;6(8):e1760. doi: 10.1371/journal.pntd.0001760. Epub 2012 Aug 7.
citation: Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI. The global distribution and burden of dengue. Nature. 2013 Apr 25;496(7446):504-7. doi: 10.1038/nature12060. Epub 2013 Apr 7.
citation: Shepard DS, Coudeville L, Halasa YA, Zambrano B, Dayan GH. Economic impact of dengue illness in the Americas. Am J Trop Med Hyg. 2011 Feb;84(2):200-7. doi: 10.4269/ajtmh.2011.10-0503.
citation: Shepard DS, Undurraga EA, Halasa YA. Economic and disease burden of dengue in Southeast Asia. PLoS Negl Trop Dis. 2013;7(2):e2055. doi: 10.1371/journal.pntd.0002055. Epub 2013 Feb 21.
citation: Shepard DS, Suaya JA, Halstead SB, Nathan MB, Gubler DJ, Mahoney RT, Wang DN, Meltzer MI. Cost-effectiveness of a pediatric dengue vaccine. Vaccine. 2004 Mar 12;22(9-10):1275-80. doi: 10.1016/j.vaccine.2003.09.019.
citation: Dengue Vaccine Initiative. Dengue vaccine candidates in clinical development. (2016). Available at: http://www.denguevaccines.org/vaccine-development. (Accessed: 13th June 2016)
citation: L'Azou M, Moureau A, Sarti E, Nealon J, Zambrano B, Wartel TA, Villar L, Capeding MR, Ochiai RL; CYD14 Primary Study Group; CYD15 Primary Study Group. Symptomatic Dengue in Children in 10 Asian and Latin American Countries. N Engl J Med. 2016 Mar 24;374(12):1155-66. doi: 10.1056/NEJMoa1503877.
citation: Capeding MR, Tran NH, Hadinegoro SR, Ismail HI, Chotpitayasunondh T, Chua MN, Luong CQ, Rusmil K, Wirawan DN, Nallusamy R, Pitisuttithum P, Thisyakorn U, Yoon IK, van der Vliet D, Langevin E, Laot T, Hutagalung Y, Frago C, Boaz M, Wartel TA, Tornieporth NG, Saville M, Bouckenooghe A; CYD14 Study Group. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet. 2014 Oct 11;384(9951):1358-65. doi: 10.1016/S0140-6736(14)61060-6. Epub 2014 Jul 10.
citation: Villar L, Dayan GH, Arredondo-Garcia JL, Rivera DM, Cunha R, Deseda C, Reynales H, Costa MS, Morales-Ramirez JO, Carrasquilla G, Rey LC, Dietze R, Luz K, Rivas E, Miranda Montoya MC, Cortes Supelano M, Zambrano B, Langevin E, Boaz M, Tornieporth N, Saville M, Noriega F; CYD15 Study Group. Efficacy of a tetravalent dengue vaccine in children in Latin America. N Engl J Med. 2015 Jan 8;372(2):113-23. doi: 10.1056/NEJMoa1411037. Epub 2014 Nov 3.
citation: Guy B, Lang J, Saville M, Jackson N. Vaccination Against Dengue: Challenges and Current Developments. Annu Rev Med. 2016;67:387-404. doi: 10.1146/annurev-med-091014-090848. Epub 2015 Oct 23.
citation: Hadinegoro SR, Arredondo-Garcia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, Muhammad Ismail HI, Reynales H, Limkittikul K, Rivera-Medina DM, Tran HN, Bouckenooghe A, Chansinghakul D, Cortes M, Fanouillere K, Forrat R, Frago C, Gailhardou S, Jackson N, Noriega F, Plennevaux E, Wartel TA, Zambrano B, Saville M; CYD-TDV Dengue Vaccine Working Group. Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease. N Engl J Med. 2015 Sep 24;373(13):1195-206. doi: 10.1056/NEJMoa1506223. Epub 2015 Jul 27.
citation: Schilte C, Staikowsky F, Couderc T, Madec Y, Carpentier F, Kassab S, Albert ML, Lecuit M, Michault A. Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study. PLoS Negl Trop Dis. 2013;7(3):e2137. doi: 10.1371/journal.pntd.0002137. Epub 2013 Mar 21.
citation: Rolph MS, Foo SS, Mahalingam S. Emergent chikungunya virus and arthritis in the Americas. Lancet Infect Dis. 2015 Sep;15(9):1007-1008. doi: 10.1016/S1473-3099(15)00231-5. No abstract available.
citation: Weaver SC, Costa F, Garcia-Blanco MA, Ko AI, Ribeiro GS, Saade G, Shi PY, Vasilakis N. Zika virus: History, emergence, biology, and prospects for control. Antiviral Res. 2016 Jun;130:69-80. doi: 10.1016/j.antiviral.2016.03.010. Epub 2016 Mar 18.
citation: World Health Organization. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. 2016. Available at. see World Health Organization. Zika virus: Fact sheet. 2016.
citation: World Health Organization. Mosquito (vector) control emergency response and preparedness for Zika virus. (2016). Available at: http://www.who.int/neglected_diseases/news/mosquito_vector_control_response/en/. (Accessed: 18th March 2016)
citation: Republic of Colombia, B. of the R. (Bogotá). D. of E. R. Colombia: Overview of its economic structure. (Printing of the Bank of the Republic, 1992).
citation: Republic of Colombia, N. C. for E. and S. P. Guidelines for the formulation of integral environmental health policy with emphasis on the components of air quality, water quality and chemical safety. (2008).
citation: Medina ÁM. El Dengue en Colombia. Epidemiología de la Reemergencia a la Hiperendemia. Medicina. 2013 Mar 5;35(1):75-6.n Ltda. Bogotá).
citation: National Institute of Health. Epidemiological bulletin: week 52/2016. (2016).
citation: Bowman LR, Donegan S, McCall PJ. Is Dengue Vector Control Deficient in Effectiveness or Evidence?: Systematic Review and Meta-analysis. PLoS Negl Trop Dis. 2016 Mar 17;10(3):e0004551. doi: 10.1371/journal.pntd.0004551. eCollection 2016 Mar.
citation: Andersson N, Nava-Aguilera E, Arostegui J, Morales-Perez A, Suazo-Laguna H, Legorreta-Soberanis J, Hernandez-Alvarez C, Fernandez-Salas I, Paredes-Solis S, Balmaseda A, Cortes-Guzman AJ, Serrano de Los Santos R, Coloma J, Ledogar RJ, Harris E. Evidence based community mobilization for dengue prevention in Nicaragua and Mexico (Camino Verde, the Green Way): cluster randomized controlled trial. BMJ. 2015 Jul 8;351:h3267. doi: 10.1136/bmj.h3267.
citation: Degener CM, Eiras AE, Azara TM, Roque RA, Rosner S, Codeco CT, Nobre AA, Rocha ES, Kroon EG, Ohly JJ, Geier M. Evaluation of the effectiveness of mass trapping with BG-sentinel traps for dengue vector control: a cluster randomized controlled trial in Manaus, Brazil. J Med Entomol. 2014 Mar;51(2):408-20. doi: 10.1603/me13107.
citation: Wilson AL, Boelaert M, Kleinschmidt I, Pinder M, Scott TW, Tusting LS, Lindsay SW. Evidence-based vector control? Improving the quality of vector control trials. Trends Parasitol. 2015 Aug;31(8):380-90. doi: 10.1016/j.pt.2015.04.015. Epub 2015 May 19.
citation: O'Neill SL, Pettigrew MM, Sinkins SP, Braig HR, Andreadis TG, Tesh RB. In vitro cultivation of Wolbachia pipientis in an Aedes albopictus cell line. Insect Mol Biol. 1997 Feb;6(1):33-9. doi: 10.1046/j.1365-2583.1997.00157.x.
citation: Stouthamer R, Breeuwer JA, Hurst GD. Wolbachia pipientis: microbial manipulator of arthropod reproduction. Annu Rev Microbiol. 1999;53:71-102. doi: 10.1146/annurev.micro.53.1.71.
citation: Rousset F, Vautrin D, Solignac M. Molecular identification of Wolbachia, the agent of cytoplasmic incompatibility in Drosophila simulans, and variability in relation with host mitochondrial types. Proc Biol Sci. 1992 Mar 23;247(1320):163-8. doi: 10.1098/rspb.1992.0023.
citation: Hilgenboecker K, Hammerstein P, Schlattmann P, Telschow A, Werren JH. How many species are infected with Wolbachia?--A statistical analysis of current data. FEMS Microbiol Lett. 2008 Apr;281(2):215-20. doi: 10.1111/j.1574-6968.2008.01110.x. Epub 2008 Feb 28.
citation: McMeniman CJ, Lane RV, Cass BN, Fong AW, Sidhu M, Wang YF, O'Neill SL. Stable introduction of a life-shortening Wolbachia infection into the mosquito Aedes aegypti. Science. 2009 Jan 2;323(5910):141-4. doi: 10.1126/science.1165326.
citation: Joubert DA, Walker T, Carrington LB, De Bruyne JT, Kien DH, Hoang Nle T, Chau NV, Iturbe-Ormaetxe I, Simmons CP, O'Neill SL. Establishment of a Wolbachia Superinfection in Aedes aegypti Mosquitoes as a Potential Approach for Future Resistance Management. PLoS Pathog. 2016 Feb 18;12(2):e1005434. doi: 10.1371/journal.ppat.1005434. eCollection 2016 Feb.
citation: Walker T, Johnson PH, Moreira LA, Iturbe-Ormaetxe I, Frentiu FD, McMeniman CJ, Leong YS, Dong Y, Axford J, Kriesner P, Lloyd AL, Ritchie SA, O'Neill SL, Hoffmann AA. The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations. Nature. 2011 Aug 24;476(7361):450-3. doi: 10.1038/nature10355.
citation: Dutra HL, Rocha MN, Dias FB, Mansur SB, Caragata EP, Moreira LA. Wolbachia Blocks Currently Circulating Zika Virus Isolates in Brazilian Aedes aegypti Mosquitoes. Cell Host Microbe. 2016 Jun 8;19(6):771-4. doi: 10.1016/j.chom.2016.04.021. Epub 2016 May 4.
citation: Johnson KN. The Impact of Wolbachia on Virus Infection in Mosquitoes. Viruses. 2015 Nov 4;7(11):5705-17. doi: 10.3390/v7112903.
citation: Rainey SM, Shah P, Kohl A, Dietrich I. Understanding the Wolbachia-mediated inhibition of arboviruses in mosquitoes: progress and challenges. J Gen Virol. 2014 Mar;95(Pt 3):517-530. doi: 10.1099/vir.0.057422-0. Epub 2013 Dec 16.
citation: Amuzu HE, Simmons CP, McGraw EA. Effect of repeat human blood feeding on Wolbachia density and dengue virus infection in Aedes aegypti. Parasit Vectors. 2015 Apr 24;8:246. doi: 10.1186/s13071-015-0853-y.
citation: Ye YH, Carrasco AM, Frentiu FD, Chenoweth SF, Beebe NW, van den Hurk AF, Simmons CP, O'Neill SL, McGraw EA. Wolbachia Reduces the Transmission Potential of Dengue-Infected Aedes aegypti. PLoS Negl Trop Dis. 2015 Jun 26;9(6):e0003894. doi: 10.1371/journal.pntd.0003894. eCollection 2015.
citation: Frentiu FD, Zakir T, Walker T, Popovici J, Pyke AT, van den Hurk A, McGraw EA, O'Neill SL. Limited dengue virus replication in field-collected Aedes aegypti mosquitoes infected with Wolbachia. PLoS Negl Trop Dis. 2014 Feb 20;8(2):e2688. doi: 10.1371/journal.pntd.0002688. eCollection 2014 Feb.
citation: Moreira LA, Iturbe-Ormaetxe I, Jeffery JA, Lu G, Pyke AT, Hedges LM, Rocha BC, Hall-Mendelin S, Day A, Riegler M, Hugo LE, Johnson KN, Kay BH, McGraw EA, van den Hurk AF, Ryan PA, O'Neill SL. A Wolbachia symbiont in Aedes aegypti limits infection with dengue, Chikungunya, and Plasmodium. Cell. 2009 Dec 24;139(7):1268-78. doi: 10.1016/j.cell.2009.11.042.
citation: Ferguson NM, Kien DT, Clapham H, Aguas R, Trung VT, Chau TN, Popovici J, Ryan PA, O'Neill SL, McGraw EA, Long VT, Dui le T, Nguyen HL, Chau NV, Wills B, Simmons CP. Modeling the impact on virus transmission of Wolbachia-mediated blocking of dengue virus infection of Aedes aegypti. Sci Transl Med. 2015 Mar 18;7(279):279ra37. doi: 10.1126/scitranslmed.3010370.
citation: Lessler J, Salje H, Grabowski MK, Cummings DA. Measuring Spatial Dependence for Infectious Disease Epidemiology. PLoS One. 2016 May 19;11(5):e0155249. doi: 10.1371/journal.pone.0155249. eCollection 2016.
citation: Dengue: Guidelines for Diagnosis, Treatment, Prevention and Control: New Edition. Geneva: World Health Organization; 2009. Available from http://www.ncbi.nlm.nih.gov/books/NBK143157/
citation: Velez ID, Santacruz E, Kutcher SC, Duque SL, Uribe A, Barajas J, Gonzalez S, Patino AC, Zuluaga L, Martinez L, Munoz E, Mejia MC, Arbelaez MP, Pulido H, Jewell NP, Dufault SM, O'Neill SL, Simmons CP, Anders KL, Tanamas SK. The impact of city-wide deployment of Wolbachia-carrying mosquitoes on arboviral disease incidence in Medellin and Bello, Colombia: study protocol for an interrupted time-series analysis and a test-negative design study. F1000Res. 2019 Aug 1;8:1327. doi: 10.12688/f1000research.19858.2. eCollection 2019.