Administrative information
Title {1} | A cluster randomized, placebo control trial to evaluate the efficacy of a spatial repellent (Mosquito Shield™) against Aedes-borne virus infection among children ≥ 4–16 years of age in the Gampaha District, Sri Lanka: study protocol (the AEGIS program) |
Trial registration {2a and 2b}. | Sri Lanka Clinical Trial Registry SLCTR/2022/018. Registered July 1, 2022. https://slctr.lk/trials/slctr-2022-018 ClinicalTrials.gov NCT05452447. Registered July 11, 2022. The Universal Trial Number is U1111-1275-3055. |
Protocol version {3} | Version 9.1 - February 3, 2022 |
Funding {4} | The project under which the data will be gathered, “Advancing Evidence for the Global Implementation of Spatial Repellents (AEGIS),” is possible thanks to Unitaid funding and support. Unitaid is a global health agency engaged in finding innovative solutions to prevent, diagnose, and treat diseases more quickly, effectively, and for affordable prices, in low- and middle-income countries. Unitaid’s work includes funding initiatives to address major diseases such as HIV/AIDS, malaria, and tuberculosis, as well as HIV co-infections and co-morbidities such as cervical cancer and hepatitis C, and cross-cutting areas, such as fever management. Unitaid is now applying its expertise to address challenges in advancing new therapies and diagnostics for the COVID-19 pandemic, serving as a key member of the Access to COVID Tools Accelerator. Unitaid is hosted by the World Health Organization. Additionally, SC Johnson, A Family Company, will use internal company financial resources for the development, manufacturing, delivery, and shipment of the intervention used in the study. |
Author details {5a} | HT: Epidemiology Unit, Ministry of Health, Sri Lanka DSAFD: National Dengue Control Unit, Ministry of Health, Sri Lanka NM: Department of Immunology and Molecular Medicine, Faculty of Medical Sciences, University of Sri Jayewardenepura, Sri Lanka HAS: Clinical Trials Unit, Faculty of Medicine, University of Kelaniya, Sri Lanka AM, TS: University of California Davis RR: University of Washington JPG, NLA: University of Notre Dame, Notre Dame, IN 46556, USA |
Name and contact information for the trial sponsor {5b} | Dr. John P. Grieco Lead Principal Investigator, Advancing Spatial Repellents for Vector-Borne Disease Control Eck Institute for Global Health University of Notre Dame 243 Galvin Life Science Notre Dame, IN 46556 jgrieco@nd.edu 574.631.7572 |
Role of sponsor {5c} | As study sponsor, the University of Notre Dame (UND) participated in study design, management, analysis, data interpretation, and manuscript development As funder, Unitaid had no role in the design of the study and collection, analysis, and interpretation of data and in the writing of the manuscript. |
Introduction
Background and rationale {6a}
Objectives {7}
Secondary objectives are:
Tertiary objectives are:
Trial design {8}
Methods: participants, interventions, and outcomes
Study setting {9}
Eligibility criteria {10}
Febrile Surveillance (clinical disease) | |
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Inclusion criteria | Exclusion criteria |
Household level (written consent) | |
● Adult head of household agrees to census, health visits, and logging resident symptoms when febrile (or in the case of suspected Zika in the absence of fever, presenting with rash, arthralgia, arthritis, or non-purulent conjunctivitis). ● Individuals spend a minimum of 4 h per week during the daytime hours or sleep in the house. | ● Adult head of household does not agree to census, health visits, or logging symptoms of residents. ● Households where study personnel identify a security risk (i.e., site where drugs are sold, residents are always drunk or hostile). ● Sites where no residents spend time during the day (i.e., work 7 days a week outside the home). |
Individual level (written consent) | |
● ≥ 6 months of age. ● Fever at the time of presentation or report of feverishness within the previous 24 h or presenting with a rash, arthralgia, arthritis, or non-purulent conjunctivitis (suspicion of ZIKV determined by project physician). ● Individual who spends a minimum of 4 h per week within the household or sleeps in the house. | ● <6 months of age. ● No fever at time of presentation or report of feverishness within the previous 24 h or not reporting with a rash, arthralgia, arthritis, or non-purulent conjunctivitis. ● Individuals who have spent less than 4 h in the household during the week prior to illness. |
Longitudinal seroconversion follow-up (to include baseline serostatus survey) Individual level | |
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Inclusion criteria | Exclusion criteria |
● ≥4 – 16 years of age ● Plans to stay in residence and/or study area for a minimum of 24 months ● Resident of household or frequent visitor (~20% of day hours in house/months) | ● <4 and >16 years of age ● Plans to leave residence and/or study area within next 24 months ● Temporary visitor to household (<20% of day hours in house/months) |
Mosquito Shield™ Household Application – Household Level (Written consent) | |
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Inclusion criteria | Exclusion criteria |
● Adult head of household agrees to have intervention applied inside the home and to provide access to team member at 4-week intervals to change products. ● Properties where study personnel do not identify a security risk (i.e., site where drugs are sold, residents are always drunk or hostile). | ● Adult head of household does not agree to Mosquito Shield™ deployment or study team access. ● Properties where study personnel identify a security risk (i.e., site where drugs are sold, residents are always drunk or hostile). |
Entomological Surveys – Household Level (Written consent) | |
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Inclusion criteria | Exclusion criteria |
● Adult head of household agrees to entomological surveys. ● Properties where study personnel do not identify a security risk (i.e., site where drugs are sold, residents are always drunk or hostile). | ● Adult head of household does not agree to entomological surveys. ● Properties where study personnel identify a security risk (i.e., site where drugs are sold, residents are always drunk or hostile). |
Who will take informed consent? {26a}
Additional consent provisions for collection and use of participant data and biological specimens {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Criteria for discontinuing or modifying allocated interventions {11b}
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Secondary outcome measures include:
Tertiary outcome measures include:
Participant timeline {13}
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Clusters delineated based on HH mapping and census data collected from the Negombo, Wattala, and Kelaniya study areas in the Gampaha District, with support of historical demographic, epidemiological, and/or entomological indices.
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House recruitment visits, distribution of information sheets, and study explanation.
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Consent and enrollment into longitudinal and/or febrile surveillance cohort(s), entomology surveys, and/or product application.
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Baseline serostatus blood sampling from longitudinal cohort participants (Baseline sample: T0).
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Indoor, adult mosquito collections using Prokopack aspirators in enrolled HHs.
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First application of intervention in consented HHs following completion of enrollment within cluster groups.
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Deployment and replacement of intervention in consented HHs (every 28 days).
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Blood sampling from longitudinal cohort participants (Annual sample T1: ~12 months from baseline sample; Annual sample T2: ~24 months from baseline sample).
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Blood sampling from longitudinal cohort participants also enrolled in febrile surveillance reporting to study health facilities at time of fever/symptoms.
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Clinical case monitoring from trial health facilities for participants in the febrile surveillance cohort; reporting at the time of fever/symptoms.
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Monthly indoor, adult mosquito collections using Prokopack aspirators.
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Disposal of intervention product.
Study period | ||||
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Baseline | Intervention | Close-out | ||
Timepoint | (2023) | (2023) | (2024) | (2024) |
Estimated duration | Study months 1–3 3 months | |||
Study months 1–24 24 months | ||||
Study months 25–27 3 months | ||||
Baseline | ||||
Recruitment, consent, enrolment | X | |||
Allocation | X | |||
Serostatus blood sampling (T0) | X | |||
Initial entomology surveys | X | |||
Initial deployment of intervention | X | |||
Intervention | ||||
Intervention replacement | X | X | ||
Longitudinal blood Sampling (T1) | X | |||
Longitudinal blood sampling (T2) | X | |||
Febrile surveillance | X | X | ||
Entomology surveys | X | X | ||
Assessments | ||||
Final analysis | X |
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: Blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Non-emergency unblinding of a single participant
Emergency unblinding
Data collection and management
Plans for assessment and collection of outcomes {18a}
Mapping of the study area and census measurements
Screening and monitoring of cohort participants
Entomological surveys
Laboratory procedures
Plans to promote participant retention and complete follow-up {18b}
Data management {19}
Data sharing policy
Data storage
Data quality control and quality assurance
Confidentiality {27}
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Incidence calculations and case classification
Case classification | Description |
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LTFU | Participants who move from the study area or choose to stop participation in febrile surveillance. |
Not DENV infected | No change in PRNT or MNT results between longitudinal bleeds |
Inapparent infection | Change in PRNT or MNT results consistent with a seroconversion between longitudinal bleeds without indication of febrile illness coincident with a laboratory-diagnosed DENV infection. Seroconversion meaning Baseline=Negative or Monotypic, 12- and 24-month sample=positive for dengue antibody or positive for antibody against a new DENV serotype in the case of monotypics. |
Symptomatic infection | Clinical case identified in passive febrile surveillance with laboratory confirmation of DENV infections (see Fig. 3), which may include laboratory-confirmed seroconversion from acute and convalescent blood samples. |
Entomological analyses
Efficacy evaluations
Role of human movement
Hypothesis
Primary hypothesis
Secondary hypothesis
Population for analysis
Subjects who moved to a new house during the intervention follow-up period
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For a subject who moved to a different house within the same cluster, that subject will be included in both the ITT and PP analyses.
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For a subject who moved to a different house in a different cluster, the subject will be included in the ITT analysis with the original treatment assignment though the new cluster although the subject moved to might have a different intervention from the original assignment. The subject will also be included in the PP analysis if the new cluster had the same intervention as the original assignment.