An Epidemiological Surveillance Study to Evaluate the Incidence of Dengue in Brazil

Study Overview
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Brief Summary
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The purpose of this study is to estimate the incidence of dengue infection in children and adults in geographically distinct locations of Brazil.

Detailed Description
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The aim of this study is to generate dengue disease burden data including estimates of incidence rates, prevalence data and the clinical presentation of dengue across different age groups. The study will be conducted in at least three cities: Rio de Janeiro, Salvador, and Manaus. This study will also prepare potential sites for future clinical trials, by setting up the logistics and training staff on site to enroll a cohort of subjects perform dengue surveillance and other study procedures. Households will be randomly selected from communities where a registry system is implemented. All individuals in the household will be eligible for participating in the study. This study will be sponsored by GSK and co-funded by GSK and Fiocruz. As study sponsor, GSK will delegate some activities to Fiocruz, according to the provisions in their Cooperative Research and Development Agreement (CRADA).

Official Title
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An Epidemiological Surveillance Study to Evaluate the Incidence of Dengue in Endemic Regions of Brazil

Conditions
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Dengue

Intervention / Treatment
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* Procedure: Blood sample collection
* Other: Data collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written, signed or thumb-printed informed consent (and assent when applicable) must be obtained from the subject or subject's parent(s)/legally acceptable representative(s) (LAR(s)). If the subject/subject's parent(s)/LAR(s) are illiterate the consent form will be countersigned by a witness. Male or female at least 6 months of age at the time of enrollment. Subject and/or subject's parent(s)/LAR(s) who the study staff believes can comply with the requirements of the protocol. Subject who plans, at the time of enrollment, to remain at same residence/study area during their study participation period). Exclusion Criteria: Child in care. Participation (current or planned) in another epidemiological study or in a clinical trial that would conflict with the current study, based on investigator's judgement. Terminal illness or severe mental incapacity.

Ages Eligible for Study
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Minimum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Total Group<br>Subjects six months of age and older at the time of enrolment, recruited from randomly selected households originating from preselected mapped communities. Preferably the recruitment period occurred outside of the peak dengue transmission season, and continued until each site had reached its foreseen target. The expected period for recruiting the target sample size was approximately three months. Recruitment of replacement subjects was done during the low dengue transmission and the recruitment period depended on the number of subjects that need to be replaced. Enrolled subjects were subjects who either lived in households in study areas with support from the Family Health Physician Program (FHP) or the Larval Index Rapid Assay (LIRA) or with field research experience in the community (preferred) or where a similar system of mapped communities with potential for surveillance existed. | Procedure: Blood sample collection<br>* Blood samples will be collected at each study visit (Day 0, Month 6, Month 12, Month 24, Month 36 and Month 48) and any time during the study that dengue is suspected. Samples collected at scheduled visits will be tested for anti-dengue antibodies. Samples collected at visits for dengue suspicion will be tested for dengue infection diagnosis.<br>Other: Data collection<br>* Diary logs will be issued to all subjects at every visit, except Month 48 (Day 0, Month 6, Month 12, Month 24, and Month 36), as required. Any completed diary logs will be verified, as applicable. Subjects will be given a diary log in the event of the occurrence of a symptom that may be associated with suspected dengue.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate (Per 1000 Person-years) of All Laboratory-confirmed Symptomatic Dengue Infection by Calendar Year | Incidence rate (IR) of laboratory-confirmed symptomatic dengue infection (lab-conf.) with 95% Confidence Interval (CI) for each year and overall, calculated as the incidence rate per 1000 person-years : numerator = number of all lab-conf. cases reported during the follow-up (FU) period at risk; denominator = total Person-years at risk, i.e. sum of FU periods at risk expressed in years until first Reverse Transcriptase quantitative Polymerase Chain Reaction (RT-qPCR) confirmed symptomatic dengue infection or subject's withdrawal, whichever came first. Lab-conf. case defined as follows: Dengue virus identification through RT-qPCR on acute serum sample or Dengue virus NS1 positive on acute serum sample through Enzyme-linked Immunosorbent Assay (ELISA) or Anti-Dengue Immunoglobulin type M (IgM) seroconversion between acute and convalescent serum samples through ELISA. Data were not analyzed by Dengue season as planned in the protocol as most of the cases occurred outside the seasons. | At each calendar year i.e. Year 2014, 2015, 2016, 2017, 2018, and overall calendar years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence Rate (Per 1000 Person-years) of All Virologically-confirmed Symptomatic Dengue Infection by Calendar Year | Incidence rate (IR) of virologically-confirmed symptomatic dengue infection with 95% Confidence Interval (CI) for each year separately and overall years calculated as the incidence rate per 1000 person-years : the numerator is the number of all virologically-confirmed dengue infection cases reported during the follow-up period at risk; the denominator is the total Person-years at risk, i.e. sum of the follow-up periods at risk expressed in years. A virologically confirmed symptomatic dengue infection is defined as a dengue case confirmed by RT-qPCR. Data were not analyzed by Dengue season as planned in the protocol as most of the cases occurred outside the seasons. Analysis was not performed by DENV-type as data would not be reliable due to the low number of cases reported. | At each calendar year i.e. Year 2014, 2015, 2016, 2017, 2018, and overall calendar years | 
| Incidence Rate (Per 1000 Person-years) of All Laboratory-confirmed or Probable Symptomatic Dengue Infection by Study Site, and Calendar Year | Incidence rate (IR) of laboratory-confirmed or probable symptomatic dengue infection with 95% Confidence Interval (CI) by study site, and for each year separately and overall years calculated as the incidence rate per 1000 person-years : the numerator is the number of all laboratory-confirmed or probable symptomatic dengue infection cases reported during the follow-up period at risk; the denominator is the total Person-years at risk, i.e. sum of the follow-up periods at risk expressed in years. For early presenters, a probable case was that case without laboratory confirmation, presenting IgG positive in the convalescent sample; for late presenters, a probable case was the case without seroconversion of IgM, presenting at least one IgG positive in one sample (acute or convalescent). Data were not analyzed by Dengue season as planned in the protocol as most of the cases occurred outside the seasons. | At each calendar year i.e. Year 2014, 2015, 2016, 2017, 2018, and overall calendar years | 
| Incidence Rate (Per 1000 Person-years) of All Laboratory-confirmed or Probable Symptomatic Dengue Infection by Age Category, and Calendar Year | Incidence rate (IR) of laboratory-confirmed or probable symptomatic dengue infection with 95% Confidence Interval (CI) by age category, and for each year separately and overall years calculated as the incidence rate per 1000 person-years : the numerator is the number of all laboratory-confirmed or probable symptomatic dengue infection cases reported during the follow-up period at risk; the denominator is the total Person-years at risk, i.e. sum of the follow-up periods at risk expressed in years. For early presenters, a probable case was that case without laboratory confirmation, presenting IgG positive in the convalescent sample; for late presenters, a probable case was the case without seroconversion of IgM, presenting at least one IgG positive in one sample (acute or convalescent). Data were not analyzed by Dengue season as planned in the protocol as most of the cases occurred outside the seasons. | At each calendar year i.e. Year 2014, 2015, 2016, 2017, 2018, and overall calendar years | 
| Incidence Rate (Per 1000 Person-years) of All Laboratory-confirmed or Probable Symptomatic Dengue Infection by Gender, and Calendar Year | Incidence rate (IR) of laboratory-confirmed or probable symptomatic dengue infection with 95% Confidence Interval (CI) by gender, and for each year separately and overall years calculated as the incidence rate per 1000 person-years : the numerator is the number of all laboratory-confirmed or probable symptomatic dengue infection cases reported during the follow-up period at risk; the denominator is the total Person-years at risk, i.e. sum of the follow-up periods at risk expressed in years. For early presenters, a probable case was that case without laboratory confirmation, presenting IgG positive in the convalescent sample; for late presenters, a probable case was the case without seroconversion of IgM, presenting at least one IgG positive in one sample (acute or convalescent). Data were not analyzed by Dengue season as planned in the protocol as most of the cases occurred outside the seasons. | At each calendar year i.e. Year 2014, 2015, 2016, 2017, 2018, and overall calendar years | 
| Number of Primary Symptomatic Dengue Infection Cases Among Laboratory-confirmed or Probable Cases | A primary symptomatic dengue case is a subject with laboratory confirmed or probable symptomatic dengue infection, and without evidence of previous dengue infection (absence of Ig G antibodies at the previous scheduled visit and absence of laboratory confirmed symptomatic case detected previously at study surveillance). Analysis was not performed by DENV-type as data would not be reliable due to the low number of cases reported. | From Year 2014 to Year 2018 (a range of 1 to 4 years for an individual subject) | 
| Number of Secondary Symptomatic Dengue Infection Cases Among Laboratory-confirmed or Probable Cases | A secondary symptomatic dengue case is a subject with laboratory confirmed or probable symptomatic dengue infection, and with evidence of previous dengue infection (presence of IgG antibodies at the previous scheduled visit(s) or laboratory-confirmed symptomatic case detected previously at study surveillance). Analysis was not performed by DENV-type as data would not be reliable due to the low number of cases reported. | From Year 2014 to Year 2018 (a range of 1 to 4 years for an individual subject) | 
| Number of Subjects With Previous Dengue Infection (Dengue Seroprevalence) at Baseline, by Study Site and Overall | A subject was considered as having previous dengue infection at baseline, based on seroprevalence at first visit, namely if Dengue IgG positive (i.e. reactive) at first visit or if Laboratory-confirmed symptomatic dengue case detected at first visit (baseline). | At the first visit of the first year | 
| Number of Subjects With Previous Dengue Infection (Dengue Seroprevalence) at Baseline, by Gender | A subject was considered as having previous dengue infection at baseline, based on seroprevalence at first visit, namely if Dengue IgG positive (i.e. reactive) at first visit or if Laboratory-confirmed symptomatic dengue case detected at first visit (baseline). | At the first visit of the first year | 
| Number of Subjects With Previous Dengue Infection (Dengue Seroprevalence) at Baseline, by Age Group at Enrolment | A subject was considered as having previous dengue infection at baseline, based on seroprevalence at first visit, namely if Dengue IgG positive (i.e. reactive) at first visit or if Laboratory-confirmed symptomatic dengue case detected at first visit (baseline). | At the first visit of the first year | 
| Incidence Rate (Per 1000 Person-years) of Primary Inapparent Dengue Infection by Study Site and Calendar Year, and Overall, Among Subjects With no Seroprevalence at the First Visit | Incidence rate (IR) of primary inapparent dengue infection with 95% Confidence Interval (CI) by site and, for each year separately and overall years calculated as the incidence rate per 1000 person-years, among subjects with no seroprevalence at the first visit: the numerator is the number of all primary inapparent dengue infection cases reported during the follow-up period at risk. The denominator is the total Person-years at risk, i.e. sum of the follow-up periods at risk expressed in years. The primary inapparent dengue infection condition was defined as a documented seroconversion (anti-dengue IgG antibodies) between two sequential sera samples obtained during the scheduled visits without clinical suspicion of dengue (identified during the time period in which seroconversion occurred). Data were not analyzed by Dengue season as planned in the protocol as most of the cases occurred outside the seasons. | At each calendar year i.e. Year 2014, 2015, 2016, 2017, 2018, and overall calendar years | 
| Incidence Rate (Per 1000 Person-years) of Primary Inapparent Dengue Infection by Age Category and Calendar Year, and Overall, Among Subjects With no Seroprevalence at the First Visit | Incidence rate (IR) of primary inapparent dengue infection with 95% Confidence Interval (CI) by age category and, for each year separately and overall years calculated as the incidence rate per 1000 person-years, among subjects with no seroprevalence at the first visit: the numerator is the number of all primary inapparent dengue infection cases reported during the follow-up period at risk. The denominator is the total Person-years at risk, i.e. sum of the follow-up periods at risk expressed in years. The primary inapparent dengue infection condition was defined as a documented seroconversion (anti-dengue IgG antibodies) between two sequential sera samples obtained during the scheduled visits without clinical suspicion of dengue (identified during the time period in which seroconversion occurred). Data were not analyzed by Dengue season as planned in the protocol as most of the cases occurred outside the seasons. | At each calendar year i.e. Year 2014, 2015, 2016, 2017, 2018, and overall calendar years | 
| Incidence Rate (Per 1000 Person-years) of Primary Inapparent Dengue Infection by Gender and Calendar Year, and Overall, Among Subjects With no Seroprevalence at the First Visit | Incidence rate (IR) of primary inapparent dengue infection with 95% Confidence Interval (CI) by gender and, for each year separately and overall years calculated as the incidence rate per 1000 person-years, among subjects with no seroprevalence at the first visit: the numerator is the number of all primary inapparent dengue infection cases reported during the follow-up period at risk. The denominator is the total Person-years at risk, i.e. sum of the follow-up periods at risk expressed in years. The primary inapparent dengue infection condition was defined as a documented seroconversion (anti-dengue IgG antibodies) between two sequential sera samples obtained during the scheduled visits without clinical suspicion of dengue (identified during the time period in which seroconversion occurred). Data were not analyzed by Dengue season as planned in the protocol as most of the cases occurred outside the seasons. | At each calendar year i.e. Year 2014, 2015, 2016, 2017, 2018, and overall calendar years | 
| Number of Suspected Dengue Cases With Severity Criteria | To describe symptoms and spectrum of dengue disease in the study population for the suspected dengue cases, excluding those reported without fever. Suspected symptomatic dengue case= Febrile illness with body temperature ≥ 38°C measured (by any route) on at least two consecutive days and less than 14 days with or without the presence of other dengue symptoms or signs, without an obvious aetiology unrelated to dengue, based on investigator's judgement; Lab-confirmed = laboratory-confirmed symptomatic dengue cases; Probable = probable symptomatic dengue cases; Negative = negative symptomatic dengue cases; Indeterminate = indeterminate symptomatic dengue case( not classified as laboratory confirmed case, probable case or negative case); Severe dengue episode = at least one criteria met for severe dengue (in accordance to the dengue with warning signs and severe dengue definitions in the 2009 WHO guidelines for dengue). | From Year 2014 to Year 2018 (a range of 1 to 4 years for an individual subject) | 
| Number of Subjects With Serious Adverse Events (SAEs) Related to a Study Procedure | Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity. | From Year 2014 to Year 2018 (a range of 1 to 4 years for an individual subject) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endemic regions, Brazil, Incidence, Surveillance, Dengue