Influenza, Respiratory Viral Infection
Conditions
Keywords
Tamiflu, Oseltamivir, Baloxavir, Influenza, Flu, Rapid Test, Xofluza
Brief summary
This study is a stepped-wedge cluster-randomized trial of on-site rapid testing and treatment for influenza in homeless shelters within the Seattle area to determine whether this strategy reduced the incidence of influenza in the shelter environment.
Detailed description
The study will be conducted over the course of two flu seasons, and all shelters will start with routine surveillance of influenza using mid-turbinate nasal swabs for sample collection and RT-PCR testing. Shelters will be randomized to implement a test-and-treat strategy at different months throughout flu season, treating individuals who present ARI symptoms or new or worsening cough within 2 days (48 hours). Shelters will continue routine surveillance until all offer the test-and-treat strategy. Eligible individuals will be tested on site with a point-of-care molecular influenza test and, if positive, offered antiviral treatment. Individuals with 3-7 days of symptoms, or who choose not to participate in the intervention strategy, will still be eligible for participation in the routine surveillance. Our primary hypothesis is that implementation of a point-of-care diagnostic and antiviral treatment intervention among sheltered individuals experiencing homelessness will reduce the incidence of influenza within this population over the course of a flu season. A process evaluation will also be conducted to explore the feasibility of point-of-care testing implementation in this population.
Interventions
COMBINATION_PRODUCTPoint-of-care molecular testing and treatment of influenza
Eligible individuals will be tested on site with a point-of-care molecular influenza test and, if positive, offered antiviral treatment with baloxavir for those aged ≥12 years, or oseltamivir for those aged \<12 years; pregnant; breastfeeding; liver disease; or are immunosuppressed. Follow-up nasal swabs and symptom diaries will be collected from participants 2 or 3 days after receiving the antiviral, and again 5, 6, or 7 days after receiving.
Sponsors
Genentech, Inc.
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* Resident for 1 or more days at a participating shelter * ≥2 ARI symptoms or acute cough alone * Willing to take study medication * Willing to comply with all study procedures, including weekly surveillance and repeat nasal swab at day 2/3 and day 5/6/7 post-treatment * Able to provide written, informed consent and/or assent
Exclusion criteria
* Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration * Inability to consent and/or comply with study protocol * Individuals who have received oseltamivir or baloxavir within past 7 days for treatment of influenza * Individuals with known hypersensitivity to baloxavir marboxil or oseltamivir * Individuals with chronic kidney disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Cases of Influenza in Shelters During the Intervention Period Compared to the Control Period | Year 1 of the intervention (4.5 months) | The intervention period is when test and treatment on-site was available and the control period is when just standard surveillance was available at a shelter. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Implementation of Influenza Treatment in Shelters | Up to 24 months | Number of influenza-positive participants identified through on-site molecular testing in the intervention period that were treated with an antiviral |
| Number of Participants That Drop Out of Study | Up to 24 months | Measured as becoming lost to follow-up (did not complete both follow-up study visits on day 2/3 and day 5/6/7) after testing positive for influenza at baseline enrollment with an on-site molecular test and receiving an antiviral |
| Number of Participants That Show Non-compliance With Study Drug | Up to 24 months | Only applicable to those that receive oseltamivir rather than baloxavir which is a single-dose antiviral. Measured based on self-report during follow-up visits with study research assistants. Non-compliance is measured as the participant self-reporting fewer doses taken than to be expected at time of of follow-up (e.g. a participant that took there first dose of oseltamivir in the AM on March 8 would be expected to have taken 6 doses if their follow-up visit was in the PM on March 10). |
| Feasibility of Implementation of Point-of-care Molecular Testing and Treatment of Influenza in Shelters | Up to 24 months | Number of participants/participant encounters with les than 48 hours between symptom onset until diagnosis with RT-PCR. |
| Influenza Viral RNA Levels | Up to 24 months | Measured mean cycle threshold (Ct) value for each laboratory-confirmed influenza-positive specimen collected at baseline enrollment, by subtype. Ct values have an inverse relationship with viral load. |
| Number of Samples With Detectable Influenza RNA Virus at Days 2/3 and Days 5/6/7 | Up to 24 months | Measured at subject follow-up visits with nasal swabs provided to study staff; provided subject has not become lost to follow up. |
| Number of Laboratory-confirmed Influenza Cases That Report Fever | Up to 24 months | Based on self-report of new or worsening fever in the past 7 days; not gold standard measurement |
Countries
United States
Participant flow
Recruitment details
Participants for this test-and-treat intervention were recruited from homeless shelters across King County, WA and implemented over two respiratory virus seasons (11/15/2019 - 3/31/2020; 11/2/2020 - 3/31/2021). In Year 1, 9 shelters were randomized to receive the intervention in a stepped-wedge approach. Due to the impact of COVID-19, residents from 6 shelters were relocated to new facilities for social distancing reasons. Re-randomization, including these new facilities, occurred Year 2.
Pre-assignment details
Since shelters were randomized to receive the intervention in cascading intervals as part of a stepped-wedge approach rather than participants themselves, participant study encounters rather than unique participants serve as the baseline unit of measure. Since participants are cross-sectionally recruited and not followed longitudinally unless they received antiviral treatment (for 1 week), there is no dropout between study periods, only new enrollments.
Participants by arm
| Arm | Count |
|---|---|
| Standard Influenza Surveillance Period Subjects exhibiting ≥ 2 ARI symptoms or new or worsening cough in the last 7 days at a participating shelter complete a survey collecting demographic and clinical data, and provide a mid-turbinate nasal swab for RT-PCR testing.
These are all participants that enrolled when only standard surveillance, no intervention, was available at their shelter given the randomized sequence. | 853 |
| Point-of-care Molecular Testing and Treatment of Influenza Period Subjects exhibiting ≥ 2 ARI symptoms, or new or worsening cough, in the last 48 hrs at a participating shelter complete a survey collecting demographic and clinical data, and provide a mid-turbinate nasal swab to be tested on-site with a molecular assay (Abbott ID NOW™ Influenza A & B (Chicago, IL)) and receive an antiviral if tested positive (XOFLUZA™ or Tamiflu®) .
Point-of-care molecular testing and treatment of influenza: Eligible individuals will be tested on site with a point-of-care molecular influenza test and, if positive, offered antiviral treatment with baloxavir for those aged ≥12 years, or oseltamivir for those aged \<12 years; pregnant; breastfeeding; liver disease; or are immunosuppressed. Follow-up nasal swabs and symptom diaries will be collected from participants 2 or 3 days after receiving the antiviral, and again 5, 6, or 7 days after receiving.
These are all participants that enrolled when both standard surveillance and the intervention was available at their shelter given the randomized sequence. | 765 |
| Total | 1,618 |
Baseline characteristics
| Characteristic | Standard Influenza Surveillance Period | Point-of-care Molecular Testing and Treatment of Influenza Period | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 85 Participants | 62 Participants | 147 Participants |
| Age, Categorical >=65 years | 41 Participants | 36 Participants | 77 Participants |
| Age, Categorical Between 18 and 65 years | 727 Participants | 667 Participants | 1394 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 109 Participants | 71 Participants | 180 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 731 Participants | 683 Participants | 1414 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 11 Participants | 24 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 24 Participants | 25 Participants | 49 Participants |
| Race (NIH/OMB) Asian | 20 Participants | 12 Participants | 32 Participants |
| Race (NIH/OMB) Black or African American | 231 Participants | 191 Participants | 422 Participants |
| Race (NIH/OMB) More than one race | 95 Participants | 84 Participants | 179 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 14 Participants | 2 Participants | 16 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 99 Participants | 96 Participants | 195 Participants |
| Race (NIH/OMB) White | 370 Participants | 355 Participants | 725 Participants |
| Sex/Gender, Customized Data missing | 0 Participants | 1 Participants | 1 Participants |
| Sex/Gender, Customized Female | 323 Participants | 181 Participants | 504 Participants |
| Sex/Gender, Customized Male | 521 Participants | 576 Participants | 1097 Participants |
| Sex/Gender, Customized Other | 4 Participants | 3 Participants | 7 Participants |
| Sex/Gender, Customized Prefer not to say | 5 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 853 | 0 / 765 |
| other Total, other adverse events | 0 / 853 | 5 / 765 |
| serious Total, serious adverse events | 0 / 853 | 0 / 765 |
Outcome results
Primary
Number of Participants With Cases of Influenza in Shelters During the Intervention Period Compared to the Control Period
The intervention period is when test and treatment on-site was available and the control period is when just standard surveillance was available at a shelter.
Time frame: Year 1 of the intervention (4.5 months)
Population: Due to the impact of COVID-19 mitigation efforts on reduced influenza transmission in Year 2 of the study and subsequent early stop due to operational futility, the analysis population for the primary outcome only includes unique participants who enrolled in Year 1 of the study (11/15/19 - 3/31/20). For this primary outcome measure, we used the number of unique participants in Year 1 as the denominator rather than all participant enrollments.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Influenza Surveillance Period | Number of Participants With Cases of Influenza in Shelters During the Intervention Period Compared to the Control Period | 23 Participants |
| Point-of-care Molecular Testing and Treatment of Influenza Period | Number of Participants With Cases of Influenza in Shelters During the Intervention Period Compared to the Control Period | 32 Participants |
Comparison: The number of influenza-positive tests was analyzed using a generalized linear mixed model following a Poisson distribution with a log link and robust variance. The model is adjusted for calendar time and an exposure time variable based on shelter capacity. This model includes symptomatic individuals who tested throughout Year 1 of the study (November 15, 2019 - March 31, 2020).95% CI: [0.35, 5.02]
Secondary
Feasibility of Implementation of Influenza Treatment in Shelters
Number of influenza-positive participants identified through on-site molecular testing in the intervention period that were treated with an antiviral
Time frame: Up to 24 months
Population: This outcome can only be assessed among participants enrollments from the intervention period as those in the control period (standard influenza surveillance) were not eligible for antiviral treatment. Those that reported symptom onset ≥48 hours that were enrolled in the intervention period were dropped from the overall number of participants analyzed. The analysis population includes only influenza-positive cases that were detected using an on-site molecular test.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Point-of-care Molecular Testing and Treatment of Influenza Period | Feasibility of Implementation of Influenza Treatment in Shelters | 21 Participants |
Secondary
Feasibility of Implementation of Point-of-care Molecular Testing and Treatment of Influenza in Shelters
Number of participants/participant encounters with les than 48 hours between symptom onset until diagnosis with RT-PCR.
Time frame: Up to 24 months
Population: Includes all participant encounters from study Years 1 and 2. 153 participant encounters were missing this data because they were asymptomatic enrollments conducted once monthly at all shelters between 11/15/2019 and 3/31/2020.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Influenza Surveillance Period | Feasibility of Implementation of Point-of-care Molecular Testing and Treatment of Influenza in Shelters | 266 Participants |
| Point-of-care Molecular Testing and Treatment of Influenza Period | Feasibility of Implementation of Point-of-care Molecular Testing and Treatment of Influenza in Shelters | 308 Participants |
Secondary
Influenza Viral RNA Levels
Measured mean cycle threshold (Ct) value for each laboratory-confirmed influenza-positive specimen collected at baseline enrollment, by subtype. Ct values have an inverse relationship with viral load.
Time frame: Up to 24 months
Population: All influenza-positive specimen detected through RT-PCR in study Years 1 and 2. One individual in the standard surveillance period was coinfected with both Influenza A and Influenza B, therefore these row numbers are not mutually exclusive.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Standard Influenza Surveillance Period | Influenza Viral RNA Levels | Influenza B | 22.08 Cycle threshold value |
| Standard Influenza Surveillance Period | Influenza Viral RNA Levels | Influenza A | 19.22 Cycle threshold value |
| Point-of-care Molecular Testing and Treatment of Influenza Period | Influenza Viral RNA Levels | Influenza B | 18.51 Cycle threshold value |
| Point-of-care Molecular Testing and Treatment of Influenza Period | Influenza Viral RNA Levels | Influenza A | 21.21 Cycle threshold value |
Secondary
Number of Laboratory-confirmed Influenza Cases That Report Fever
Based on self-report of new or worsening fever in the past 7 days; not gold standard measurement
Time frame: Up to 24 months
Population: All influenza positive cases detected in study Years 1 and 2; there were no cases of influenza detected in year 2 of the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard Influenza Surveillance Period | Number of Laboratory-confirmed Influenza Cases That Report Fever | 12 Participants |
| Point-of-care Molecular Testing and Treatment of Influenza Period | Number of Laboratory-confirmed Influenza Cases That Report Fever | 16 Participants |
Secondary
Number of Participants That Drop Out of Study
Measured as becoming lost to follow-up (did not complete both follow-up study visits on day 2/3 and day 5/6/7) after testing positive for influenza at baseline enrollment with an on-site molecular test and receiving an antiviral
Time frame: Up to 24 months
Population: Only participant enrollments from the intervention period that tested positive for influenza at baseline enrollment with an on-site molecular test and received an antiviral are included in this analysis population as participant enrollments under the standard influenza surveillance period did not receive follow-up.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Point-of-care Molecular Testing and Treatment of Influenza Period | Number of Participants That Drop Out of Study | 1 Participants |
Secondary
Number of Participants That Show Non-compliance With Study Drug
Only applicable to those that receive oseltamivir rather than baloxavir which is a single-dose antiviral. Measured based on self-report during follow-up visits with study research assistants. Non-compliance is measured as the participant self-reporting fewer doses taken than to be expected at time of of follow-up (e.g. a participant that took there first dose of oseltamivir in the AM on March 8 would be expected to have taken 6 doses if their follow-up visit was in the PM on March 10).
Time frame: Up to 24 months
Population: This analysis population includes all participants that received oseltamivir as an antiviral and returned for at least one follow-up study visit when a number of doses of the medication was reported to study staff.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Point-of-care Molecular Testing and Treatment of Influenza Period | Number of Participants That Show Non-compliance With Study Drug | 1 Participants |
Secondary
Number of Samples With Detectable Influenza RNA Virus at Days 2/3 and Days 5/6/7
Measured at subject follow-up visits with nasal swabs provided to study staff; provided subject has not become lost to follow up.
Time frame: Up to 24 months
Population: Only includes influenza-positive samples from participant enrollments collected in the intervention period and detected with an on-site molecular test. Of the 21 participants that received an antiviral and, according to the protocol, should have returned for follow-up sample collect and study visits, only 14 returned on day 2/3 and only 1 returned for day 2/3 and day 5/6/7 study visits.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Point-of-care Molecular Testing and Treatment of Influenza Period | Number of Samples With Detectable Influenza RNA Virus at Days 2/3 and Days 5/6/7 | Detectable at day 5/6/7 | 0 Participants |
| Point-of-care Molecular Testing and Treatment of Influenza Period | Number of Samples With Detectable Influenza RNA Virus at Days 2/3 and Days 5/6/7 | Detectable at day 2/3 | 7 Participants |