Influenza
Conditions
Keywords
Influenza, Antiviral treatment, Emergency department, Influenza therapeutics, Rapid influenza testing
Brief summary
This pilot study is designed to demonstrate the feasibility of utilizing Emergency Departments (EDs) as a primary site for subject enrollment in clinical trials evaluating influenza therapeutics, and to provide pilot data for future clinical trial design and planning. Primary Objective: To prospectively enroll high-risk subjects with laboratory-confirmed influenza into a randomized, open label study of oral versus IV influenza therapeutic to include symptom evaluation and outcome assessments. Secondary Objective 1: To identify influenza positive patients utilizing a previously established triage-based assessment and rapid testing algorithm for suspected influenza infection. Secondary Objective 2: To retrospectively evaluate all potentially eligible patients for potential enrollment biases. Secondary Objective 3: To create a repository of residual nasopharyngeal samples collected from ED patients with suspected influenza illness.
Detailed description
Title: A Pilot Randomized Controlled Trial for Feasibility of Enrolling Subjects for Influenza Therapeutic Trials and Administering Influenza Antivirals in the Emergency Department to High Risk Subjects Population: Adults presenting to the emergency department (ED) with laboratory confirmed influenza who meet Centers for Disease Control and Prevention (CDC) criteria for antiviral treatment Informed consent: Written informed consent Number of Sites: 2 - large, urban, academically-affiliated, US EDs Study Duration: November 2015 - June 2018 Subject Participation Duration: 4 weeks Description of Agent or Intervention: Subjects will be randomized to either oral (oseltamivir) or intravenous (IV) (peramivir) antiviral treatment. Description of Study Design: This is an open-label randomized controlled clinical trial in which subjects with influenza are randomized to either oral (oseltamivir) or IV (peramivir) antiviral treatment. Estimated Time to Complete Enrollment: Subject enrollment will occur over two influenza seasons (November 2015 - April 2016 and November 2016 - April 2017) or longer, at the Principal Investigator's discretion, based on influenza prevalence.
Interventions
DRUGOseltamivir
Oral
DRUGPeramivir
IV Note: Subjects admitted to the hospital directly from the ED Enrollment Visit may receive more doses at the discretion of the treating physician.
Sponsors
Department of Health and Human Services
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Eligible patients include all patients who present to the emergency department (ED) between November and April of each influenza season, or later, at the Co-PIs' discretion, based on influenza prevalence, with the following criteria: 1. 18 years of age or older 2. Laboratory confirmed positive influenza test associated with their current ED visit 3. Symptoms of acute respiratory illness for ≤4 days (96 hours) 4. Meets CDC criteria for antiviral treatment * For the purpose of this study, acute respiratory illness is defined as presence of any of the following symptoms: new or increased cough, new or increased shortness of breath, change in sputum production (for adults 65 years or older), sinus pain, nasal congestion, rhinorrhea, sore throat, subjective fever reported at time of triage or documented fever (defined here as ≥ 38 degrees Celsius). * CDC criteria for influenza antiviral treatment is defined as: being age 65 years old or older, pregnant or less than two weeks postpartum, American Indian or Alaska native, morbid obesity (BMI ≥40), a current resident of nursing home or other chronic-care facility, having chronic pulmonary disease, cardiovascular disease (except hypertension alone), renal disease, hepatic disease, hematologic disease, metabolic disorders, neurologic and neurodevelopment conditions, immunosuppression (including that caused by medications or by HIV infection), being admitted to inpatient or an observation unit, or having a clinical diagnosis of pneumonia (by the ED physician).
Exclusion criteria
1. Does not speak and understand English (or English or Spanish) 2. Unable or unwilling to provide informed consent 3. Previously enrolled in the study during the current influenza season 4. Unable to take oral medication 5. Unable to comply with all planned study procedures including availability for follow-up and willingness to complete study diary and self-assessment 6. Use of neuraminidase inhibitors within the past seven days 7. Known allergic reaction to neuraminidase inhibitors 8. Pregnant or breastfeeding 9. End-stage renal disease, defined as 9a. Currently undergoing dialysis (either hemo or peritoneal); or 9b. Creatinine clearance (CrCl) of \<10 mL/min. 10. End-stage liver disease, as determined by the treating ED provider 11. Glucose-6-phosphate dehydrogenase (G6PD) deficiency by patient report 12. Immunodeficiency, defined as: 12a. Solid organ transplant patients receiving immunosuppression; 12b. Hematopoietic stem cell transplant patients within 12 months of transplant or with ongoing immunosuppression; 12c. Oncology patients who have had chemotherapy within the past 30 days; 12d. Current treatment with steroids equivalent to 10 mg of prednisone or more per day for greater than two weeks; 12e. Rheumatologic patients receiving immunosuppressive therapy; or 12f. HIV patients who meet one of the following criteria: 12fi. Have a cluster of differentiation 4 (CD4) cell count of \<200 cells/mm3 within the past 3 months ; 12fii. Not actively receiving highly active antiretroviral therapy (HAART); or 12fiii. Have an absolute lymphocyte count \<1.0 x 103 cells/μL conducted at the current ED visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | ED Enrollment Visit through Day 14 ( 2015-2016 influenza season) | Symptom evaluation during the 2015-2016 influenza season as recorded through FLU-PRO™: a daily diary developed to assess occurrence and severity of influenza symptoms. Item responses: 1. Not at all 2. A little bit 3. Somewhat 4. Quite a bit 5. Very much |
| Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | ED Enrollment Visit through Day 14 ( 2016-2017 influenza season) | Symptom evaluation during the 2016-2017 influenza season as recorded through FLU-PRO™: a daily diary developed to assess occurrence and severity of influenza symptoms. Item responses: 1. Not at all 2. A little bit 3. Somewhat 4. Quite a bit 5. Very much |
| Mean Karnofsky Performance Scale Score During the 2015-2016 Influenza Season | ED Enrollment Visit through Day 14 ( 2015-2016 influenza season) | The Karnofsky Performance Scale is a tool for assessing subject functional impairment. Subjects provided or received (from a healthcare provider such as a doctor or nurse) a daily rating from 0 (Dead) to 100 (Normal - no complaints, no evidence of disease) from enrollment through Day 14 of the 2015-2016 influenza season. |
| Mean Karnofsky Performance Scale Score During the 2016-2017 Influenza Season | ED Enrollment Visit through Day 14 ( 2016-2017 influenza season) | The Karnofsky Performance Scale is a tool for assessing subject functional impairment. Subjects provided or received (from a healthcare provider such as a doctor or nurse) a daily rating from 0 (Dead) to 100 (Normal - no complaints, no evidence of disease) from enrollment through Day 14 of the 2016-2017 influenza season. |
Countries
United States
Participant flow
Recruitment details
This study recruited adult patients through both clinical testing and screening with a Clinical Decision Guideline (CDG) over two influenza seasons at the following academically affiliated U.S. Emergency Departments (EDs): * November 2015- April 2016: Johns Hopkins Hospital (JHH) * November 2016- April 2017: JHH and Maricopa Medical Center (MMC)
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Oseltamivir Subjects randomized to the oral treatment arm will receive 5 days of oral oseltamivir. | 84 |
| Experimental: Peramivir Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir. | 95 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Influenza Season 2015-2016 | Lost to Follow-up | 3 | 2 |
| Influenza Season 2016-2017 | Found ineligible after randomization | 1 | 0 |
| Influenza Season 2016-2017 | Lost to Follow-up | 8 | 5 |
Baseline characteristics
| Characteristic | Experimental: Oseltamivir | Experimental: Peramivir | Total |
|---|---|---|---|
| Age, Continuous | 47.3 years | 47.5 years | 47.4 years |
| Age, Continuous (Influenza Season 2015-2016) | 48.7 years | 43.7 years | 46 years |
| Age, Continuous (Influenza Season 2016-2017) | 46.6 years | 49.3 years | 48.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 19 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 74 Participants | 76 Participants | 150 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) (Influenza Season 2015-2016) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) (Influenza Season 2015-2016) Not Hispanic or Latino | 27 Participants | 31 Participants | 58 Participants |
| Ethnicity (NIH/OMB) (Influenza Season 2016-2017) Hispanic or Latino | 10 Participants | 19 Participants | 29 Participants |
| Ethnicity (NIH/OMB) (Influenza Season 2016-2017) Not Hispanic or Latino | 47 Participants | 45 Participants | 92 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 60 Participants | 60 Participants | 120 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 21 Participants | 29 Participants | 50 Participants |
| Race (NIH/OMB) (Influenza Season 2015-2016) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) (Influenza Season 2015-2016) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) (Influenza Season 2015-2016) Black or African American | 22 Participants | 24 Participants | 46 Participants |
| Race (NIH/OMB) (Influenza Season 2015-2016) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) (Influenza Season 2015-2016) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) (Influenza Season 2015-2016) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) (Influenza Season 2015-2016) White | 5 Participants | 5 Participants | 10 Participants |
| Race (NIH/OMB) (Influenza Season 2016-2017) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) (Influenza Season 2016-2017) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) (Influenza Season 2016-2017) Black or African American | 38 Participants | 36 Participants | 74 Participants |
| Race (NIH/OMB) (Influenza Season 2016-2017) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) (Influenza Season 2016-2017) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) (Influenza Season 2016-2017) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) (Influenza Season 2016-2017) White | 16 Participants | 24 Participants | 40 Participants |
| Region of Enrollment United States | 84 participants | 95 participants | 179 participants |
| Sex: Female, Male Female | 48 Participants | 58 Participants | 106 Participants |
| Sex: Female, Male Male | 36 Participants | 37 Participants | 73 Participants |
| Sex: Female, Male (Influenza Season 2015-2016) Female | 11 Participants | 17 Participants | 28 Participants |
| Sex: Female, Male (Influenza Season 2015-2016) Male | 16 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male (Influenza Season 2016-2017) Female | 37 Participants | 41 Participants | 78 Participants |
| Sex: Female, Male (Influenza Season 2016-2017) Male | 20 Participants | 23 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 84 | 0 / 95 |
| other Total, other adverse events | 49 / 84 | 54 / 95 |
| serious Total, serious adverse events | 4 / 84 | 9 / 95 |
Outcome results
Primary
Mean Karnofsky Performance Scale Score During the 2015-2016 Influenza Season
The Karnofsky Performance Scale is a tool for assessing subject functional impairment. Subjects provided or received (from a healthcare provider such as a doctor or nurse) a daily rating from 0 (Dead) to 100 (Normal - no complaints, no evidence of disease) from enrollment through Day 14 of the 2015-2016 influenza season.
Time frame: ED Enrollment Visit through Day 14 ( 2015-2016 influenza season)
Population: All subjects enrolled and randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oseltamivir | Mean Karnofsky Performance Scale Score During the 2015-2016 Influenza Season | 77.1 units on a scale | Standard Deviation 20.8 |
| Peramivir | Mean Karnofsky Performance Scale Score During the 2015-2016 Influenza Season | 73.2 units on a scale | Standard Deviation 19.9 |
Primary
Mean Karnofsky Performance Scale Score During the 2016-2017 Influenza Season
The Karnofsky Performance Scale is a tool for assessing subject functional impairment. Subjects provided or received (from a healthcare provider such as a doctor or nurse) a daily rating from 0 (Dead) to 100 (Normal - no complaints, no evidence of disease) from enrollment through Day 14 of the 2016-2017 influenza season.
Time frame: ED Enrollment Visit through Day 14 ( 2016-2017 influenza season)
Population: All enrolled and randomized subjects with the exception of 1 inadvertent enrollment (subject found to be ineligible shortly after randomization)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Oseltamivir | Mean Karnofsky Performance Scale Score During the 2016-2017 Influenza Season | 80.0 units on a scale | Standard Deviation 10.7 |
| Peramivir | Mean Karnofsky Performance Scale Score During the 2016-2017 Influenza Season | 79.9 units on a scale | Standard Deviation 9.1 |
Primary
Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire
Symptom evaluation during the 2015-2016 influenza season as recorded through FLU-PRO™: a daily diary developed to assess occurrence and severity of influenza symptoms. Item responses: 1. Not at all 2. A little bit 3. Somewhat 4. Quite a bit 5. Very much
Time frame: ED Enrollment Visit through Day 14 ( 2015-2016 influenza season)
Population: All subjects enrolled and randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oseltamivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Eyes | 1.2 units on a scale | Standard Deviation 0.6 |
| Oseltamivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Gastrointestinal | 1.5 units on a scale | Standard Deviation 1.1 |
| Oseltamivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Throat | 1.3 units on a scale | Standard Deviation 0.8 |
| Oseltamivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Body/Systemic | 1.7 units on a scale | Standard Deviation 1.2 |
| Oseltamivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Chest/Respiratory | 1.9 units on a scale | Standard Deviation 1.2 |
| Oseltamivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Total/Overall | 1.6 units on a scale | Standard Deviation 1.1 |
| Oseltamivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Nose | 1.4 units on a scale | Standard Deviation 0.8 |
| Peramivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Total/Overall | 1.9 units on a scale | Standard Deviation 1.4 |
| Peramivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Nose | 1.9 units on a scale | Standard Deviation 1.3 |
| Peramivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Throat | 1.7 units on a scale | Standard Deviation 1.2 |
| Peramivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Eyes | 1.6 units on a scale | Standard Deviation 1.2 |
| Peramivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Chest/Respiratory | 2.3 units on a scale | Standard Deviation 1.5 |
| Peramivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Gastrointestinal | 1.5 units on a scale | Standard Deviation 1.1 |
| Peramivir | Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire | Body/Systemic | 1.9 units on a scale | Standard Deviation 1.4 |
Primary
Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire
Symptom evaluation during the 2016-2017 influenza season as recorded through FLU-PRO™: a daily diary developed to assess occurrence and severity of influenza symptoms. Item responses: 1. Not at all 2. A little bit 3. Somewhat 4. Quite a bit 5. Very much
Time frame: ED Enrollment Visit through Day 14 ( 2016-2017 influenza season)
Population: All enrolled and randomized subjects with the exception of 1 inadvertent enrollment (subject found to be ineligible shortly after randomization)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Oseltamivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Eyes | 1.3 units on a scale | Standard Deviation 0.7 |
| Oseltamivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Gastrointestinal | 1.3 units on a scale | Standard Deviation 0.7 |
| Oseltamivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Throat | 1.3 units on a scale | Standard Deviation 0.6 |
| Oseltamivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Body/Systemic | 1.5 units on a scale | Standard Deviation 0.8 |
| Oseltamivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Chest/Respiratory | 1.7 units on a scale | Standard Deviation 0.8 |
| Oseltamivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Total/Overall | 1.4 units on a scale | Standard Deviation 0.6 |
| Oseltamivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Nose | 1.5 units on a scale | Standard Deviation 0.8 |
| Peramivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Total/Overall | 1.5 units on a scale | Standard Deviation 0.6 |
| Peramivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Nose | 1.5 units on a scale | Standard Deviation 0.7 |
| Peramivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Throat | 1.4 units on a scale | Standard Deviation 0.8 |
| Peramivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Eyes | 1.2 units on a scale | Standard Deviation 0.5 |
| Peramivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Chest/Respiratory | 1.8 units on a scale | Standard Deviation 0.9 |
| Peramivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Gastrointestinal | 1.3 units on a scale | Standard Deviation 0.7 |
| Peramivir | Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire | Body/Systemic | 1.5 units on a scale | Standard Deviation 0.8 |