ED Influenza Therapeutic Pilot Study: Oseltamivir vs. Peramivir

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02609399
• Collaborator: Department of Health and Human Services (U.S. Fed)
• Enrollment: 180
• Locations: 2
• Arms: 2
• Actual Duration (Months): 30.9
• Patients Per Site: 90
• Patients Per Site Per Month: 2.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Influenza	Drug: Oseltamivir; Drug: Peramivir	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 180 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Influenza Therapeutic Trial: 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
• Actual Study Start Date: Nov 1, 2015
• Actual Primary Completion Date: May 26, 2017
• Actual Study Completion Date: May 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oseltamivir Subjects randomized to the oral treatment arm will receive 5 days of oral oseltamivir.	Drug: Oseltamivir; Oral; Other Names: Tamiflu
Experimental: Peramivir Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir.	Drug: Peramivir; IV Note: Subjects admitted to the hospital directly from the ED Enrollment Visit may receive more doses at the discretion of the treating physician.; Other Names: Rapivab

Outcome Measures

Primary Outcome Measures

1. 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: Not at all A little bit Somewhat Quite a bit Very much

2. 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: Not at all A little bit Somewhat Quite a bit Very much

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Maricopa Integrated Health System	Phoenix	Arizona	United States	85008
2	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287

Sponsors and Collaborators

• Johns Hopkins University
• Department of Health and Human Services

Investigators

• Principal Investigator: Richard Rothman, MD, PhD, Johns Hopkins University

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Sep 26, 2016

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT02609399
• Other Study ID Numbers: IRB00080405; 1 IDSEP150026-01-00; 1 IDSEP160031-01-00
• First Posted: Nov 20, 2015
• Last Update Posted: Oct 4, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Johns Hopkins University: Influenza; Antiviral treatment; Emergency department; Influenza therapeutics; Rapid influenza testing
• Additional relevant MeSH terms: Influenza, Human; Oseltamivir; Peramivir

Study Results

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)

Arm/Group Title	Oseltamivir	Peramivir
Arm/Group Description	Subjects randomized to the oral treatment arm will receive 5 days of oral oseltamivir.	Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir. (Subjects admitted to the hospital directly from the ED Enrollment Visit may receive more doses at the discretion of the treating physician).
Period Title: Influenza Season 2015-2016
STARTED	27	31
COMPLETED	24	29
NOT COMPLETED	3	2
Period Title: Influenza Season 2015-2016
STARTED	58	64
COMPLETED	49	59
NOT COMPLETED	9	5

Baseline Characteristics

Arm/Group Title	Experimental: Oseltamivir	Experimental: Peramivir	Total
Arm/Group Description	Subjects randomized to the oral treatment arm will receive 5 days of oral oseltamivir.	Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir.	Total of all reporting groups
Overall Participants	84	95	179
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	47.3	47.5	47.4
Sex: Female, Male (Count of Participants)
Female	48 57.1%	58 61.1%	106 59.2%
Male	36 42.9%	37 38.9%	73 40.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 11.9%	19 20%	29 16.2%
Not Hispanic or Latino	74 88.1%	76 80%	150 83.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.2%	2 2.1%	3 1.7%
Asian	2 2.4%	1 1.1%	3 1.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	60 71.4%	60 63.2%	120 67%
White	21 25%	29 30.5%	50 27.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	3 3.2%	3 1.7%
Region of Enrollment (participants) [Number]
United States	84 100%	95 100%	179 100%
Age, Continuous (Influenza Season 2015-2016) (years) [Mean (Full Range) ]
Mean (Full Range) [years]	48.7	43.7	46
Age, Continuous (Influenza Season 2016-2017) (years) [Mean (Full Range) ]
Mean (Full Range) [years]	46.6	49.3	48.0
Sex: Female, Male (Influenza Season 2015-2016) (Count of Participants)
Female	11 13.1%	17 17.9%	28 15.6%
Male	16 19%	14 14.7%	30 16.8%
Sex: Female, Male (Influenza Season 2016-2017) (Count of Participants)
Female	37 44%	41 43.2%	78 43.6%
Male	20 23.8%	23 24.2%	43 24%
Ethnicity (NIH/OMB) (Influenza Season 2015-2016) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	27 32.1%	31 32.6%	58 32.4%
Ethnicity (NIH/OMB) (Influenza Season 2016-2017) (Count of Participants)
Hispanic or Latino	10 11.9%	19 20%	29 16.2%
Not Hispanic or Latino	47 56%	45 47.4%	92 51.4%
Race (NIH/OMB) (Influenza Season 2015-2016) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.1%	1 0.6%
Asian	0 0%	1 1.1%	1 0.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	22 26.2%	24 25.3%	46 25.7%
White	5 6%	5 5.3%	10 5.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Influenza Season 2016-2017) (Count of Participants)
American Indian or Alaska Native	1 1.2%	1 1.1%	2 1.1%
Asian	2 2.4%	0 0%	2 1.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	38 45.2%	36 37.9%	74 41.3%
White	16 19%	24 25.3%	40 22.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	3 3.2%	3 1.7%

Outcome Measures

1. Primary Outcome

Title	Mean Symptom Severity Score During the 2015-2016 Influenza Season for Symptom Domains as Assessed Using the Influenza-Patient Reported Outcome (FLU-PRO™) Questionnaire
Description	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: Not at all A little bit Somewhat Quite a bit Very much
Time Frame	ED Enrollment Visit through Day 14 ( 2015-2016 influenza season)

Outcome Measure Data

Analysis Population Description

All subjects enrolled and randomized.

Arm/Group Title	Oseltamivir	Peramivir
Arm/Group Description	Subjects randomized to the oral treatment arm will receive 5 days of oral oseltamivir.	Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir. (Subjects admitted to the hospital directly from the ED Enrollment Visit may receive more doses at the discretion of the treating physician).
Measure Participants	27	31
Nose	1.4 (0.8)	1.9 (1.3)
Throat	1.3 (0.8)	1.7 (1.2)
Eyes	1.2 (0.6)	1.6 (1.2)
Chest/Respiratory	1.9 (1.2)	2.3 (1.5)
Gastrointestinal	1.5 (1.1)	1.5 (1.1)
Body/Systemic	1.7 (1.2)	1.9 (1.4)
Total/Overall	1.6 (1.1)	1.9 (1.4)

2. Primary Outcome

Title	Mean Symptom Severity Score During the 2016-2017 Influenza Season for Symptom Domains as Assessed Using the FLU-PRO™ Questionnaire
Description	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: Not at all A little bit Somewhat Quite a bit Very much
Time Frame	ED Enrollment Visit through Day 14 ( 2016-2017 influenza season)

Outcome Measure Data

Analysis Population Description

All enrolled and randomized subjects with the exception of 1 inadvertent enrollment (subject found to be ineligible shortly after randomization)

Arm/Group Title	Oseltamivir	Peramivir
Arm/Group Description	Subjects randomized to the oral treatment arm will receive 5 days of oral oseltamivir.	Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir. (Subjects admitted to the hospital directly from the ED Enrollment Visit may receive more doses at the discretion of the treating physician).
Measure Participants	57	64
Nose	1.5 (0.8)	1.5 (0.7)
Throat	1.3 (0.6)	1.4 (0.8)
Eyes	1.3 (0.7)	1.2 (0.5)
Chest/Respiratory	1.7 (0.8)	1.8 (0.9)
Gastrointestinal	1.3 (0.7)	1.3 (0.7)
Body/Systemic	1.5 (0.8)	1.5 (0.8)
Total/Overall	1.4 (0.6)	1.5 (0.6)

3. Primary Outcome

Title	Mean Karnofsky Performance Scale Score During the 2015-2016 Influenza Season
Description	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)

Outcome Measure Data

Analysis Population Description

All subjects enrolled and randomized.

Arm/Group Title	Experimental: Oseltamivir	Experimental: Peramivir
Arm/Group Description	Subjects randomized to the oral treatment arm received 5 days of oral oseltamivir.	Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir. (Subjects admitted to the hospital directly from the ED Enrollment Visit may receive more doses at the discretion of the treating physician).
Measure Participants	27	31
Mean (Standard Deviation) [units on a scale]	77.1 (20.8)	73.2 (19.9)

4. Primary Outcome

Title	Mean Karnofsky Performance Scale Score During the 2016-2017 Influenza Season
Description	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)

Outcome Measure Data

Analysis Population Description

All enrolled and randomized subjects with the exception of 1 inadvertent enrollment (subject found to be ineligible shortly after randomization)

Arm/Group Title	Experimental: Oseltamivir	Experimental: Peramivir
Arm/Group Description	Subjects randomized to the oral treatment arm received 5 days of oral oseltamivir.	Subjects randomized to the IV treatment group will receive 1 dose of IV peramivir. (Subjects admitted to the hospital directly from the ED Enrollment Visit may receive more doses at the discretion of the treating physician).
Measure Participants	57	64
Mean (Standard Deviation) [units on a scale]	80.0 (10.7)	79.9 (9.1)

Adverse Events

Time Frame	Accrual for the 2015-2016 influenza season opened on 11/1/2015 and closed on 4/30/2016. Accrual for the 2016-2017 influenza season opened on 11/1/2016 and closed on 4/30/2017. All enrolled participants were assessed for adverse events from enrollment visit until the end of study follow up on Day 28.
Arm/Group Title	Oseltamivir		Peramivir
Arm/Group Description	Subjects randomized to the oral treatment arm will receive 5 days of oral oseltamivir. Oseltamivir: Oral		Subjects randomized to the IV treatment group will receive 1 dose (or more as appropriate at the discretion of the treating physician) of IV peramivir. Peramivir: IV Note: Should a patient remain in the hospital after 5 days of treatment, and the patient is symptomatically better, treatment will stop. If the patient remains hospitalized after 5 days of treatment and has not improved, the treating physician will continue to have an option to continue use of peramivir daily for another 5 day course.
All Cause Mortality
	Oseltamivir		Peramivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/84 (0%)		0/95 (0%)
Serious Adverse Events
	Oseltamivir		Peramivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/84 (4.8%)		9/95 (9.5%)
Cardiac disorders
Myocardial infarction	0/84 (0%)	0	1/95 (1.1%)	1
Coronary artery disease	0/84 (0%)	0	1/95 (1.1%)	1
Gastrointestinal disorders
Intestinal perforation	1/84 (1.2%)	1	0/95 (0%)	0
Investigations
Blood creatinine increased	1/84 (1.2%)	1	0/95 (0%)	0
Musculoskeletal and connective tissue disorders
Abdominal Pain	0/84 (0%)	0	1/95 (1.1%)	1
Nervous system disorders
Syncope	0/84 (0%)	0	1/95 (1.1%)	1
Facial paralysis	0/84 (0%)	0	1/95 (1.1%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	1/84 (1.2%)	1	0/95 (0%)	0
Pneumonia	1/84 (1.2%)	1	0/95 (0%)	0
Pulmonary embolism	0/84 (0%)	0	1/95 (1.1%)	1
Chronic obstructive pulmonary disease (COPD)	0/84 (0%)	0	1/95 (1.1%)	1
Surgical and medical procedures
Pre-op admission	0/84 (0%)	0	1/95 (1.1%)	1
Vascular disorders
Hypotension	0/84 (0%)	0	2/95 (2.1%)	2
Other (Not Including Serious) Adverse Events
	Oseltamivir		Peramivir
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/84 (58.3%)		54/95 (56.8%)
Ear and labyrinth disorders
Vertigo	9/84 (10.7%)	9	10/95 (10.5%)	12
Gastrointestinal disorders
Diarrhea	28/84 (33.3%)	32	31/95 (32.6%)	36
Nausea	27/84 (32.1%)	29	21/95 (22.1%)	23
Vomiting	19/84 (22.6%)	20	16/95 (16.8%)	17
Nervous system disorders
Confusion/Hallucinations	6/84 (7.1%)	6	7/95 (7.4%)	7
Psychiatric disorders
Insomnia	12/84 (14.3%)	14	18/95 (18.9%)	18
Skin and subcutaneous tissue disorders
Rash	7/84 (8.3%)	8	5/95 (5.3%)	6

Limitations/Caveats

Not designed or powered to assess differences in clinical outcomes. Planned to recruit >= 50 subjects/site, but MMC enrolled 44 due to lower-than-expected flu incidence and Hopkins Uni. increased enrollment to make up for the shortfall.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.