Exploring Safety & Clinical Benefit of Anti-Influenza Immunoglobulin Intravenous in Hospitalized Adults With Influenza A

• Sponsor: Emergent BioSolutions (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03315104
• Collaborator: (none)
• Enrollment: 65
• Locations: 55
• Arms: 3
• Actual Duration (Months): 19
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Influenza, or the flu, is an infectious respiratory disease that can range in severity from mild to severe to even death. This study aims to evaluate a treatment for people who are hospitalized with the flu. The study is looking to see if antibodies collected from people who have recovered from the seasonal flu or who have had the seasonal flu shot can be used safely as a study drug to treat hospitalized patients with severe flu infections. Also, this study will help to find the right dose for this study drug for treatment of severe flu in hospitalized patients. Overall, this study will evaluate if the hospitalized patients receiving standard of care along with the study drug get better more quickly than those treated with standard of care and placebo. The study drug that contains antibodies against the flu is called anti-influenza immunoglobulin intravenous (FLU-IGIV).

Condition or Disease	Intervention/Treatment	Phase
Influenza A H3N2; Influenza A H1N1	Biological: FLU-IGIV; Other: Placebo for FLU-IGIV	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Staggered enrollment for the first 9 subjects, then parallel low and high dose treatment with a placebo groupStaggered enrollment for the first 9 subjects, then parallel low and high dose treatment with a placebo group
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Dose Ranging Study Evaluating Safety, Pharmacokinetics and Clinical Benefit of FLU-IGIV in Hospitalized Patients With Serious Influenza A Infection
• Actual Study Start Date: Nov 17, 2017
• Actual Primary Completion Date: Jun 17, 2019
• Actual Study Completion Date: Jun 17, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FLU-IGIV High Dose Participants will receive a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Participants will also receive standard of care (SOC) antiviral treatment for flu. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Biological: FLU-IGIV; Single dose, sterile liquid formulation for IV administration.; Other Names: Anti-influenza immunoglobulin intravenous (Human) NP-025
Experimental: FLU-IGIV Low Dose Participants will receive a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Participants will also receive SOC antiviral treatment for flu. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Biological: FLU-IGIV; Single dose, sterile liquid formulation for IV administration.; Other Names: Anti-influenza immunoglobulin intravenous (Human) NP-025
Placebo Comparator: FLU-IGIV Placebo Participants will receive a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Participants will also receive SOC antiviral treatment for flu. Administered IV as 500 mL of normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.	Other: Placebo for FLU-IGIV; Single dose, normal saline solution for IV administration.

Outcome Measures

Primary Outcome Measures

1. Frequency Counts and Percentage of Subjects With Adverse Events [Measured through Day 60]

   Frequency counts and percentage of subjects with Adverse Events by severity

2. Area Under the Plasma Concentration Curve [AUC] From Time 0 to 48 Hours Post-dose by Hemagglutinin Inhibition Assay [Measured through 48 Hours post-dose]

   Levels of anti-influenza A antibodies circulating in blood over time. We initially intended to look at this variable through Day 8, however, potential native antibody level changes and sparse sampling confounded results from 0 to 48 hours post-dose from PK samples collected from Baseline Day 1 pre-dose (time 0), Day 1 post-dose, Day 2 and Day 3 (if continued hospitalization), and Day 8. For AUC from time 0 to 48 hours, subjects who did not have a sample collected within +/-10% of 48 hours post-dose had this parameter set to missing, which is why the number of subjects who contributed data for this outcome measure is lower than the overall number of subjects analyzed.

3. Maximum Plasma Concentration [Cmax] Reported as a Titer for Hemagglutinin Inhibition Assay [Measured through Day 8 post-dose]

   Maximum observed concentration (reported as a titer) of anti-influenza A antibodies measured from Day 1 pre-dose (time 0) through Day 8 post-dose from PK samples collected from Baseline Day 1 pre-dose (time 0), Day 1 post-dose, Day 2 and Day 3 (if continued hospitalization), and Day 8.

4. Time Cmax is Observed [Tmax] by Hemagglutinin Inhibition Assay [Measured through Day 8 post-dose]

   Time that anti-influenza A antibodies are at maximum concentration from Day 1 pre-dose (time 0) through Day 8 post-dose from PK samples collected from Baseline Day 1 pre-dose (time 0), Day 1 post-dose, Day 2 and Day 3 (if continued hospitalization), and Day 8. The rate of study drug elimination and dependent parameters were not accurately estimable due to rising or sustained levels of anti-influenza A antibodies, this includes First Order Terminal Elimination Rate Constant [Kel], Plasma Clearance [Cl] and Total Volume of Distribution [Vz].

Secondary Outcome Measures

1. Ordinal Scale Subject Distribution Reflecting Clinical Status [At Day 8 post-dose]

   Score (physician-assessed): 1=death; 2=hospitalization in the intensive care unit (ICU); 3=non-ICU hospitalization requiring supplemental oxygen; 4=non-ICU hospitalization not requiring supplemental oxygen; 5=no longer hospitalized but unable to resume normal activities; 6=no longer hospitalized with full resumption of normal activities. A higher score reflects improved clinical status. Not all ITT subjects had ordinal scale data available at Day 8 post-dose which explains why the overall number of participants analyzed is not consistent with the overall number of subjects included at baseline. For subjects who were discharged with unknown ordinal score the more conservative of two relevant discharged categories was imputed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provision of voluntary informed consent in writing by patient, or legally authorized representative.

• Age ≥ 18 years of age.

• Locally determined positive influenza A infection (Rapid Antigen (Ag) Test or PCR) from a specimen obtained within 2 days prior to randomization.

• Onset of symptoms ≤ 6 days before randomization, defined as when the patient first experienced at least one respiratory symptom or fever.

• Hospitalized (or in observation unit) with influenza, with anticipated hospitalization for more than 24 hours and will be/already are receiving antiviral SOC.

• Experiencing ≥ 1 respiratory symptom (ex. cough, sore throat, nasal congestion) and ≥ 1 constitutional symptom (ex. headache, myalgia, feverishness or fatigue).

• For women of child-bearing potential: willingness to abstain from sexual intercourse or use at least 1 form of hormonal or barrier contraception through Day 60 of the study.

• Willingness to have blood and respiratory samples obtained and stored.

• National Early Warning Score (NEW score) ≥ 3 at screening.

Exclusion Criteria:

• Use of any investigational product within the past 30 days prior to screening.

• History of hypersensitivity to blood or plasma products (as judged by the site investigator).

• History of allergy to latex or rubber.

• Known medical history of IgA deficiency.

• Pregnancy or lactation.

• Medical conditions for which receipt of a 500 mL volume of intravenous fluid may be dangerous to the patient (e.g. decompensated congestive heart failure), based on investigator's medical opinion with careful consideration of lab results.

• Liver function: liver function test (LFT) > 2.5 times upper limit of normal (ULN).

• Renal Function: glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 (age and sex adjusted).

• A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the individual at a substantially increased risk of thrombosis (e.g. cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically significant monoclonal gammopathy).

• An opinion of the investigator that it would be unwise to allow participation of the patient in the study (the reason for exclusion of the patient must be documented).

• Receiving extracorporeal membrane oxygenation (ECMO).

• Anticipated life expectancy of < 90 days.

• Confirmed bacterial pneumonia or any concurrent respiratory viral infection that is not influenza A (ex. respiratory syncytial virus (RSV) infection).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	HonorHealth	Scottsdale	Arizona	United States	85258
3	Baptist Health Center for Clinical Research	Little Rock	Arkansas	United States	72205
4	University of California, Irvine Emergency Medicine	Orange	California	United States	92868
5	Denver public Health	Denver	Colorado	United States	80212
6	Yale University School of Medicine	New Haven	Connecticut	United States	06519
7	Christiana Care Health Systems	Newark	Delaware	United States	19718
8	Northside Hospital	Atlanta	Georgia	United States	30342
9	Atlanta Institute for Medical Research Inc.	Atlanta	Georgia	United States	30350
10	Augusta University	Augusta	Georgia	United States	30912
11	Northwestern University	Chicago	Illinois	United States	60611
12	University of Chicago	Chicago	Illinois	United States	60637
13	University of Iowa	Iowa City	Iowa	United States	52242
14	University of Kansas medical Center	Kansas City	Kansas	United States	66160
15	John Hopkins Hospital	Baltimore	Maryland	United States	21287
16	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
17	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts	United States	01605
18	Wayne State University/Detroit Receiving Hospital	Detroit	Michigan	United States	48201
19	Wayne State University/Sinai Grace Hospital	Detroit	Michigan	United States	48202
20	Providence-Providence Park Hospital, Southfield	Southfield	Michigan	United States	48075
21	Mayo Clinic	Rochester	Minnesota	United States	55905
22	Washington University	Saint Louis	Missouri	United States	63110
23	University of Nebraska Medical Center	Omaha	Nebraska	United States	985400
24	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
25	Montefiore Medical Center	Bronx	New York	United States	10467
26	University of North Carolina	Chapel Hill	North Carolina	United States	27599
27	Pulmonlx LLC Pulmonary & Critical Care Medicine	Greensboro	North Carolina	United States	27403
28	Premier Health Miami Valley Hospital	Dayton	Ohio	United States	45409
29	University of Oklahoma	Oklahoma City	Oklahoma	United States	73104
30	St Luke's University Health Network	Bethlehem	Pennsylvania	United States	18015
31	Einstein Medical Center	Philadelphia	Pennsylvania	United States	19141
32	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
33	Reading Hospital	West Reading	Pennsylvania	United States	19611
34	Regional Health	Rapid City	South Dakota	United States	57701
35	UT Southwestern Medical Center	Dallas	Texas	United States	75390
36	Baylor University Medical Center	Dallas	Texas	United States	77030
37	Baylor College of Medicine	Houston	Texas	United States	77030
38	Michael E. DeBakey VA Medical Center	Houston	Texas	United States	77030
39	UT Health San Antonio	San Antonio	Texas	United States	78229
40	University of Utah HealthCare	Salt Lake City	Utah	United States	84108
41	Carilion Medical Center	Roanoke	Virginia	United States	24014
42	MultiCare Institute for Research & Innovation	Tacoma	Washington	United States	98405
43	Foothills Medical Centre	Calgary	Alberta	Canada	T2N 2T9
44	Health Sciences Center	Winnipeg	Manitoba	Canada	R3A 1R9
45	St. Boniface Hospital	Winnipeg	Manitoba	Canada	R3A 1R9
46	Grace Hospital	Winnipeg	Manitoba	Canada	R3J 3M7
47	CISSS BSL/Hopital Regional de Rimouski	Rimouski	Quebec	Canada	G5L 5T1
48	Ciusss McQ	Trois-Rivières	Quebec	Canada	G8Z 3R9
49	Mayaguez Medical Center	Mayagüez		Puerto Rico	00680
50	San Cristobal Hospital	Ponce		Puerto Rico	00780
51	Hospital Clinic of Barcelona	Barcelona		Spain	08036
52	Hospital del Mar	Barcelona		Spain	08036
53	Hospital Universitari Mutua Terrassa	Barcelona		Spain	08225
54	Reina Sofia University Hospital	Córdoba		Spain	14004
55	Hospital Universitari de Tarragona Joan XXIII	Tarragona		Spain	43007

Sponsors and Collaborators

• Emergent BioSolutions

Investigators

• Study Director: Christine Hall, Emergent BioSolutions Inc

Study Documents (Full-Text)

• Statistical Analysis Plan - Nov 7, 2019
• Study Protocol - Jan 24, 2019

More Information

Publications

None provided.

• Responsible Party: Emergent BioSolutions
• ClinicalTrials.gov Identifier: NCT03315104
• Other Study ID Numbers: IA-001
• First Posted: Oct 19, 2017
• Last Update Posted: Oct 5, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Emergent BioSolutions: influenza A; hospitalized; H1N1; H3N2; human flu; respiratory tract infection; serious illness; flu
• Additional relevant MeSH terms: Influenza, Human; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin

Study Results

Participant Flow

Recruitment Details	This study included patients hospitalized with serious illness with laboratory-confirmed influenza A infection. Total 75 subjects were screened with 10 screen failures. Out of 65 randomized subjects, 60 received study treatment and 53 completed the study.

Arm/Group Title	FLU-IGIV High Dose (450 mL)	FLU-IGIV Low Dose (225 mL)	Placebo (500 mL Normal Saline)
Arm/Group Description	Participants received a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Administered IV as 500 mL of normal saline. Participants also received SOC antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.
Period Title: Overall Study
STARTED	21	20	24
Dosed (Safety Population)	19	19	22
COMPLETED	18	16	19
NOT COMPLETED	3	4	5

Baseline Characteristics

Arm/Group Title	FLU-IGIV High Dose (450 mL)	FLU-IGIV Low Dose (225 mL)	Placebo (500 mL Normal Saline)	Total
Arm/Group Description	Participants received a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Administered IV as 500 mL of normal saline. Participants also received SOC antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.	Total of all reporting groups
Overall Participants	21	20	24	65
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.4 (16.2)	49.1 (14.2)	59.5 (14.1)	52.7 (15.5)
Age, Customized (Count of Participants)
18-54	13 61.9%	11 55%	8 33.3%	32 49.2%
55 and over	8 38.1%	9 45%	16 66.7%	33 50.8%
Sex: Female, Male (Count of Participants)
Female	12 57.1%	10 50%	12 50%	34 52.3%
Male	9 42.9%	10 50%	12 50%	31 47.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 14.3%	4 20%	3 12.5%	10 15.4%
Not Hispanic or Latino	18 85.7%	16 80%	21 87.5%	55 84.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	9 42.9%	9 45%	14 58.3%	32 49.2%
White	12 57.1%	11 55%	10 41.7%	33 50.8%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
North America	20 95.2%	20 100%	22 91.7%	62 95.4%
Spain	1 4.8%	0 0%	2 8.3%	3 4.6%

Outcome Measures

1. Primary Outcome

Title	Frequency Counts and Percentage of Subjects With Adverse Events
Description	Frequency counts and percentage of subjects with Adverse Events by severity
Time Frame	Measured through Day 60

Outcome Measure Data

Analysis Population Description

The safety population includes all subjects who receive any amount of study medication (FLU-IGIV or placebo). In the case of incorrect treatment administration, subjects are analyzed according to the treatment received. The safety population is the primary analysis population for all safety data.

Arm/Group Title	FLU-IGIV High Dose (450 mL)	FLU-IGIV Low Dose (225 mL)	Placebo (500 mL Normal Saline)
Arm/Group Description	Participants received a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Administered IV as 500 mL of normal saline. Participants also received SOC antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.
Measure Participants	19	19	22
Mild	6 28.6%	6 30%	1 4.2%
Moderate	3 14.3%	5 25%	6 25%
Severe	1 4.8%	1 5%	4 16.7%

2. Primary Outcome

Title	Area Under the Plasma Concentration Curve [AUC] From Time 0 to 48 Hours Post-dose by Hemagglutinin Inhibition Assay
Description	Levels of anti-influenza A antibodies circulating in blood over time. We initially intended to look at this variable through Day 8, however, potential native antibody level changes and sparse sampling confounded results from 0 to 48 hours post-dose from PK samples collected from Baseline Day 1 pre-dose (time 0), Day 1 post-dose, Day 2 and Day 3 (if continued hospitalization), and Day 8. For AUC from time 0 to 48 hours, subjects who did not have a sample collected within +/-10% of 48 hours post-dose had this parameter set to missing, which is why the number of subjects who contributed data for this outcome measure is lower than the overall number of subjects analyzed.
Time Frame	Measured through 48 Hours post-dose

Outcome Measure Data

Analysis Population Description

The PK population includes all safety subjects who have adequate PK data for analysis that includes Day 1 baseline (pre-infusion) and at least one post-infusion time point. Subjects are analyzed according to the treatment received. See outcome measure description for subject exclusion details.

Arm/Group Title	FLU-IGIV High Dose (450 mL)	FLU-IGIV Low Dose (225 mL)	Placebo (500 mL Normal Saline)
Arm/Group Description	Participants received a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Administered IV as 500 mL of normal saline. Participants also received SOC antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.
Measure Participants	7	10	13
H1N1 California	8589.9 (65.2)	4955.4 (87.8)	1973.1 (85.0)
H1N1 Michigan	5266.3 (67.6)	3446.3 (123.2)	1630.2 (106.4)
H3N2 Hong Kong	11729.3 (47.4)	7054.8 (39.1)	3682.5 (126.7)
H3N2 Singapore	6754.0 (34.2)	4431.6 (45.3)	2511.3 (219.6)

3. Primary Outcome

Title	Maximum Plasma Concentration [Cmax] Reported as a Titer for Hemagglutinin Inhibition Assay
Description	Maximum observed concentration (reported as a titer) of anti-influenza A antibodies measured from Day 1 pre-dose (time 0) through Day 8 post-dose from PK samples collected from Baseline Day 1 pre-dose (time 0), Day 1 post-dose, Day 2 and Day 3 (if continued hospitalization), and Day 8.
Time Frame	Measured through Day 8 post-dose

Outcome Measure Data

Analysis Population Description

The PK population includes all safety subjects who have adequate PK data for analysis that includes Day 1 baseline (pre-infusion) and at least one post-infusion time point. Subjects are analyzed according to the treatment received.

Arm/Group Title	FLU-IGIV High Dose (450 mL)	FLU-IGIV Low Dose (225 mL)	Placebo (500 mL Normal Saline)
Arm/Group Description	Participants received a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Administered IV as 500 mL of normal saline. Participants also received SOC antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.
Measure Participants	19	19	21
H1N1 California	408.3 (99.8)	152.5 (81.6)	54.7 (135.9)
H1N1 Michigan	371.6 (138.2)	121.7 (114.6)	54.7 (155.8)
H3N2 Hong Kong	309.6 (38.4)	239.8 (97.2)	117.7 (317.2)
H3N2 Singapore	206.7 (35.1)	192.7 (95.2)	86.7 (297.0)

4. Primary Outcome

Title	Time Cmax is Observed [Tmax] by Hemagglutinin Inhibition Assay
Description	Time that anti-influenza A antibodies are at maximum concentration from Day 1 pre-dose (time 0) through Day 8 post-dose from PK samples collected from Baseline Day 1 pre-dose (time 0), Day 1 post-dose, Day 2 and Day 3 (if continued hospitalization), and Day 8. The rate of study drug elimination and dependent parameters were not accurately estimable due to rising or sustained levels of anti-influenza A antibodies, this includes First Order Terminal Elimination Rate Constant [Kel], Plasma Clearance [Cl] and Total Volume of Distribution [Vz].
Time Frame	Measured through Day 8 post-dose

Outcome Measure Data

Analysis Population Description

The PK population includes all safety subjects who have adequate PK data for analysis that includes Day 1 baseline (pre-infusion) and at least one post-infusion time point. Subjects are analyzed according to the treatment received.

Arm/Group Title	FLU-IGIV High Dose (450 mL)	FLU-IGIV Low Dose (225 mL)	Placebo (500 mL Normal Saline)
Arm/Group Description	Participants received a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Administered IV as 500 mL of normal saline. Participants also received SOC antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.
Measure Participants	19	19	21
H1N1 California	24.4 (660.7)	17.4 (358.8)	108.7 (64.3)
H1N1 Michigan	40.3 (522.5)	13.9 (423.6)	120.3 (58.4)
H3N2 Hong Kong	4.8 (127.1)	14.6 (298.4)	76.8 (119.9)
H3N2 Singapore	6.0 (146.0)	23.0 (328.2)	64.8 (171.4)

5. Secondary Outcome

Title	Ordinal Scale Subject Distribution Reflecting Clinical Status
Description	Score (physician-assessed): 1=death; 2=hospitalization in the intensive care unit (ICU); 3=non-ICU hospitalization requiring supplemental oxygen; 4=non-ICU hospitalization not requiring supplemental oxygen; 5=no longer hospitalized but unable to resume normal activities; 6=no longer hospitalized with full resumption of normal activities. A higher score reflects improved clinical status. Not all ITT subjects had ordinal scale data available at Day 8 post-dose which explains why the overall number of participants analyzed is not consistent with the overall number of subjects included at baseline. For subjects who were discharged with unknown ordinal score the more conservative of two relevant discharged categories was imputed.
Time Frame	At Day 8 post-dose

Outcome Measure Data

Analysis Population Description

Intent to Treat (ITT) Population: includes all randomized subjects regardless of study medication (FLU-IGIV or placebo) dosing, influenza type or Protocol Deviations. Not all subjects had ordinal scale data available at Day 8 which is why the overall number of subjects analyzed is not consistent with the overall number of baseline subjects.

Arm/Group Title	FLU-IGIV High Dose (450 mL)	FLU-IGIV Low Dose (225 mL)	Placebo (500 mL Normal Saline)
Arm/Group Description	Participants received a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.	Participants received a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Administered IV as 500 mL of normal saline. Participants also received SOC antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.
Measure Participants	19	17	21
1-Death	0 0%	0 0%	0 0%
2-Hospitalization in the ICU	1 4.8%	0 0%	0 0%
3-Non-ICU hospitalization, requiring supp O2	0 0%	2 10%	4 16.7%
4-Non-ICU hospitalization, not requiring supp O2	0 0%	0 0%	0 0%
5-No longer hospitalized, no normal activities	7 33.3%	7 35%	9 37.5%
6-No longer hospitalized, normal activities	11 52.4%	8 40%	8 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FLU-IGIV High Dose (450 mL), Placebo (500 mL Normal Saline)
	Comments	Pairwise Wilcoxon rank-sum test for a location shift
	Type of Statistical Test	Superiority
	Comments	A median estimated value of 0.000 indicates no difference between groups.
Statistical Test of Hypothesis	p-Value	0.174
	Comments	No adjustment for multiple comparisons, two-sided significance level of 0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments	Exact test
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.000
	Confidence Interval	(2-Sided) 95.0%; 0.000 to 1.000
	Parameter Dispersion	Type: Value:
	Estimation Comments	FLU-IGIV High Dose (450 mL) - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FLU-IGIV Low Dose (225 mL), Placebo (500 mL Normal Saline)
	Comments	Pairwise Wilcoxon rank-sum test for a location shift
	Type of Statistical Test	Superiority
	Comments	A median estimated value of 0.000 indicates no difference between groups.
Statistical Test of Hypothesis	p-Value	0.572
	Comments	No adjustment for multiple comparisons, two-sided significance level of 0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments	Exact test
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.000
	Confidence Interval	(2-Sided) 95.0%; 0.000 to 1.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FLU-IGIV High Dose (450 mL), FLU-IGIV Low Dose (225 mL)
	Comments	Pairwise Wilcoxon rank-sum test for a location shift
	Type of Statistical Test	Superiority
	Comments	A median estimated value of 0.000 indicates no difference between groups.
Statistical Test of Hypothesis	p-Value	0.534
	Comments	No adjustment for multiple comparisons. two-sided significance level of 0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments	Exact test
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.000
	Confidence Interval	(2-Sided) 95.0%; 0.000 to 1.000
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FLU-IGIV High Dose (450 mL), FLU-IGIV Low Dose (225 mL), Placebo (500 mL Normal Saline)
	Comments	Pairwise Wilcoxon rank-sum test for a location shift where the two active dose groups were pooled and compared to placebo.
	Type of Statistical Test	Superiority
	Comments	A median estimated value of 0.000 indicates no difference between groups.
Statistical Test of Hypothesis	p-Value	0.534
	Comments	No adjustment for multiple comparisons, two-sided significance level of 0.05
	Method	Wilcoxon (Mann-Whitney)
	Comments	Exact test
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	0.000
	Confidence Interval	(2-Sided) 95.0%; 0.000 to 1.000
	Parameter Dispersion	Type: Value:
	Estimation Comments	FLU-IGIV pooled (450 mL + 250 mL) - Placebo

Adverse Events

Time Frame	From start of infusion on Day 1 through Day 60 (2 months).
Arm/Group Title	FLU-IGIV High Dose (450 mL)		FLU-IGIV Low Dose (225 mL)		Placebo (Normal Saline)
Arm/Group Description	Participants received a single infusion of high dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 450 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.		Participants received a single infusion of low dose of FLU-IGIV, administered over approximately 3 hours on Day 1. Administered intravenously at a dose of 225 mL of 65 g/mL FLU-IGIV diluted to 500 mL with normal saline. Participants also received standard of care (SOC) antiviral treatment for flu. FLU-IGIV: Single dose, sterile liquid formulation for IV administration.		Participants received a single infusion of placebo for FLU-IGIV, administered over approximately 3 hours on Day 1. Administered IV as 500 mL of normal saline. Participants also received SOC antiviral treatment for flu. Placebo for FLU-IGIV: Single dose, normal saline solution for IV administration.
All Cause Mortality
	FLU-IGIV High Dose (450 mL)		FLU-IGIV Low Dose (225 mL)		Placebo (Normal Saline)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/19 (0%)		0/22 (0%)
Serious Adverse Events
	FLU-IGIV High Dose (450 mL)		FLU-IGIV Low Dose (225 mL)		Placebo (Normal Saline)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		2/19 (10.5%)		5/22 (22.7%)
Cardiac disorders
Cardiac Failure	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Supraventricular tachycardia	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Infections and infestations
Cellulitis	0/19 (0%)	0	1/19 (5.3%)	1	0/22 (0%)	0
Urosepsis	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Metabolism and nutrition disorders
Dehydration	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Hypokalaemia	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Nervous system disorders
Dizziness	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Renal and urinary disorders
Acute Kidney Injury	1/19 (5.3%)	1	0/19 (0%)	0	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Aspiration	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Asthma	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	2
Chronic obstructive pulmonary disease	0/19 (0%)	0	0/19 (0%)	0	1/22 (4.5%)	1
Dyspnoea	0/19 (0%)	0	1/19 (5.3%)	1	1/22 (4.5%)	1
Stridor	1/19 (5.3%)	1	0/19 (0%)	0	0/22 (0%)	0
Acute respiratory distress syndrome	1/19 (5.3%)	1	0/19 (0%)	0	0/22 (0%)	0
Vascular disorders
Shock	1/19 (5.3%)	1	0/19 (0%)	0	0/22 (0%)	0
Other (Not Including Serious) Adverse Events
	FLU-IGIV High Dose (450 mL)		FLU-IGIV Low Dose (225 mL)		Placebo (Normal Saline)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/19 (26.3%)		6/19 (31.6%)		8/22 (36.4%)
Blood and lymphatic system disorders
Leukocytosis	1/19 (5.3%)	1	0/19 (0%)	0	1/22 (4.5%)	1
Gastrointestinal disorders
Constipation	1/19 (5.3%)	1	0/19 (0%)	0	3/22 (13.6%)	3
Nausea	0/19 (0%)	0	1/19 (5.3%)	1	1/22 (4.5%)	1
General disorders
Physical deconditioning	1/19 (5.3%)	1	1/19 (5.3%)	1	0/22 (0%)	0
Pyrexia	1/19 (5.3%)	1	0/19 (0%)	0	1/22 (4.5%)	1
Infections and infestations
Oral candidiasis	0/19 (0%)	0	0/19 (0%)	0	2/22 (9.1%)	2
Investigations
Transaminases increased	2/19 (10.5%)	2	1/19 (5.3%)	1	0/22 (0%)	0
White blood cell count increased	0/19 (0%)	0	1/19 (5.3%)	1	1/22 (4.5%)	1
Metabolism and nutrition disorders
Fluid overload	1/19 (5.3%)	1	1/19 (5.3%)	1	1/22 (4.5%)	1
Hypomagnesaemia	1/19 (5.3%)	1	1/19 (5.3%)	1	1/22 (4.5%)	1
Hyperglycaemia	1/19 (5.3%)	1	1/19 (5.3%)	1	0/22 (0%)	0
Hypoglycaemia	2/19 (10.5%)	3	0/19 (0%)	0	0/22 (0%)	0
Nervous system disorders
Headache	0/19 (0%)	0	2/19 (10.5%)	3	1/22 (4.5%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/19 (0%)	0	1/19 (5.3%)	1	1/22 (4.5%)	2
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/19 (5.3%)	1	0/19 (0%)	0	1/22 (4.5%)	1

Limitations/Caveats

This phase 2 study was not powered to show efficacy. The target enrollment of 75 subjects randomized was not met (65 randomized and 60 dosed); the study was completed after the second northern hemisphere influenza season.

More Information

Certain Agreements

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

The result of the study may not be published until prior publication of the global results by the Sponsor, in the case of multi-center studies.