Evaluating the Safety and Efficacy of Anti-Influenza Intravenous Hyperimmune Immunoglobulin (IVIG) in Adults Hospitalized With Influenza

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02287467
• Collaborator: University of Minnesota (Other), International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) (Other)
• Enrollment: 329
• Locations: 21
• Arms: 2
• Duration (Months): 41.2
• Patients Per Site: 15.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Influenza (the flu) is a common illness that usually occurs in autumn and winter. The flu is usually mild, but can cause serious illness or death. The purpose of this study is to test the safety and effectiveness of an antibody against the flu (called intravenous hyperimmune immunoglobulin or IVIG) in people who are hospitalized for severe flu.

Condition or Disease	Intervention/Treatment	Phase
Influenza A; Influenza B	Biological: Intravenous hyperimmune immunoglobulin (IVIG); Biological: Placebo for IVIG	Phase 3

Detailed Description

Influenza is responsible for thousands of hospitalizations and deaths each year in the United States and worldwide. One possible new treatment for the flu involves the use of IVIG, a blood product containing antibodies from people who have recovered from the flu or who have had a flu shot. The purpose of this study is to evaluate whether IVIG can reduce the severity and duration of flu in people who are hospitalized with the flu.

The study will enroll participants 18 years and older who are hospitalized with the flu. The study will enroll participants over one or more flu seasons. Regardless of the date of enrollment, each participant will be in the study for about 28 days.

At study entry (Day 0), participants will be randomly assigned to one of two groups (Arms A and B). Participants in both groups will receive standard of care (SOC) treatment for the flu, but those in Arm A will also receive one dose of IVIG and those in Arm B will receive a placebo for IVIG. Both IVIG and placebo will be given intravenously over at least 2 hours.

On Day 0, before receiving IVIG or placebo, participants will undergo a symptoms assessment, blood collection, and a nasopharyngeal (NP) swab to collect a sample of secretions from the nose and throat.

Additional study visits will occur on Days 1, 2, 3, 7, 14, and 28. Depending on the visit, participants may take part in the same study procedures that took place on Day 0. On Days 2, 14, and 28, visits for participants who are no longer hospitalized may be conducted over the phone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 329 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Anti-Influenza Hyperimmune Intravenous Immunoglobulin Clinical Outcome Study (INSIGHT 006: FLU-IVIG)
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Jun 7, 2018
• Actual Study Completion Date: Jun 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: hIVIG Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu.	Biological: Intravenous hyperimmune immunoglobulin (IVIG); Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)
Placebo Comparator: Arm B: Placebo Participants will receive a single infusion of placebo for hIVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu.	Biological: Placebo for IVIG; Administered IV as 500 mL of normal saline

Outcome Measures

Primary Outcome Measures

1. Number of Patients in Each of 6 Clinical Status Categories on Day 7 [Assessed on Day 7]

   This is the primary outcome, a 6-category ordinal outcome ranging from death (worst) to discharged from hospital with resumption of normal activities (best).

Secondary Outcome Measures

1. Number of Patients in Each of 5 Clinical Status Categories on Day 3 [Assessed on Day 3]

   5-category ordinal outcome assessed on day 3; clinical status ranges from death (worst) to discharged from the hospital (best).

2. Number of Patients in Each of 6 Clinical Status Categories on Day 3 [Measured on Day 3]

   6-category ordinal outcome evaluated on Day 3; clinical status ranges from death (worst) to discharged from hospital with resumption of normal activities (best).

3. Number of Patients With a Favorable Outcome on Day 7 [Assessed on Day 7]

   Sliding dichotomy defined as non-ICU hospitalization or discharge if enrolled from ICU, and discharge if enrolled from the general ward.

4. Hospital Discharge [Measured through Day 7]

   Number of participants alive and discharged from the hospital

5. Mortality [Measured through day 28]

   Number of participants dying through day 28.

6. Number of Patients Alive and Out of Hospital [Measured through Day 28]

   Number and percent alive and out of hospital on day 28

7. Change in Viral Load [Day 3]

   Change in nasopharyngeal viral load from baseline to day 3

8. Death or Re-hospitalization [Day 28]

   Number and percent of participants who died or were re-hospitalized after initial discharge

9. Percent of Participants Developing Complications [Measured through Day 28]

   Number and percent of participants developing respiratory distress syndrome, acute renal failure, sepsis, pneumonia, enteritis, or bronchitis

10. Number of Patients in Each of 6 Clinical Status Categories on Day 14 [Measured on day 14]

    6-category ordinal outcome measured on day 14

11. Number of Patients Alive and Out of Hospital on Day 14 [day 14]

    Number and percentage of participants alive and out of the hospital on Day 14

12. Resumption of Normal Activities by Day 14 [day 14]

    Participants reporting resumption of normal daily activities by Day 14

13. Number of Patients in Each of 6 Clinical Status Categories on Day 28 [day 28]

    6-category ordinal outcome corresponding to clinical status on day 28

14. Number of Influenza A-Infected Patients in Each of 6 Clinical Status Categories on Day 7 [Day 7]

    Primary 6-category ordinal outcome for participants infected with Influenza A

15. Number of Influenza B-Infected Patients in Each of 6 Clinical Status Categories on Day 7 [Day 7]

    Primary 6-category ordinal outcome for subgroup of participants infected with influenza B

16. pH1N1 Titers at Day 7 [Day 7]

    pH1N1 hemagglutination inhibition assay (HAI) titers among participants infected with pH1N1 using A/Cal/2009 as reference virus

17. H3N2 Titers at Day 7 [Day 7]

    H3N2 HAI titers among participants infected with H3N2 using A/HongKong/2014 as reference virus

18. Influenza B Titers at Day 7 [Day 7]

    Flu B HAI titers among participants infected with influenza B using B/Phuket/2013 as reference virus

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Signed informed consent

• Locally determined positive influenza test (by polymerase chain reaction [PCR] or other nucleic acid test, or by rapid antigen [Ag]) from a specimen obtained within 2 days prior to randomization

• Onset of illness no more than 7 days before randomization, defined as when the participant first experienced at least one respiratory symptom or fever

• Hospitalized (or in observation unit) for influenza, with anticipated hospitalization for more than 24 hours. Criteria for hospitalization will be up to the individual treating clinician.

• For women of child-bearing potential: willingness to abstain from sexual intercourse or use at least one form of hormonal or barrier contraception through Day 28 of the study

• Willingness to have blood and respiratory samples obtained and stored

• NEW score greater than or equal to 2 at screening (see the protocol for more information on this criterion)

Exclusion Criteria:

• Women who are pregnant or breast-feeding

• Strong clinical evidence (in the judgment of the site investigator) that the etiology of illness is primarily bacterial in origin

• Prior treatment with any investigational drug therapy within 30 days prior to screening

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

• Known immunoglobulin A (IgA) deficiency

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

• Presence of any pre-existing illness that, in the opinion of the site investigator, would place the participant at an unreasonably increased risk through participation in this study

• Participants who, in the judgment of the site investigator, will be unlikely to comply with the requirements of this protocol

• Medical conditions for which receipt of a 500 mL volume of intravenous fluid may be dangerous to the participant (e.g., decompensated congestive heart failure)

• Receiving extracorporeal membrane oxygenation (ECMO)

• Suspicion that infection is due to an influenza strain or subtype other than A(H1N1)pdm09, H3N2, or influenza B (e.g., H5N1, H7N9)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSD Antiviral Research Center (A VRC)	San Diego	California	United States	92103
2	Denver Public Health	Denver	Colorado	United States	80204
3	University of Illinois	Chicago	Illinois	United States	60612
4	National Institutes of Health Clinical Center	Bethesda	Maryland	United States	20892
5	Henry Ford Hospital	Detroit	Michigan	United States	48202
6	Minneapolis VA Medical Center	Minneapolis	Minnesota	United States	55417
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	Cooper University Hospital	Camden	New Jersey	United States	08103
9	Montefiore Medical Center	Bronx	New York	United States	10467
10	Cornell CRS	New York	New York	United States	10010
11	Duke University	Durham	North Carolina	United States	27710
12	Case Western Reserve University	Cleveland	Ohio	United States	44106
13	OHIO State University (OSU) Wexner Medical Center	Columbus	Ohio	United States	43210
14	Miami Valley Hospital	Dayton	Ohio	United States	45409
15	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
16	UT Southwestern Medical Center	Dallas	Texas	United States	75235
17	West Virginia University	Morgantown	West Virginia	United States	26506
18	Westmead Hospital	Sydney		Australia
19	Odense University Hospital	Odense		Denmark
20	St James's University Hospital	Leeds		United Kingdom
21	Churchill Hospital	Oxford		United Kingdom

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• University of Minnesota
• International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)

Investigators

• Study Chair: Richard T. Davey, Jr., MD, National Institute of Allergy and Infectious Diseases (NIAID)
• Study Chair: Eduardo Fernández-Cruz, MD, PhD, Hospital General Universitario Gregorio Marañón
• Study Chair: Norman P. Markowitz, MD, The Henry Ford Hospital
• Study Chair: Sarah L. Pett, MD, MBBS, DTM, MRCP (UK), University College, London

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 17, 2018
• Study Protocol - May 31, 2016

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02287467
• Other Study ID Numbers: INSIGHT 006: FLU-IVIG
• First Posted: Nov 10, 2014
• Last Update Posted: Nov 14, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Antiviral; IVIG; Hemagglutination inhibition (HAI); Antibody
• Additional relevant MeSH terms: Influenza, Human; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin

Study Results

Participant Flow

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive standard of care (SOC )treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Period Title: Overall Study
STARTED	168	161
COMPLETED	156	152
NOT COMPLETED	12	9

Baseline Characteristics

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo	Total
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline	Total of all reporting groups
Overall Participants	156	152	308
Age (Count of Participants)
<=18 years	1 0.6%	1 0.7%	2 0.6%
Between 18 and 65 years	109 69.9%	100 65.8%	209 67.9%
>=65 years	46 29.5%	51 33.6%	97 31.5%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	55	57	57
Sex: Female, Male (Count of Participants)
Female	80 51.3%	88 57.9%	168 54.5%
Male	76 48.7%	64 42.1%	140 45.5%
Race/Ethnicity, Customized (Count of Participants)
Asian	33 21.2%	36 23.7%	69 22.4%
Black/African American	27 17.3%	30 19.7%	57 18.5%
Hispanic	27 17.3%	24 15.8%	51 16.6%
White/Caucasian	67 42.9%	61 40.1%	128 41.6%
Other	2 1.3%	1 0.7%	3 1%
Region of Enrollment (Count of Participants)
United States	91 58.3%	84 55.3%	175 56.8%
United Kingdom	8 5.1%	10 6.6%	18 5.8%
Australia	5 3.2%	5 3.3%	10 3.2%
Argentina	4 2.6%	4 2.6%	8 2.6%
Denmark	5 3.2%	3 2%	8 2.6%
Spain	5 3.2%	5 3.3%	10 3.2%
Greece	5 3.2%	4 2.6%	9 2.9%
Mexico	1 0.6%	2 1.3%	3 1%
Thailand	32 20.5%	35 23%	67 21.8%
National Early Warning (NEW) score (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	4	4	4

Outcome Measures

1. Primary Outcome

Title	Number of Patients in Each of 6 Clinical Status Categories on Day 7
Description	This is the primary outcome, a 6-category ordinal outcome ranging from death (worst) to discharged from hospital with resumption of normal activities (best).
Time Frame	Assessed on Day 7

Outcome Measure Data

Analysis Population Description

All infused participants, using multiple imputation to impute outcome for 4 participants with missing data.

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	156	152
Died	3 1.9%	2 1.3%
Hospitalized, in ICU	6 3.8%	11 7.2%
Non-ICU hospitalization, using supplemental oxygen	15 9.6%	16 10.5%
Non-ICU hospitalization, no supplemental oxygen	8 5.1%	12 7.9%
Discharged, not back to normal activities	56 35.9%	51 33.6%
Discharged, back to normal activities	68 43.6%	60 39.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments	Odds ratio of being in a better category, as assessed using a proportional odds model. Multiple imputation techniques were used to impute an outcome for 4 patients for whom the outcome was unknown.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.33
	Comments
	Method	Regression, Logistic
	Comments	Adjusted for baseline clinical status, region, and participation in the pilot study.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 95%; 0.79 to 1.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is hIVIG vs. placebo. A value greater than 1 favors the hIVIG group.

2. Secondary Outcome

Title	Number of Patients in Each of 5 Clinical Status Categories on Day 3
Description	5-category ordinal outcome assessed on day 3; clinical status ranges from death (worst) to discharged from the hospital (best).
Time Frame	Assessed on Day 3

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	156	152
Death	1 0.6%	0 0%
Hospitalized, in ICU	8 5.1%	13 8.6%
Non-ICU hospitalization, NEW score 3+	25 16%	31 20.4%
Non-ICU hospitalization, NEW score < 3	55 35.3%	46 30.3%
Discharged	67 42.9%	62 40.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments	Odds ratio for being in a better category, from a proportional odds model
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.84
	Comments
	Method	Regression, Logistic
	Comments	Adjusted for baseline clinical status, region, and participation in the pilot study.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is for hIVIG vs placebo. An odds ratio greater than 1 favors the hIVIG group.

3. Secondary Outcome

Title	Number of Patients in Each of 6 Clinical Status Categories on Day 3
Description	6-category ordinal outcome evaluated on Day 3; clinical status ranges from death (worst) to discharged from hospital with resumption of normal activities (best).
Time Frame	Measured on Day 3

Outcome Measure Data

Analysis Population Description

All participants with clinical data available on Day 3

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	155	152
Death	1 0.6%	0 0%
Hospitalized, in ICU	8 5.1%	13 8.6%
Non-ICU hospitalization, on supplemental oxygen	37 23.7%	34 22.4%
Non-ICU hospitalizaiton, no supplemental oxygen	43 27.6%	43 28.3%
Discharged, not back to normal activities	53 34%	53 34.9%
Discharged, back to normal activities	13 8.3%	9 5.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments	Odds ratio for being in a better group, from a proportional odds model.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.52
	Comments
	Method	Regression, Cox
	Comments	adjusted for baseline clinical status, region, and participation in the pilot study.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is for hIVIG vs. placebo. An odds ratio > 1 favors the hIVIG group.

4. Secondary Outcome

Title	Number of Patients With a Favorable Outcome on Day 7
Description	Sliding dichotomy defined as non-ICU hospitalization or discharge if enrolled from ICU, and discharge if enrolled from the general ward.
Time Frame	Assessed on Day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	156	152
favorable outcome	128 82.1%	115 75.7%
unfavorable outcome	28 17.9%	37 24.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.20
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in the pilot study.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 0.81 to 2.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio for hIVIG vs placebo. An odds ratio > 1.0 favors the hIVIG group.

5. Secondary Outcome

Title	Hospital Discharge
Description	Number of participants alive and discharged from the hospital
Time Frame	Measured through Day 7

Outcome Measure Data

Analysis Population Description

All participants

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	156	152
Discharged alive	119 76.3%	110 72.4%
Not discharged alive	37 23.7%	42 27.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments	Deaths during hospitalization are censored after day 7.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.44
	Comments
	Method	Regression, Cox
	Comments	Stratified by baseline clinical status, region, and participation in the pilot study.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 95%; .85 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	hazard ratio is hIVIG vs placebo; a hazard ratio >1 favors the hIVIG group.

6. Secondary Outcome

Title	Mortality
Description	Number of participants dying through day 28.
Time Frame	Measured through day 28

Outcome Measure Data

Analysis Population Description

all participants

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for hIVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	156	152
Died	6 3.8%	5 3.3%
Did not die	150 96.2%	147 96.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.40
	Comments
	Method	Regression, Cox
	Comments	stratified by baseline clinical status, region, and participation in pilot study
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.72
	Confidence Interval	(2-Sided) 95%; .48 to 6.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	hazard ratio is for hIVIG vs placebo; a hazard ratio < 1.0 favors the hIVIG group.

7. Secondary Outcome

Title	Number of Patients Alive and Out of Hospital
Description	Number and percent alive and out of hospital on day 28
Time Frame	Measured through Day 28

Outcome Measure Data

Analysis Population Description

All participants with vital status known on Day 28

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	155	151
Alive and out of hospital	140 89.7%	137 90.1%
Died or hospitalized	15 9.6%	14 9.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.74
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in pilot study
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; .38 to 1.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	odds ratio is for hIVIG vs placebo; an odds ratio > 1.0 favors hIVIG

8. Secondary Outcome

Title	Change in Viral Load
Description	Change in nasopharyngeal viral load from baseline to day 3
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Participants with viral load results at both baseline and day 3. Participants with undetectable viral load results at baseline are excluded.

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for hIVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	134	136
Mean (Standard Error) [log10 RNA]	-1.99 (.16)	-2.32 (.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.49
	Comments
	Method	Regression, Linear
	Comments	Adjusted for baseline RNA, geographic region, and influenza subtype
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -.26 to .54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Change is calculated as day 3 - baseline. Difference in changes is hIVIG - placebo.

9. Secondary Outcome

Title	Death or Re-hospitalization
Description	Number and percent of participants who died or were re-hospitalized after initial discharge
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

all participants with data

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	150	146
Count of Participants [Participants]	19 12.2%	19 12.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.93
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in pilot study.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is for hIVIG vs placebo.

10. Secondary Outcome

Title	Percent of Participants Developing Complications
Description	Number and percent of participants developing respiratory distress syndrome, acute renal failure, sepsis, pneumonia, enteritis, or bronchitis
Time Frame	Measured through Day 28

Outcome Measure Data

Analysis Population Description

all participants

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	156	152
Count of Participants [Participants]	20 12.8%	22 14.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.81
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in pilot study
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.5 to 1.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	odds ratio is for hIVIG group vs placebo

11. Secondary Outcome

Title	Number of Patients in Each of 6 Clinical Status Categories on Day 14
Description	6-category ordinal outcome measured on day 14
Time Frame	Measured on day 14

Outcome Measure Data

Analysis Population Description

participants with observed data on day 14

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	152	151
Died	4 2.6%	4 2.6%
Hospitalized in ICU	5 3.2%	6 3.9%
Hospitalized on supplement oxygen	8 5.1%	5 3.3%
Hospitalized not on supplemental oxygen	4 2.6%	11 7.2%
Discharged, not back to normal activities	29 18.6%	33 21.7%
Discharged, back to normal activities	102 65.4%	92 60.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments	Proportional odds for being in a better category
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.55
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in the pilot study
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (hIVIG vs placebo) of being in a better category. An odds ratio > 1 favors the hIVIG group.

12. Secondary Outcome

Title	Number of Patients Alive and Out of Hospital on Day 14
Description	Number and percentage of participants alive and out of the hospital on Day 14
Time Frame	day 14

Outcome Measure Data

Analysis Population Description

all participants

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	155	151
Count of Participants [Participants]	134 85.9%	125 82.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.77
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in pilot study
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; .5 to 2.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	odds ratio is for hIVIG vs placebo

13. Secondary Outcome

Title	Resumption of Normal Activities by Day 14
Description	Participants reporting resumption of normal daily activities by Day 14
Time Frame	day 14

Outcome Measure Data

Analysis Population Description

Participants with observed data

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for hIVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	152	151
Count of Participants [Participants]	102 65.4%	92 60.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.34
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in pilot study
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 0.7 to 2.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	odds ratio is expressed as hIVIG vs placebo

14. Secondary Outcome

Title	Number of Patients in Each of 6 Clinical Status Categories on Day 28
Description	6-category ordinal outcome corresponding to clinical status on day 28
Time Frame	day 28

Outcome Measure Data

Analysis Population Description

participants with observed data

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	151	150
Died	6 3.8%	5 3.3%
Hospitalized in ICU	2 1.3%	2 1.3%
Hospitalized, on supplemental oxygen	6 3.8%	2 1.3%
Hospitalized, not on supplemental oxygen	1 0.6%	5 3.3%
Discharged, not back to normal activities	21 13.5%	22 14.5%
Discharged, back to normal activities	115 73.7%	114 75%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.73
	Comments	adjusted for baseline clinical status, region, and participation in pilot study
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in pilot study
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	.90
	Confidence Interval	(2-Sided) 95%; .50 to 1.62
	Parameter Dispersion	Type: Value:
	Estimation Comments	odds ratio (hIVIG vs placebo) is for being in a better category. An odds ratio >1 favors the hIVIG group.

15. Secondary Outcome

Title	Number of Influenza A-Infected Patients in Each of 6 Clinical Status Categories on Day 7
Description	Primary 6-category ordinal outcome for participants infected with Influenza A
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

all participants infected with influenza A

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	114	110
Died	3 1.9%	0 0%
Hospitalized in ICU	5 3.2%	7 4.6%
Hospitalized on supplemental oxygen	14 9%	9 5.9%
Hospitalized not on supplemental oxygen	7 4.5%	10 6.6%
Discharged, not back to normal activities	40 25.6%	39 25.7%
Discharged, back to normal activities	45 28.8%	45 29.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments	Multiple imputation was used to estimate the outcome for 3 participants for whom the outcome was partially unknown.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.82
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in the pilot study.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (hIVIG vs placebo) is for being in a better category.

16. Secondary Outcome

Title	Number of Influenza B-Infected Patients in Each of 6 Clinical Status Categories on Day 7
Description	Primary 6-category ordinal outcome for subgroup of participants infected with influenza B
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	42	42
Died	0 0%	2 1.3%
Hospitalized in ICU	1 0.6%	4 2.6%
Hospitalized on supplemental oxygen	1 0.6%	7 4.6%
Hospitalized not on supplemental oxygen	1 0.6%	2 1.3%
Discharged, not back to normal activities	16 10.3%	12 7.9%
Discharged, back to normal activities	23 14.7%	15 9.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments	Multiple imputation was used to estimate the outcome for one participant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.02
	Comments
	Method	Regression, Logistic
	Comments	adjusted for baseline clinical status, region, and participation in pilot study
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.19
	Confidence Interval	(2-Sided) 95%; 1.21 to 8.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio (hIVIG vs placebo) for a better outcome. An odds ratio > 1 favors the hIVIG group.

17. Secondary Outcome

Title	pH1N1 Titers at Day 7
Description	pH1N1 hemagglutination inhibition assay (HAI) titers among participants infected with pH1N1 using A/Cal/2009 as reference virus
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

participants infected with pH1N1 with HAI titers measured at day 7

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	23	26
Mean (Standard Deviation) [titer]	285 (374)	229 (341)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments	HAI measurements were log-transformed to compute treatment differences and the model was adjusted for baseline titer.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.18
	Comments
	Method	Mixed Models Analysis
	Comments	longitudinal regression with adjustment for baseline titer
Method of Estimation	Estimation Parameter	ratio of geometric means
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 0.84 to 2.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of hIVIG group to placebo group. A ratio > 1.0 indicates higher titers for the hIVIG group.

18. Secondary Outcome

Title	H3N2 Titers at Day 7
Description	H3N2 HAI titers among participants infected with H3N2 using A/HongKong/2014 as reference virus
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

participants infected with H3N2 with HAI titers measured at day 7

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	54	49
Mean (Standard Deviation) [titer]	259 (291)	225 (277)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.13
	Comments
	Method	Mixed Models Analysis
	Comments	longitudinal analysis of log-transformed titers adjust for baseline titer.
Method of Estimation	Estimation Parameter	ratio of geometric means
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; 0.93 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of geometric means of hIVIG vs placebo. A ratio >1.0 indicates higher titers in the hIVIG group on day 7.

19. Secondary Outcome

Title	Influenza B Titers at Day 7
Description	Flu B HAI titers among participants infected with influenza B using B/Phuket/2013 as reference virus
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

participants infected with influenza B with HAI titers measured at day 7

Arm/Group Title	Arm A: hIVIG	Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)	Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
Measure Participants	39	40
Mean (Standard Deviation) [titer]	112 (161)	84 (83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: hIVIG, Arm B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.78
	Comments
	Method	Mixed Models Analysis
	Comments	log-transformed titers adjusted for baseline titer
Method of Estimation	Estimation Parameter	ratio of geometric means
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.58 to 1.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	ratio of geometric mean for hIVIG vs placebo. A ratio > 1.0 indicates higher titers at day 7 for the hIVIG group.

Adverse Events

Time Frame	28 days
Adverse Event Reporting Description	Serious adverse events plus all grade 3 and 4 adverse events, as graded according to the National Institute of Health Division of AIDS (DAIDS) toxicity table.
Arm/Group Title	Arm A: hIVIG		Arm B: Placebo
Arm/Group Description	Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (IVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Intravenous hyperimmune immunoglobulin (IVIG): Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)		Participants will receive a single infusion of placebo for IVIG (saline), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. Placebo for IVIG: Administered IV as 500 mL of normal saline
All Cause Mortality
	Arm A: hIVIG		Arm B: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/156 (3.8%)		5/152 (3.3%)
Serious Adverse Events
	Arm A: hIVIG		Arm B: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/156 (16%)		26/152 (17.1%)
Blood and lymphatic system disorders
Anaemia	1/156 (0.6%)	1	0/152 (0%)	0
Leukopenia	0/156 (0%)	0	1/152 (0.7%)	1
Cardiac disorders
Acute myocardial infarction	2/156 (1.3%)	2	0/152 (0%)	0
Atrial fibrillation	0/156 (0%)	0	2/152 (1.3%)	2
Cardiac failure	0/156 (0%)	0	1/152 (0.7%)	1
Gastrointestinal disorders
Internal hernia	0/156 (0%)	0	1/152 (0.7%)	1
Nausea	1/156 (0.6%)	1	0/152 (0%)	0
Retroperitoneal haemorrhage	0/156 (0%)	0	1/152 (0.7%)	1
Vomiting	1/156 (0.6%)	1	0/152 (0%)	0
Infections and infestations
Breast abscess	0/156 (0%)	0	1/152 (0.7%)	1
Enterococcal bacteraemia	1/156 (0.6%)	1	0/152 (0%)	0
Influenza	2/156 (1.3%)	2	0/152 (0%)	0
Pneumonia	0/156 (0%)	0	1/152 (0.7%)	1
Pneumonia bacterial	1/156 (0.6%)	1	1/152 (0.7%)	1
Pneumonia fungal	0/156 (0%)	0	1/152 (0.7%)	1
Pyelonephritis	1/156 (0.6%)	1	0/152 (0%)	0
Sepsis	1/156 (0.6%)	1	1/152 (0.7%)	1
Septic shock	0/156 (0%)	0	1/152 (0.7%)	1
Injury, poisoning and procedural complications
Post lumbar puncture syndrome	0/156 (0%)	0	1/152 (0.7%)	1
Rib fracture	1/156 (0.6%)	1	0/152 (0%)	0
Road traffic accident	0/156 (0%)	0	1/152 (0.7%)	1
Investigations
Blood creatinine increased	1/156 (0.6%)	1	0/152 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/156 (0.6%)	1	1/152 (0.7%)	1
Fluid overload	1/156 (0.6%)	2	0/152 (0%)	0
Hyperkalaemia	1/156 (0.6%)	1	0/152 (0%)	0
Hypoglycaemia	1/156 (0.6%)	1	0/152 (0%)	0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	1/156 (0.6%)	1	0/152 (0%)	0
Nervous system disorders
Dizziness	1/156 (0.6%)	1	0/152 (0%)	0
Haemorrhage intracranial	1/156 (0.6%)	1	0/152 (0%)	0
Headache	0/156 (0%)	0	1/152 (0.7%)	1
Vocal cord paresis	0/156 (0%)	0	1/152 (0.7%)	1
Psychiatric disorders
Dysthymic disorders	1/156 (0.6%)	1	0/152 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/156 (0%)	0	2/152 (1.3%)	2
Renal failure	0/156 (0%)	0	1/152 (0.7%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/156 (0.6%)	1	0/152 (0%)	0
Acute respiratory failure	0/156 (0%)	0	1/152 (0.7%)	1
Aspiration	1/156 (0.6%)	1	0/152 (0%)	0
Asthma	1/156 (0.6%)	1	0/152 (0%)	0
Bronchospasm	0/156 (0%)	0	1/152 (0.7%)	1
Chronic obstructive pulmonary disease	1/156 (0.6%)	1	5/152 (3.3%)	8
Dyspnoea	1/156 (0.6%)	1	1/152 (0.7%)	1
Hypoxia	1/156 (0.6%)	1	0/152 (0%)	0
Pleural effusion	0/156 (0%)	0	1/152 (0.7%)	1
Pneumonia aspiration	1/156 (0.6%)	1	0/152 (0%)	0
Pulmonary embolism	2/156 (1.3%)	2	0/152 (0%)	0
Pulmonary oedema	1/156 (0.6%)	1	0/152 (0%)	0
Respiratory distress	0/156 (0%)	0	1/152 (0.7%)	1
Respiratory failure	1/156 (0.6%)	1	2/152 (1.3%)	2
Skin and subcutaneous tissue disorders
Diabetic foot	0/156 (0%)	0	1/152 (0.7%)	1
Vascular disorders
Hypotension	0/156 (0%)	0	1/152 (0.7%)	1
Thrombophlebitis superficial	0/156 (0%)	0	1/152 (0.7%)	1
Other (Not Including Serious) Adverse Events
	Arm A: hIVIG		Arm B: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/156 (8.3%)		14/152 (9.2%)
Investigations
Blood creatinine increased	4/156 (2.6%)	5	1/152 (0.7%)	1
Haemoglobin decreased	2/156 (1.3%)	4	4/152 (2.6%)	6
Metabolism and nutrition disorders
Hyperglycaemia	1/156 (0.6%)	1	4/152 (2.6%)	4
Musculoskeletal and connective tissue disorders
Myalgia	2/156 (1.3%)	2	4/152 (2.6%)	4
Respiratory, thoracic and mediastinal disorders
Cough	5/156 (3.2%)	5	4/152 (2.6%)	4
Dyspnoea	4/156 (2.6%)	5	3/152 (2%)	3

Limitations/Caveats

[Not Specified]

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.