Exploring Safety & Clinical Benefit of Anti-Influenza Imm... | NCT03315104

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
FLU-IGIV High Dose	Experimental	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
FLU-IGIV Low Dose	Experimental	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
FLU-IGIV Placebo	Placebo Comparator	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

Name	Type	Description	Arm Group Labels	Other Names
FLU-IGIV	Biological	Single dose, sterile liquid formulation for IV administration.	FLU-IGIV High Dose FLU-IGIV Low Dose

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Frequency Counts and Percentage of Subjects With Adverse Events	Frequency counts and percentage of subjects with Adverse Events by severity	Measured through Day 60
Area Under the Plasma Concentration Curve [AUC] From Time 0 to 48 Hours Post-dose by Hemagglutinin Inhibition Assay	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.	Measured through 48 Hours post-dose
Maximum Plasma Concentration [Cmax] Reported as a Titer for Hemagglutinin Inhibition Assay	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.	Measured through Day 8 post-dose
Time Cmax is Observed [Tmax] by Hemagglutinin Inhibition Assay	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 Outcomes

Measure	Description	Time Frame
Ordinal Scale Subject Distribution Reflecting Clinical Status	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 Module

Eligibility Criteria

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).

Name	Affiliation	Role
Christine Hall	Emergent BioSolutions Inc	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
University of Alabama at Birmingham		Birmingham	Alabama	35294	United States
HonorHealth

ID	Title	Description
FG000	FLU-IGIV High Dose (450 mL)	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.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jan 24, 2019	Jun 15, 2020

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Frequency Counts and Percentage of Subjects With Adverse Events

Frequency counts and percentage of subjects with Adverse Events by severity

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.

Posted

Count of Participants

Participants

Measured through Day 60

ID	Title	Description
OG000	FLU-IGIV High Dose (450 mL)	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.
OG001	FLU-IGIV Low Dose (225 mL)	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.
OG002	Placebo (500 mL Normal Saline)	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.

Units	Counts
Participants	OG00019 OG00119 OG00222

Title

Denominators

Categories

Mild

Title	Measurements
	OG0006 OG0016 OG0021

Moderate

Primary

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

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.

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

titer*hours/mL

Measured through 48 Hours post-dose

ID	Title	Description
OG000	FLU-IGIV High Dose (450 mL)	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.

Primary

Maximum Plasma Concentration [Cmax] Reported as a Titer for Hemagglutinin Inhibition Assay

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.

Posted

Geometric Mean

Geometric Coefficient of Variation

titer

Measured through Day 8 post-dose

ID	Title	Description
OG000	FLU-IGIV High Dose (450 mL)	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.
OG001	FLU-IGIV Low Dose (225 mL)	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.

Primary

Time Cmax is Observed [Tmax] by Hemagglutinin Inhibition Assay

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].

Posted

Geometric Mean

Geometric Coefficient of Variation

hours

Measured through Day 8 post-dose

ID	Title	Description
OG000	FLU-IGIV High Dose (450 mL)	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.
OG001	FLU-IGIV Low Dose (225 mL)	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.

Secondary

Ordinal Scale Subject Distribution Reflecting Clinical Status

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.

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.

Posted

Count of Participants

Participants

At Day 8 post-dose

ID	Title	Description
OG000	FLU-IGIV High Dose (450 mL)	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.

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Cardiac Failure	Cardiac disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Supraventricular tachycardia	Cardiac disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Cellulitis	Infections and infestations	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected22 at risk
Urosepsis	Infections and infestations	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Dehydration	Metabolism and nutrition disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Hypokalaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Dizziness	Nervous system disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Acute Kidney Injury	Renal and urinary disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Acute Respiratory Failure	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Aspiration	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0022 events1 affected22 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0021 events1 affected22 at risk
Stridor	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0020 events0 affected22 at risk
Shock	Vascular disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0020 events0 affected22 at risk
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0020 events0 affected22 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Fluid overload	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0011 events1 affected19 at risk EG0021 events1 affected22 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0011 events1 affected19 at risk EG0021 events1 affected22 at risk
Hyperglycaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected22 at risk
Hypoglycaemia	Metabolism and nutrition disorders	Systematic Assessment	EG0003 events2 affected19 at risk EG0010 events0 affected19 at risk EG0020 events0 affected22 at risk
Constipation	Gastrointestinal disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0023 events3 affected22 at risk
Nausea	Gastrointestinal disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0021 events1 affected22 at risk
Transaminases increased	Investigations	Systematic Assessment	EG0002 events2 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected22 at risk
White blood cell count increased	Investigations	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0021 events1 affected22 at risk
Physical deconditioning	General disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0011 events1 affected19 at risk EG0020 events0 affected22 at risk
Pyrexia	General disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Headache	Nervous system disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0013 events2 affected19 at risk EG0021 events1 affected22 at risk
Leukocytosis	Blood and lymphatic system disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk
Oral candidiasis	Infections and infestations	Systematic Assessment	EG0000 events0 affected19 at risk EG0010 events0 affected19 at risk EG0022 events2 affected22 at risk
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0000 events0 affected19 at risk EG0011 events1 affected19 at risk EG0022 events1 affected22 at risk
Decubitus ulcer	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0001 events1 affected19 at risk EG0010 events0 affected19 at risk EG0021 events1 affected22 at risk

ID	Term
D009976	Orthomyxoviridae Infections
D007251	Influenza, Human
D012141	Respiratory Tract Infections

ID	Term
D012327	RNA Virus Infections
D014777	Virus Diseases
D007239	Infections
D012140	Respiratory Tract Diseases

ID	Title	Description
BG000	FLU-IGIV High Dose (450 mL)	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.
BG001	FLU-IGIV Low Dose (225 mL)	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.
BG002	Placebo (500 mL Normal Saline)	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.
BG003	Total	Total of all reporting groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	FLU-IGIV High Dose (450 mL)	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.	19	1	19	5	19
EG001	FLU-IGIV Low Dose (225 mL)	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.	19	2	19	6	19
EG002	Placebo (Normal Saline)	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.	22	5	22	8	22