Comparing the Efficacy and Safety of High-Titer Versus Low-Titer Anti-Influenza Immune Plasma for the Treatment of Severe Influenza A

A Randomized Double-Blind, Phase 3 Study Comparing the Efficacy and Safety of High-Titer Versus Low-Titer Anti-Influenza Immune Plasma for the Treatment of Severe Influenza A

This study assessed the efficacy and safety of anti-influenza immune plasma, as an addition to standard of care antivirals, in participants hospitalized with severe influenza A infection.

Study Overview

• Status: Completed
• Conditions: Influenza A Virus Infection
• Intervention / Treatment: Biological: High-titer anti-influenza plasma; Biological: Low-titer anti-influenza plasma

Detailed Description

Despite antivirals and vaccines, influenza is responsible for thousands of hospitalizations and deaths each year worldwide. Because of this, additional treatments for influenza are needed. One potential treatment may be the use of high-titer anti-influenza immune plasma. The purpose of this study is to evaluate the efficacy and safety of treatment with high-titer versus low-titer anti-influenza immune plasma, in addition to standard care, in participants hospitalized with severe influenza A infection.

This study enrolled people aged 2 weeks or older who are hospitalized with severe influenza A infection. Participants were randomly assigned to receive either high-titer anti-influenza plasma or low-titer (control) anti-influenza plasma on Day 0. In addition, all participants received standard care antivirals. Participants were assessed on Day 0 (baseline) and on Days 1, 2, 3, 7, 14, and 28. For participants who were not hospitalized on Days 2, 14, and 28, researchers could contact participants by telephone. Study procedures included clinical assessments, blood collection, and oropharyngeal swabs.

• Study Type: Interventional
• Enrollment (Actual): 138
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Health Sciences Center
  • California
    • Los Angeles, California, United States, 90095-1752
      • UCLA Pediatrics Infectious Diseases
    • San Diego, California, United States, 92134
      • Naval Medical Center San Diego (NMCSD)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Connecticut
    • Bridgeport, Connecticut, United States, 06610
      • Bridgeport Hospital
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
    • Boston, Massachusetts, United States, 021141
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Hospital - Royal Oak
    • Troy, Michigan, United States, 48085
      • Beaumont Hospital, Troy
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Campus Saint Mary's
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital at Washington University
  • Nebraska
    • Omaha, Nebraska, United States, 68124
      • Creighton University Medical Center
  • New York
    • New York, New York, United States, 10016
      • New York University/Bellevue Hospital
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Carolinas Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke University
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Texas
    • Dallas, Texas, United States, 75235
      • UT Southwestern Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont
  • Washington
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center (MAMC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 weeks and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for Enrollment (Screening):

• Subjects must be aged 2 weeks or older.

• Hospitalization due to signs and symptoms of influenza.

  * Note: The decision for hospitalization will be made by the treating clinician. To be considered eligible, the hospitalization may either be an initial hospitalization, or a prolongation of a hospitalization due to a respiratory illness that was found to be from influenza. Influenza could be a component of a larger respiratory syndrome (i.e. COPD exacerbation thought to be triggered by influenza). However, respiratory syndromes that are not likely due to the virus should not be included (i.e. a subject that had mild influenza then developed pulmonary embolism and respiratory distress from the embolism).

• Study plasma available on-site or available within 24 hours after randomization.
• Not previously screened nor randomized in this study.
• Willingness to have blood and respiratory samples obtained and stored.
• Willingness to return for all required study visits and participate in study follow up.

Inclusion Criteria for Randomization:

• Locally determined positive test for influenza A (by polymerase chain reaction [PCR], other nucleic acid testing, or by rapid Ag) from a specimen obtained less than or equal to 48 hours prior to randomization.
• Onset of illness less than or equal to 6 days before randomization, defined as when the subject first experienced at least one respiratory symptom or fever.
• Note: For subjects with chronic respiratory symptoms (chronic cough, or COPD with baseline dyspnea), the onset of symptoms is defined as the point when the symptoms changed during this illness). Hospitalized due to influenza, with anticipated hospitalization for more than 24 hours after randomization. Criteria for hospitalization will be up to the individual treating clinician.
• National Early Warning (NEW) or Pediatric Early Warning (PEW) score greater than or equal to 3 within 12 hours prior to randomization.
• ABO-compatible plasma available on-site or available within 24 hours after randomization.

Exclusion Criteria for Randomization:

• Strong clinical evidence in the judgment of the site investigator that the etiology of illness is primarily bacterial super-infection in origin. Co-infection would be allowed, as there may be benefit to resolving influenza illness faster. Super-infection, where influenza illness occurred and is resolving, and new bacterial illness causing deterioration should be excluded (e.g., if the subject's respiratory infection is thought unlikely to benefit from additional antiviral therapy, this exclusion criteria would be met).
• Prior treatment with any anti-influenza investigational drug, anti-influenza investigational intravenous immune globulin (IVIG), or anti-influenza investigational plasma therapy within 30 days prior to screening. Other investigational drug therapies (non-influenza) and administration of plasma and/or IVIG for non-influenza reasons are allowed.
• History of allergic reaction to blood or plasma products (as judged by the site investigator).
• 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). Prior IVIG use alone would not meet exclusion criteria, but the investigator should consider the potential for a hyper-coagulable state.
• Subjects who, in the judgment of the site investigator, will be unlikely to comply with the requirements of this protocol, including being not contactable following discharge from hospital.
• Medical conditions for which receipt of 500-600 mL (or pediatric equivalent) of intravenous fluid may be dangerous to the subject (e.g., decompensated congestive heart failure).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-titer anti-influenza plasma; Participants received two intravenous infusions of high-titer anti-influenza plasma on Study Day 0.	Biological: High-titer anti-influenza plasma; Human plasma (FFP or FP24, 225-350 mL per unit or pediatric equivalent) with both an influenza A/H1N1 and A/H3N2 HAI titer of at least 1:80
Active Comparator: Low-titer anti-influenza plasma; Participants received two intravenous infusions of low-titer anti-influenza plasma on Study Day 0.	Biological: Low-titer anti-influenza plasma; Human plasma (FFP or FP24, 225-350 mL per unit or pediatric equivalent) with both an influenza A/H1N1 and A/H3N2 HAI titer of 1:10 or less

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Status at Day 7	The clinical status at Day 7 was based on a 6-point ordinal scale: Death; In ICU; Non-ICU hospitalization, requiring supplemental oxygen (O2); Non-ICU hospitalization, not requiring supplemental oxygen; Not hospitalized, but unable to resume normal activities; Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome	Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Status at Day 1	The clinical status at Day 1 was based on a 6-point ordinal scale: Death; In ICU; Non-ICU hospitalization, requiring supplemental oxygen (O2); Non-ICU hospitalization, not requiring supplemental oxygen; Not hospitalized, but unable to resume normal activities; Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome	Day 1
Clinical Status at Day 2	The clinical status at Day 2 was based on a 6-point ordinal scale: Death; In ICU; Non-ICU hospitalization, requiring supplemental oxygen (O2); Non-ICU hospitalization, not requiring supplemental oxygen; Not hospitalized, but unable to resume normal activities; Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome	Day 2
Clinical Status at Day 3	The clinical status at Day 3 was based on a 6-point ordinal scale: Death; In ICU; Non-ICU hospitalization, requiring supplemental oxygen (O2); Non-ICU hospitalization, not requiring supplemental oxygen; Not hospitalized, but unable to resume normal activities; Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome	Day 3
Clinical Status at Day 14	The clinical status at Day 14 was based on a 6-point ordinal scale: Death; In ICU; Non-ICU hospitalization, requiring supplemental oxygen (O2); Non-ICU hospitalization, not requiring supplemental oxygen; Not hospitalized, but unable to resume normal activities; Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome	Day 14
Clinical Status at Day 28	The clinical status at Day 28 was based on a 6-point ordinal scale: Death; In ICU; Non-ICU hospitalization, requiring supplemental oxygen (O2); Non-ICU hospitalization, not requiring supplemental oxygen; Not hospitalized, but unable to resume normal activities; Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome	Day 28
Duration of Initial Hospitalization	Duration (in days) of initial hospitalization, restricted to duration between randomization and last visit	From Day 0 to Day 28
28-day Mortality	Number of deaths during study follow-up	From Day 0 to Day 28
In-hospital Mortality During Initial Hospitalization	Number of deaths in the hospital during initial hospitalization	From Day 0 to Day 28
Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28	Two categories were considered for the composite of mortality and hospitalization: Dead or hospitalized Alive and not hospitalized	Day 7, Day 14, Day 28
Change From Baseline to Day 3 and Day 7 in National Early Warning (NEW) Score	The National Early Warning (NEW) score was only measured for the adult participants. The range of the NEW score is from 0 to 20, with lower values representing a better outcome. Baseline is defined as the Day 0. Change was defined as the value at Day 3 or Day 7 minus the value at baseline.	Day 0, Day 3, Day 7
Change From Baseline to Day 3 and Day 7 in Pediatric Early Warning (PEW) Score	The Pediatric Early Warning (PEW) score was only measured for the pediatric participants. The range is from 0 to 26, with lower values representing a better outcome. Baseline is defined as the Day 0. Change was defined as the value at Day 3 or Day 7 minus the value at baseline.	Day 0, Day 3, Day 7
Duration of Supplemental Oxygen	Duration (in days) of total supplemental oxygen use among those participants who required new or increased oxygen at randomization. The duration is restricted to duration between randomization and last visit.	From Day 0 to Day 28 visit. The window of the Day 28 visit was 28-32 days from study entry.
Incidence of New Oxygen Use During the Study	Incidence of new oxygen use during the study among those participants who did not require oxygen at randomization	From Day 0 to Day 28
Duration of Intensive Care Unit (ICU) Stay	Duration (in days) of ICU stay among those participants who were in ICU at randomization. The duration is restricted to duration between randomization and last visit.	From Day 0 to Day 28
Incidence of New ICU Admission Use During the Study	Incidence of new ICU admission during the study among those participants who were not in ICU at randomization	From Day 0 to Day 28
Duration of Mechanical Ventilation Use	Duration (in days) of mechanical ventilation use among those participants who were on mechanical ventilation at randomization. The duration is restricted to duration between randomization and last visit.	From Day 0 to Day 28 visit. The window of the Day 28 visit was 28-32 days from study entry
Incidence of New Mechanical Ventilation Use Stay Use During the Study	Incidence of new mechanical ventilation use during the study among those participants who were not on mechanical ventilation at randomization	From Day 0 to Day 28
Duration of Acute Respiratory Distress Syndrome (ARDS)	Duration (in days) of ARDS use among those participants with ARDS at randomization. The duration is restricted to duration between randomization and last visit.	From Day 0 to Day 28
Incidence of New ARDS During the Study	Incidence of new ARDS during the study among those participants without ARDS at randomization	From Day 0 to Day 28
Duration of Extracorporeal Membrane Oxygenation (ECMO)	Duration (in days) of ECMO use among those participants on ECMO at randomization. The duration is restricted to duration between randomization and last visit.	From Day 0 to Day 28
Incidence of New ECMO Use During the Study	Incidence of new ECMO use during the study among those participants not on ECMO at randomization	From Day 0 to Day 28
Change From Baseline to Day 3 and Day 7 in Sequential Organ Failure Assessment (SOFA) Score	The Sequential Organ Failure Assessment (SOFA) score was only measured for the adult participants. The range is from 0 to 24, with lower values representing a better outcome. Baseline is defined as the Day 0. Change was defined as the value at Day 3 or Day 7 minus the value at baseline.	Day 0, Day 3, Day 7
Change From Baseline to Day 3 and Day 7 in Pediatric Logistic Organ Dysfunction (PELOD) Score	The Pediatric Logistic Organ Dysfunction (PELOD) score was only measured for the pediatric participants. The range is from 0 to 71, with lower values representing a better outcome. Baseline is defined as the Day 0. Change was defined as the value at Day 3 or Day 7 minus the value at baseline.	Day 0, Day 3, Day 7
Disposition After Initial Hospitalization	Disposition at discharge after initial hospitalization was categorized as follows: Death, Ongoing at 28 days, Chronic nursing facility, Rehabilitation, Home with home health care, Home without assistance. The number of deaths at discharge after initial hospitalization do not necessarily match the overall number of deaths.	From Day 0 to Day 28
Detectable Influenza Virus at Day 3	Detectable influenza virus at Day 3 in oropharyngeal samples	Day 3
Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/H1N1	Hemagglutination inhibition assay (HAI) titers as measured by serial dilutions at Days 1, 3, 7 for A/H1N1. HAI for A/H1N1 was tested in all influenza seasons while the study was ongoing.	Day 1, Day 3, Day 7
Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/HongKong/4801/2014 H3N2	Hemagglutination inhibition assay (HAI) titers as measured by serial dilutions at Days 1, 3, 7 for A/HongKong/4801/2014 H3N2. HAI for A/HongKong/4801/2014 H3N2 was tested in all influenza seasons while the study was ongoing.	Day 1, Day 3, Day 7
Number of Participants With Grade 3 and 4 Adverse Events (AEs).	Number of participants with reported grade 3 and 4 adverse events (AEs) throughout the study duration. In cases where participants had multiple reports of grade 3 and 4 AEs, they were only counted once.	From Day 0 to Day 28
Number of Participants With Serious Adverse Events (SAEs).	Number of participants with reported serious adverse events (SAEs) throughout the study duration.	From Day 0 to Day 28

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: John Beigel, MD, Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, National Institutes of Health

Publications and helpful links

General Publications

• Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996 Jul;22(7):707-10. doi: 10.1007/BF01709751. No abstract available.
• Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL, Colardyn F, Blecher S. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med. 1998 Nov;26(11):1793-800. doi: 10.1097/00003246-199811000-00016.
• Leteurtre S, Martinot A, Duhamel A, Proulx F, Grandbastien B, Cotting J, Gottesman R, Joffe A, Pfenninger J, Hubert P, Lacroix J, Leclerc F. Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet. 2003 Jul 19;362(9379):192-7. doi: 10.1016/S0140-6736(03)13908-6. Erratum In: Lancet. 2006 Mar 18;367(9514):902. Lancet. 2006 Mar 18;367(9514):897; author reply 900-2.
• Leteurtre S, Duhamel A, Grandbastien B, Lacroix J, Leclerc F. Paediatric logistic organ dysfunction (PELOD) score. Lancet. 2006 Mar 18;367(9514):897; author reply 900-2. doi: 10.1016/S0140-6736(06)68371-2. No abstract available.
• Smith GB, Prytherch DR, Meredith P, Schmidt PE, Featherstone PI. The ability of the National Early Warning Score (NEWS) to discriminate patients at risk of early cardiac arrest, unanticipated intensive care unit admission, and death. Resuscitation. 2013 Apr;84(4):465-70. doi: 10.1016/j.resuscitation.2012.12.016. Epub 2013 Jan 4.
• Parshuram CS, Bayliss A, Reimer J, Middaugh K, Blanchard N. Implementing the Bedside Paediatric Early Warning System in a community hospital: A prospective observational study. Paediatr Child Health. 2011 Mar;16(3):e18-22. doi: 10.1093/pch/16.3.e18.
• Beigel JH, Aga E, Elie-Turenne MC, Cho J, Tebas P, Clark CL, Metcalf JP, Ozment C, Raviprakash K, Beeler J, Holley HP Jr, Warner S, Chorley C, Lane HC, Hughes MD, Davey RT Jr; IRC005 Study Team. Anti-influenza immune plasma for the treatment of patients with severe influenza A: a randomised, double-blind, phase 3 trial. Lancet Respir Med. 2019 Nov;7(11):941-950. doi: 10.1016/S2213-2600(19)30199-7. Epub 2019 Sep 30.

Study record dates

Study Major Dates

• Study Start: November 1, 2015
• Primary Completion (Actual): April 26, 2018
• Study Completion (Actual): May 18, 2018

Study Registration Dates

• First Submitted: October 7, 2015
• First Submitted That Met QC Criteria: October 7, 2015
• First Posted (Estimate): October 9, 2015

Study Record Updates

• Last Update Posted (Actual): June 25, 2019
• Last Update Submitted That Met QC Criteria: June 14, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Anti-Influenza Immune Plasma
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human
• Other Study ID Numbers: IRC-005