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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02572817
Recruitment Status : Completed
First Posted : October 9, 2015
Results First Posted : June 14, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Influenza A Virus Infection Biological: High-titer anti-influenza plasma Biological: Low-titer anti-influenza plasma Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 138 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : November 2015
Actual Primary Completion Date : April 26, 2018
Actual Study Completion Date : May 18, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Flu Flu Shot

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




Primary Outcome Measures :
  1. Clinical Status at Day 7 [ Time Frame: Day 7 ]

    The clinical status at Day 7 was based on a 6-point ordinal scale:

    1. Death
    2. In ICU
    3. Non-ICU hospitalization, requiring supplemental oxygen (O2)
    4. Non-ICU hospitalization, not requiring supplemental oxygen
    5. Not hospitalized, but unable to resume normal activities
    6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome


Secondary Outcome Measures :
  1. Clinical Status at Day 1 [ Time Frame: Day 1 ]

    The clinical status at Day 1 was based on a 6-point ordinal scale:

    1. Death
    2. In ICU
    3. Non-ICU hospitalization, requiring supplemental oxygen (O2)
    4. Non-ICU hospitalization, not requiring supplemental oxygen
    5. Not hospitalized, but unable to resume normal activities
    6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

  2. Clinical Status at Day 2 [ Time Frame: Day 2 ]

    The clinical status at Day 2 was based on a 6-point ordinal scale:

    1. Death
    2. In ICU
    3. Non-ICU hospitalization, requiring supplemental oxygen (O2)
    4. Non-ICU hospitalization, not requiring supplemental oxygen
    5. Not hospitalized, but unable to resume normal activities
    6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

  3. Clinical Status at Day 3 [ Time Frame: Day 3 ]

    The clinical status at Day 3 was based on a 6-point ordinal scale:

    1. Death
    2. In ICU
    3. Non-ICU hospitalization, requiring supplemental oxygen (O2)
    4. Non-ICU hospitalization, not requiring supplemental oxygen
    5. Not hospitalized, but unable to resume normal activities
    6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

  4. Clinical Status at Day 14 [ Time Frame: Day 14 ]

    The clinical status at Day 14 was based on a 6-point ordinal scale:

    1. Death
    2. In ICU
    3. Non-ICU hospitalization, requiring supplemental oxygen (O2)
    4. Non-ICU hospitalization, not requiring supplemental oxygen
    5. Not hospitalized, but unable to resume normal activities
    6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

  5. Clinical Status at Day 28 [ Time Frame: Day 28 ]

    The clinical status at Day 28 was based on a 6-point ordinal scale:

    1. Death
    2. In ICU
    3. Non-ICU hospitalization, requiring supplemental oxygen (O2)
    4. Non-ICU hospitalization, not requiring supplemental oxygen
    5. Not hospitalized, but unable to resume normal activities
    6. Not hospitalized with full resumption of normal activities A higher score corresponds to a better health outcome

  6. Duration of Initial Hospitalization [ Time Frame: From Day 0 to Day 28 ]
    Duration (in days) of initial hospitalization, restricted to duration between randomization and last visit

  7. 28-day Mortality [ Time Frame: From Day 0 to Day 28 ]
    Number of deaths during study follow-up

  8. In-hospital Mortality During Initial Hospitalization [ Time Frame: From Day 0 to Day 28 ]
    Number of deaths in the hospital during initial hospitalization

  9. Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28 [ Time Frame: Day 7, Day 14, Day 28 ]

    Two categories were considered for the composite of mortality and hospitalization:

    Dead or hospitalized Alive and not hospitalized


  10. Change From Baseline to Day 3 and Day 7 in National Early Warning (NEW) Score [ Time Frame: Day 0, Day 3, Day 7 ]

    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.


  11. Change From Baseline to Day 3 and Day 7 in Pediatric Early Warning (PEW) Score [ Time Frame: Day 0, Day 3, Day 7 ]

    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.


  12. Duration of Supplemental Oxygen [ Time Frame: From Day 0 to Day 28 visit. The window of the Day 28 visit was 28-32 days from study entry. ]

    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.


  13. Incidence of New Oxygen Use During the Study [ Time Frame: From Day 0 to Day 28 ]
    Incidence of new oxygen use during the study among those participants who did not require oxygen at randomization

  14. Duration of Intensive Care Unit (ICU) Stay [ Time Frame: From Day 0 to Day 28 ]

    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.


  15. Incidence of New ICU Admission Use During the Study [ Time Frame: From Day 0 to Day 28 ]
    Incidence of new ICU admission during the study among those participants who were not in ICU at randomization

  16. Duration of Mechanical Ventilation Use [ Time Frame: From Day 0 to Day 28 visit. The window of the Day 28 visit was 28-32 days from study entry ]

    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.


  17. Incidence of New Mechanical Ventilation Use Stay Use During the Study [ Time Frame: From Day 0 to Day 28 ]
    Incidence of new mechanical ventilation use during the study among those participants who were not on mechanical ventilation at randomization

  18. Duration of Acute Respiratory Distress Syndrome (ARDS) [ Time Frame: From Day 0 to Day 28 ]

    Duration (in days) of ARDS use among those participants with ARDS at randomization.

    The duration is restricted to duration between randomization and last visit.


  19. Incidence of New ARDS During the Study [ Time Frame: From Day 0 to Day 28 ]
    Incidence of new ARDS during the study among those participants without ARDS at randomization

  20. Duration of Extracorporeal Membrane Oxygenation (ECMO) [ Time Frame: From Day 0 to Day 28 ]

    Duration (in days) of ECMO use among those participants on ECMO at randomization.

    The duration is restricted to duration between randomization and last visit.


  21. Incidence of New ECMO Use During the Study [ Time Frame: From Day 0 to Day 28 ]
    Incidence of new ECMO use during the study among those participants not on ECMO at randomization

  22. Change From Baseline to Day 3 and Day 7 in Sequential Organ Failure Assessment (SOFA) Score [ Time Frame: Day 0, Day 3, Day 7 ]

    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.


  23. Change From Baseline to Day 3 and Day 7 in Pediatric Logistic Organ Dysfunction (PELOD) Score [ Time Frame: Day 0, Day 3, Day 7 ]

    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.


  24. Disposition After Initial Hospitalization [ Time Frame: From Day 0 to Day 28 ]

    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.


  25. Detectable Influenza Virus at Day 3 [ Time Frame: Day 3 ]
    Detectable influenza virus at Day 3 in oropharyngeal samples

  26. Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/H1N1 [ Time Frame: Day 1, Day 3, Day 7 ]
    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.

  27. Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/HongKong/4801/2014 H3N2 [ Time Frame: Day 1, Day 3, Day 7 ]
    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.

  28. Number of Participants With Grade 3 and 4 Adverse Events (AEs). [ Time Frame: From Day 0 to Day 28 ]
    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.

  29. Number of Participants With Serious Adverse Events (SAEs). [ Time Frame: From Day 0 to Day 28 ]
    Number of participants with reported serious adverse events (SAEs) throughout the study duration.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02572817


Locations
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Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Study Chair: John Beigel, MD Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, National Institutes of Health
  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):
Study Protocol  [PDF] June 15, 2017
Statistical Analysis Plan  [PDF] May 25, 2016

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02572817    
Obsolete Identifiers: NCT02610478
Other Study ID Numbers: IRC-005
First Posted: October 9, 2015    Key Record Dates
Results First Posted: June 14, 2019
Last Update Posted: June 25, 2019
Last Verified: June 2019
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Anti-Influenza Immune Plasma
Additional relevant MeSH terms:
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Influenza, Human
Orthomyxoviridae Infections
RNA Virus Infections
Virus Diseases
Respiratory Tract Infections
Respiratory Tract Diseases