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

Influenza A Virus Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02572817
• Other study ID #: IRC-005
• Status: Completed
• Phase: Phase 3
• Start date: November 2015
• Est. completion date: May 18, 2018

Study information

• Verified date: June 2019
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT02610478

Recruitment information / eligibility

• Status: Completed
• Enrollment: 138
• Est. completion date: May 18, 2018
• Est. primary completion date: April 26, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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).

Related Conditions & MeSH terms

• Influenza A Virus Infection
• Influenza, Human
• Virus Diseases

Intervention

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
• 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

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Children's Hospital Colorado	Aurora	Colorado
United States	University of Colorado Denver	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Bridgeport Hospital	Bridgeport	Connecticut
United States	University of Vermont	Burlington	Vermont
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University of Cincinnati	Cincinnati	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	University of Florida	Gainesville	Florida
United States	UCLA Pediatrics Infectious Diseases	Los Angeles	California
United States	New York University/Bellevue Hospital	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Creighton University Medical Center	Omaha	Nebraska
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Mayo Clinic Campus Saint Mary's	Rochester	Minnesota
United States	Beaumont Hospital - Royal Oak	Royal Oak	Michigan
United States	St. Louis Children's Hospital at Washington University	Saint Louis	Missouri
United States	Naval Medical Center San Diego (NMCSD)	San Diego	California
United States	Madigan Army Medical Center (MAMC)	Tacoma	Washington
United States	Beaumont Hospital, Troy	Troy	Michigan
United States	University of Arizona Health Sciences Center	Tucson	Arizona
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

References & Publications (6)

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. — View Citation

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. Erratum in: Lancet. 2006 Mar 18;367(9514):902. Lancet. 2006 Mar 18;367(9514):897; author reply 900-2. — View Citation

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. — View Citation

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. — View Citation

Vincent JL, de Mendonça 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. — View Citation

Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Duration of Initial Hospitalization	Duration (in days) of initial hospitalization, restricted to duration between randomization and last visit	From Day 0 to Day 28
Secondary	28-day Mortality	Number of deaths during study follow-up	From Day 0 to Day 28
Secondary	In-hospital Mortality During Initial Hospitalization	Number of deaths in the hospital during initial hospitalization	From Day 0 to Day 28
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Detectable Influenza Virus at Day 3	Detectable influenza virus at Day 3 in oropharyngeal samples	Day 3
Secondary	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
Secondary	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
Secondary	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
Secondary	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