Clinical trial NCT02572817: Comparing the Efficacy and Safety of High-Titer Versus Low-Titer Anti-Influenza Immune Plasma for the Treatment of Severe Influenza A
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Influenza A Virus Infection
Keywords: Anti-Influenza Immune Plasma
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2015-10-09
Enrollment: 138
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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).

Primary outcomes:
measure: Clinical Status at Day 7
timeFrame: Day 7
Secondary outcomes:
measure: Clinical Status at Day 1
timeFrame: Day 1
measure: Clinical Status at Day 2
timeFrame: Day 2
measure: Clinical Status at Day 3
timeFrame: Day 3
measure: Clinical Status at Day 14
timeFrame: Day 14
measure: Clinical Status at Day 28
timeFrame: Day 28
measure: Duration of Initial Hospitalization
timeFrame: From Day 0 to Day 28
measure: 28-day Mortality
timeFrame: From Day 0 to Day 28
measure: In-hospital Mortality During Initial Hospitalization
timeFrame: From Day 0 to Day 28
measure: Composite of Mortality and Hospitalization at Day 7, Day 14, Day 28
timeFrame: Day 7, Day 14, Day 28
measure: Change From Baseline to Day 3 and Day 7 in National Early Warning (NEW) Score
timeFrame: Day 0, Day 3, Day 7
measure: Change From Baseline to Day 3 and Day 7 in Pediatric Early Warning (PEW) Score
timeFrame: Day 0, Day 3, Day 7
measure: Duration of Supplemental Oxygen
timeFrame: From Day 0 to Day 28 visit. The window of the Day 28 visit was 28-32 days from study entry.
measure: Incidence of New Oxygen Use During the Study
timeFrame: From Day 0 to Day 28
measure: Duration of Intensive Care Unit (ICU) Stay
timeFrame: From Day 0 to Day 28
measure: Incidence of New ICU Admission Use During the Study
timeFrame: From Day 0 to Day 28
measure: Duration of Mechanical Ventilation Use
timeFrame: From Day 0 to Day 28 visit. The window of the Day 28 visit was 28-32 days from study entry
measure: Incidence of New Mechanical Ventilation Use Stay Use During the Study
timeFrame: From Day 0 to Day 28
measure: Duration of Acute Respiratory Distress Syndrome (ARDS)
timeFrame: From Day 0 to Day 28
measure: Incidence of New ARDS During the Study
timeFrame: From Day 0 to Day 28
measure: Duration of Extracorporeal Membrane Oxygenation (ECMO)
timeFrame: From Day 0 to Day 28
measure: Incidence of New ECMO Use During the Study
timeFrame: From Day 0 to Day 28
measure: Change From Baseline to Day 3 and Day 7 in Sequential Organ Failure Assessment (SOFA) Score
timeFrame: Day 0, Day 3, Day 7
measure: Change From Baseline to Day 3 and Day 7 in Pediatric Logistic Organ Dysfunction (PELOD) Score
timeFrame: Day 0, Day 3, Day 7
measure: Disposition After Initial Hospitalization
timeFrame: From Day 0 to Day 28
measure: Detectable Influenza Virus at Day 3
timeFrame: Day 3
measure: Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/H1N1
timeFrame: Day 1, Day 3, Day 7
measure: Hemagglutination Inhibition Assay (HAI) Titers at Days 1, 3, 7 for A/HongKong/4801/2014 H3N2
timeFrame: Day 1, Day 3, Day 7
measure: Number of Participants With Grade 3 and 4 Adverse Events (AEs).
timeFrame: From Day 0 to Day 28
measure: Number of Participants With Serious Adverse Events (SAEs).
timeFrame: From Day 0 to Day 28
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Health Sciences Center
state: Arizona
city: Los Angeles
country: United States
facility: UCLA Pediatrics Infectious Diseases
state: California
city: San Diego
country: United States
facility: Naval Medical Center San Diego (NMCSD)
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Bridgeport
country: United States
facility: Bridgeport Hospital
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Royal Oak
country: United States
facility: Beaumont Hospital - Royal Oak
state: Michigan
city: Troy
country: United States
facility: Beaumont Hospital, Troy
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Campus Saint Mary's
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital at Washington University
state: Missouri
city: Omaha
country: United States
facility: Creighton University Medical Center
state: Nebraska
city: New York
country: United States
facility: New York University/Bellevue Hospital
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
city: Tacoma
country: United States
facility: Madigan Army Medical Center (MAMC)
state: Washington
Study officials:
affiliation: Leidos Biomedical Research, Inc. in support of Clinical Research Section, LIR, NIAID, National Institutes of Health
name: John Beigel, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
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. 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. doi: 10.1016/S0140-6736(06)68371-2.
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.
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. doi: 10.1093/pch/16.3.e18.
citation: 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.