This randomized, open-label, multicenter phase 2 trial will assess the safety, efficacy, and pharmacokinetics (PK) of anti-influenza plasma in subjects with influenza A or B. Hospitalized subjects with influenza A or B that have either a low oxygen level or a high respiratory rate will be eligible for study participation. This study will enroll adults, children and pregnant women.
Morbidity and mortality occur despite treatment with current antivirals. Circulating influenza H1N1 and H3N2 isolates are highly resistant to amantadine and rimantadine, whereas previous seasonal H1N1 isolates were highly resistant to oseltamivir. So there is concern that circulating influenza A/H1N1 2009 virus may also acquire oseltamivir resistance. This randomized, open-label, multicenter phase 2 trial will assess the safety, efficacy, and pharmacokinetics (PK) of anti-influenza plasma in subjects with influenza. Hospitalized subjects with influenza at risk for severe disease (as defined in the inclusion criteria) will be eligible for study participation. This study will enroll adults, children and pregnant women. Up to 40 sites in the United States will participate in this protocol. One hundred eligible subjects will be randomized in a 1:1 ratio to receive either 2 units (or pediatric equivalent) of anti-influenza immune plasma on Study Day 0 in addition to standard care or standard care alone (50 subjects receiving standard care alone; 50 subjects receiving anti-influenza immune plasma and standard care). Subjects will be assessed on Study Day 0 (pre-dose), 30 minutes post-dose (plasma arm only), and on Study Days 1, 2, 4, 7, 14, and 28. All subjects will undergo a series of efficacy, safety, and PK (HAI) assessments during the study. Blood samples will be collected at each time point (except Day 1). Nasal and oropharyngeal swabs for influenza PCR will be obtained on Days 0,1,2,4 and 7.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
98
2 units of plasma with high titer anti-influenza A or anti-influenza B antibodies at baseline
All subjects will receive an anti-influenza antiviral (e.g., oseltamivir or zanamivir), but may include treatment with licensed antivirals in patient populations or at doses not covered in the package insert, or with medications available under a EUA. Standard care may also include antibiotics and other medications.
Time to Normalization of Respiratory Status (Primary Efficacy Population)
Normalized respiratory status is defined as room air saturation of oxygen \[SaO2\] greater than or equal to 93% AND respiratory rate within normal ranges.
Time frame: Measured from Day 0 through Day 28
Time to Normalization of Respiratory Status (All Randomized Participants)
Normalized respiratory status is defined as room air saturation of oxygen \[SaO2\] greater than or equal to 93% AND respiratory rate within normal ranges.
Time frame: Measured from Day 0 through Day 28
Duration of Time to Resolution of Clinical Symptoms
The assessed clinical symptoms were nausea, vomiting, diarrhea, sore throat, headache, muscle ache, cough, and shortness of breath. Symptoms were assessed at days 0, 1, 2, 4, 7, 14, and 28.
Time frame: Measured from Day 0 through Day 28
Duration of Time to Resolution of Fever
Fever was defined as either a temperature \> 38.0 C, or a report of a Grade 1 or higher fever as an adverse event.
Time frame: Measured from Day 0 through Day 28
Duration of Time to Resolution of All Symptoms and Fever
The assessed symptoms were nausea, vomiting, diarrhea, sore throat, headache, muscle ache, cough, and shortness of breath. Fever was defined as either a temperature \> 38.0 C, or a report of a Grade 1 or higher fever as an adverse event.
Time frame: Measured from Day 0 through Day 28
Time to 20% Improvement in Sequential Organ Failure Assessment (SOFA) Score for Participants >= 18 Years Old and Pediatric Logistic Organ Dysfunction (PELOD) Score for Participants < 18 Years Old
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David Geffen School of Medicine at UCLA
Los Angeles, California, United States
Naval Medical Center San Diego
San Diego, California, United States
Los Angeles Biomedical Research Institute, CA
Torrance, California, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Washington, DC VA Med Center
Washington D.C., District of Columbia, United States
University of Florida
Gainesville, Florida, United States
Emory University Hospital
Atlanta, Georgia, United States
Northwestern University (NU)
Chicago, Illinois, United States
The Rush University Medical Center
Chicago, Illinois, United States
University of Maryland School of Medicine Center for Vaccine Development
Baltimore, Maryland, United States
...and 25 more locations
The analysis is restricted to participants \>= 18 years old and the SOFA score because there were very few evaluations of the PELOD score during follow-up for the participants \< 18 years old. The adult population was further subset to those with a non-missing and non-zero SOFA score at Day 0; those with missing SOFA score at Day 0 did not have a starting point, and those with SOFA = 0 at Day 0 could not have an improvement.
Time frame: Measured from Day 0 through Day 28
50 Millimeters of Mercury (mm/Hg) Improvement in PaO2/FiO2 Ratio Over Time
Number of participants with ABG done and no increase of 50 millimeters of mercury (mm/Hg) or greater in PaO2/FiO2 ratio. PaO2/FiO2 ratio was evaluated by an ABG. ABG was performed only when clinically indicated.
Time frame: Measured at Days 1, 2, 4, 7, 14, 28
In-hospital Mortality
Number of deaths in hospital during initial hospital admission
Time frame: Measured from Day 0 through Day 28
28-day Mortality
Number of deaths during study follow-up
Time frame: Measured from Day 0 through Day 28
Duration of Hospitalization
Days that a participant spent at the hospital. Multiple hospitalizations are summed up.
Time frame: Measured from Day 0 through Day 28
Number of ICU Admissions
Number of ICU admissions during study follow-up. The intent was to analyze any number of ICU admissions.
Time frame: Measured from Day 0 through Day 28
Duration of Stay in ICU
Days that a participant spent in ICU. Multiple ICU admissions are summed up.
Time frame: Measured from Day 0 through Day 28
Days on Supplemental Oxygen
Time (in days) of supplemental oxygen use
Time frame: Measured from Day 0 through Day 28
Duration of Supplemental Oxygen
Duration of supplemental oxygen use in days
Time frame: Measured from Day 0 through Day 28
Incidence of Acute Respiratory Distress Syndrome (ARDS) Present
Incidence of participants with acute respiratory distress syndrome (ARDS), restricted to those without ARDS at Day 0.
Time frame: Measured at Days 0, 1, 2, 4, 7, 14, 28
Days on Mechanical Ventilation
Time (in days) of mechanical ventilation use
Time frame: Measured from Day 0 through Day 28
Duration of Mechanical Ventilation
Duration of mechanical ventilation use in days. Multiple mechanical ventilation durations are summed up.
Time frame: Measured from Day 0 through Day 28
Disposition Following Initial Hospitalization
Disposition following initial hospitalization was categorized as follows: "released home - home health care not required", " released home with home health care", "transferred to long-term care facility", "hospitalization ongoing at Day 28", "deceased".
Time frame: Measured from Day 0 through Day 28
Duration of Viral Shedding < Lower Limit of Quantification (LLOQ) in Nasal Swabs
Duration of viral shedding \< lower limit of quantification (LLOQ) in nasal swabs (restricted to participants with viral shedding \>= LLOQ in nasal swabs at Day 0)
Time frame: Measured from Day 0 through Day 28
Incidence and Week of Gestation of Delivery of a Live Pre-term Infant for Pregnant Women
Incidence and week of gestation of delivery of a live pre-term infant for pregnant female participants
Time frame: Measured through to Day 28
Incidence and Duration of Pre-term Labor (Defined as Labor Occurring < 36 Weeks) for Pregnant Women
Incidence and duration of pre-term labor (defined as labor occurring \< 36 weeks) for pregnant female participants
Time frame: Measured through Day 28
Incidence of Spontaneous Abortion or Stillborn Fetus for Pregnant Women
Incidence of spontaneous abortion or stillborn fetus for pregnant female participants
Time frame: Measured from Day 0 through Day 28