Please select the eligibility criteria that correspond to the clinical trial below.
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
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.


Options:
A: Inclusion Criteria:

* Signed informed consent
* Locally determined positive influenza test (by polymerase chain reaction \[PCR\] or other nucleic acid test, or by rapid antigen \[Ag\]) from a specimen obtained within 2 days prior to randomization
* Onset of illness no more than 7 days before randomization, defined as when the participant first experienced at least one respiratory symptom or fever
* Hospitalized (or in observation unit) for influenza, with anticipated hospitalization for more than 24 hours. Criteria for hospitalization will be up to the individual treating clinician.
* For women of child-bearing potential: willingness to abstain from sexual intercourse or use at least one form of hormonal or barrier contraception through Day 28 of the study
* Willingness to have blood and respiratory samples obtained and stored
* NEW score greater than or equal to 2 at screening (see the protocol for more information on this criterion)

Exclusion Criteria:

* Women who are pregnant or breast-feeding
* Strong clinical evidence (in the judgment of the site investigator) that the etiology of illness is primarily bacterial in origin
* Prior treatment with any investigational drug therapy within 30 days prior to screening
* History of allergic reaction to blood or plasma products (as judged by the site investigator)
* Known immunoglobulin A (IgA) deficiency
* A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the participant at a substantially increased risk of thrombosis (e.g., cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically significant monoclonal gammopathy)
* Presence of any pre-existing illness that, in the opinion of the site investigator, would place the participant at an unreasonably increased risk through participation in this study
* Participants who, in the judgment of the site investigator, will be unlikely to comply with the requirements of this protocol
* Medical conditions for which receipt of a 500 mL volume of intravenous fluid may be dangerous to the participant (e.g., decompensated congestive heart failure)
* Receiving extracorporeal membrane oxygenation (ECMO)
* Suspicion that infection is due to an influenza strain or subtype other than A(H1N1)pdm09, H3N2, or influenza B (e.g., H5N1, H7N9)
B: Inclusion Criteria:

* Diagnosis of influenza A or B within 72 hours prior to enrollment (by local assay including rapid antigen, direct fluorescent antibody (DFA), polymerase chain reaction (PCR), or culture, and must be able to detect and distinguish influenza A from influenza B)
* Hospitalization for signs and symptoms of influenza (decision for hospitalization will be up to the individual treating clinician).
* Abnormal respiratory status, defined as room air saturation of oxygen (SaO2) less than 93% or tachypnea (respiratory rate above an age adjusted normal range)
* Agree to the storage of specimens and data
* ABO compatible plasma available on site or available within 24 hours after randomization with activity against locally circulating strains of influenza

Exclusion Criteria:

* Receipt of non-licensed treatment for influenza within the last 2 weeks (or plans to receive any time during the study). This does not include licensed drugs at non approved doses, off-label indications, or drugs available under an Emergency Use Authorization (EUA).
* History of severe allergic reaction to blood products (as judged by the investigator).
* Medical conditions for which receipt of 500 mL volume (or 8 mL/kg for pediatric patients) may be dangerous to the subject (e.g. decompensated congestive heart failure \[CHF\], etc.)
* Clinical suspicion that etiology of acute illness is primarily due to a condition other than active influenza virus replication (e.g., a bacterial or fungal infection)
C: 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).
D: Inclusion Criteria:

* (fulfill all criteria): male or female patients 18 years or older
* written informed consent by patient or next of kin (if patients too ill)
* diagnosis of H1N1 2009 infection satisfying both clinical and laboratory criteria:

  1. Laboratory criteria: at least one RT-PCR positive for H1N1 2009 from one of the clinical specimens (NPA, ETA, blood, urine or stool).
  2. Clinical criteria: patients admitted to ICU with severe community acquired pneumonia as defined by a CURB-65 score of 3 or more
* deterioration during treatment with optimal antiviral (oral or inhaler agents only) and typical and atypical antimicrobial coverage
* required ICU and ventilatory support and within 7 days onset of symptoms.

Exclusion Criteria:

* age below 18 years
* known hypersensitivity to immune globulin or any components of the formulation
* known IgA deficiency
* acquire the H1N1 2009 infection from health care facility
* moribund patients or refusal of informed consent.

Answer: C