Safety and Efficacy of Investigational Immune Plasma in Treating Influenza A (IRC002)

• Duration of clinical symptoms, fever, intensive care unit (ICU) stay, and hospitalization [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Time to resolution of symptoms and fever [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Mortality [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Acute lung injury [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Acute respiratory distress syndrome (ARDS) [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Time to 20% improvement in sequential organ failure assessment (SOFA) score for participants at least 18 years old and pediatric logistic organ dysfunction (PELOD) score for those younger than 18 years old [ Time Frame: Measured at study completion ] [ Designated as safety issue: Yes ]
• Time to 50 millimeters of mercury (mm/Hg) improvement in partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio [ Time Frame: Measured at study completion ] [ Designated as safety issue: No ]
• Incidence and duration of both supplemental oxygen use and mechanical ventilation use [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Disposition following initial hospitalization [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Birth complications for pregnant women [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Adverse events and laboratory abnormalities [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
• Relationship between hemagglutination inhibition assay (HAI) and measures of viral clearance [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]

Influenza A/H1N1 2009 (commonly referred to as "swine flu") is a novel influenza virus. Severe morbidity and mortality occur despite treatment with current antivirals. H1N1 vaccines are available, but much of the population remains unvaccinated. Of most concern, are 2 types of influenza A that widely circulate in humans and cause seasonal outbreaks and epidemics - H1N1 and H3N2. This randomized, open-label, multi-center, Phase 2 trial will assess the safety, efficacy, and pharmacokinetics of anti-influenza plasma in participants with influenza A (H1N1, H3N2). Hospitalized participants with influenza A at risk of severe disease (as defined in the inclusion criteria) will be eligible for study participation. This study will enroll adults, children and pregnant women.

Influenza A/H1N1 2009 (also referred to as "swine flu") is a novel influenza virus. H1N1 vaccines are available, but much of the population remains unvaccinated. Initial reports suggested a high mortality rate (6-7%). More recent statistics suggest a much lower mortality rate similar to seasonal influenza, though in contrast to seasonal influenza, influenza A/H1N1 2009 affects a younger, healthier population.

Morbidity and mortality occur despite treatment with current antivirals. Circulating influenza A/H1N1 2009 isolates are highly resistant to amantadine and rimantadine, whereas previous seasonal H1N1 isolates were highly resistant to oseltamivir. So there is concern that the 2009 H1N1 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 A. Hospitalized subjects with influenza A 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.

Approximately 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 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 plasma and standard care).

Subjects will be assessed on Study Day 0 (pre-dose), 30 minutes post-dose, 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).

• Biological: Anti-Influenza Plasma
  2 units of plasma with high titer anti-influenza A antibodies at baseline
• Behavioral: Standard Care
  Standard care for hospitalized people with influenza A

• Experimental: Anti-Influenza Plasma and Standard Care
  Participants will receive plasma with high titer anti-influenza A antibodies and standard care.
  Interventions:

  • Biological: Anti-Influenza Plasma
  • Behavioral: Standard Care
• Active Comparator: Standard Care
  Participants will receive standard care.
  Intervention: Behavioral: Standard Care

• Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis. 1995 Jan-Mar;1(1):7-15. Review.
• Bean WJ, Schell M, Katz J, Kawaoka Y, Naeve C, Gorman O, Webster RG. Evolution of the H3 influenza virus hemagglutinin from human and nonhuman hosts. J Virol. 1992 Feb;66(2):1129-38.
• de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, Bach VC, Phan TQ, Do QH, Guan Y, Peiris JS, Tran TH, Farrar J. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med. 2005 Dec 22;353(25):2667-72.

Inclusion Criteria:

• Diagnosis of influenza A (confirmed by local assay that may test for either influenza A or more specific influenza A H1N1 2009, including rapid antigen, direct fluorescent antibody [DFA], polymerase chain reaction [PCR], or culture)
• 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
• Agree to the storage of specimens and data
• ABO compatible H1N1 plasma available

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 nonapproved doses, off-label indications, or drugs available under an Emergency Use Authorization (EUA).
• Symptoms or signs of the acute influenza-like illness have occurred for more than 7 days prior to enrollment.
• 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 illness is primarily bacterial