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

A Randomized, Open-Label, Phase 2, Multicenter Safety and Exploratory Efficacy Study of Investigational Anti-Influenza Immune Plasma for the Treatment of Influenza (IRC002)

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.

Study Overview

• Status: Completed
• Conditions: Influenza A; Influenza B
• Intervention / Treatment: Biological: Anti-Influenza Immune Plasma; Drug: Standard Care

Detailed Description

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
• Enrollment (Actual): 98
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095-1752
      • David Geffen School of Medicine at UCLA
    • San Diego, California, United States, 92134
      • Naval Medical Center San Diego
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Research Institute, CA
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20010
      • Children's National Medical Center
    • Washington, D.C., District of Columbia, United States, 20422
      • Washington, DC VA Med Center
  • Florida
    • Gainesville, Florida, United States, 32608
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University (NU)
    • Chicago, Illinois, United States, 60612
      • The Rush University Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine Center for Vaccine Development
    • Baltimore, Maryland, United States, 21218
      • John Hopkins University (JHU)
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center (WRNMMC)
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital/Harvard Medical School
    • Boston, Massachusetts, United States, 02118
      • Boston Med Center
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Healthcare Group
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Saint Mary's Hospital (Mayo Clinic)
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10467
      • Montefiore Medical Center/Albert Einstein College of Medicine
    • New York, New York, United States, 10065
      • Cornell Clinical Trials Unit, New York Presbyterian Hospital, Weill Cornell Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0405
      • University of Cincinnati College of Medicine
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center (UPMC)
  • Texas
    • Amarillo, Texas, United States, 79106
      • Texas Tech University Health Science Center (HSC)- Amarillo
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Lubbock, Texas, United States, 79430
      • Texas Tech HSC-Lubbock, TX
  • Virginia
    • Portsmouth, Virginia, United States, 23708
      • Naval Medical Center Portsmouth
  • Washington
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center (MAMC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Plasma and Standard Care; Participants will receive plasma with high titer anti-influenza A or anti-influenza B antibodies (Anti-Influenza Immune Plasma) in addition to standard care.	Biological: Anti-Influenza Immune Plasma; 2 units of plasma with high titer anti-influenza A or anti-influenza B antibodies at baseline; Drug: Standard Care; 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.
ACTIVE_COMPARATOR: Standard Care; Participants will receive standard care.	Drug: Standard Care; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Measured from Day 0 through Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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	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.	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.	Measured at Days 1, 2, 4, 7, 14, 28
In-hospital Mortality	Number of deaths in hospital during initial hospital admission	Measured from Day 0 through Day 28
28-day Mortality	Number of deaths during study follow-up	Measured from Day 0 through Day 28
Duration of Hospitalization	Days that a participant spent at the hospital. Multiple hospitalizations are summed up.	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.	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.	Measured from Day 0 through Day 28
Days on Supplemental Oxygen	Time (in days) of supplemental oxygen use	Measured from Day 0 through Day 28
Duration of Supplemental Oxygen	Duration of supplemental oxygen use in days	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.	Measured at Days 0, 1, 2, 4, 7, 14, 28
Days on Mechanical Ventilation	Time (in days) of mechanical ventilation use	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.	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".	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)	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	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	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	Measured from Day 0 through Day 28

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: John Beigel, MD, Leidos Biomedical Research, Inc. in support of Laboratory of Immunoregulation, NIAID, NIH; Study Chair: Richard Davey, MD, Laboratory of Immunoregulation, NIAID, NIH

Publications and helpful links

General Publications

• Morse SS. Factors in the emergence of infectious diseases. Emerg Infect Dis. 1995 Jan-Mar;1(1):7-15. doi: 10.3201/eid0101.950102.
• 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. doi: 10.1128/JVI.66.2.1129-1138.1992.
• 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. doi: 10.1056/NEJMoa054512.
• Beigel JH, Tebas P, Elie-Turenne MC, Bajwa E, Bell TE, Cairns CB, Shoham S, Deville JG, Feucht E, Feinberg J, Luke T, Raviprakash K, Danko J, O'Neil D, Metcalf JA, King K, Burgess TH, Aga E, Lane HC, Hughes MD, Davey RT; IRC002 Study Team. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med. 2017 Jun;5(6):500-511. doi: 10.1016/S2213-2600(17)30174-1. Epub 2017 May 15. Erratum In: Lancet Respir Med. 2017 Jul;5(7):e26.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2010
• Primary Completion (ACTUAL): March 1, 2015
• Study Completion (ACTUAL): November 1, 2015

Study Registration Dates

• First Submitted: January 16, 2010
• First Submitted That Met QC Criteria: January 16, 2010
• First Posted (ESTIMATE): January 20, 2010

Study Record Updates

• Last Update Posted (ACTUAL): September 5, 2017
• Last Update Submitted That Met QC Criteria: August 3, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Emerging Infectious Disease; Antiviral; Anti-Influenza Immune Plasma; Swine Flu
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human
• Other Study ID Numbers: 10-I-0043; IRC002 (OTHER: NIAID Influenza Research Collaboration)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No