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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Influenza A, Influenza B

Intervention / Treatment
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* Biological: Anti-Influenza Immune Plasma
* Drug: Standard Care


Participation Criteria
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Eligibility Criteria
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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)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Plasma and Standard Care<br>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<br>* 2 units of plasma with high titer anti-influenza A or anti-influenza B antibodies at baseline<br>Drug: Standard Care<br>* 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.<br>|
| Active Comparator: Standard Care<br>Participants will receive standard care. | Drug: Standard Care<br>* 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antiviral, Anti-Influenza Immune Plasma, Emerging Infectious Disease, Swine Flu