Evaluating the Safety and Efficacy of Anti-Influenza Intravenous Hyperimmune Immunoglobulin (IVIG) in Adults Hospitalized With Influenza

Study Overview
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Brief Summary
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Influenza (the flu) is a common illness that usually occurs in autumn and winter. The flu is usually mild, but can cause serious illness or death. The purpose of this study is to test the safety and effectiveness of an antibody against the flu (called intravenous hyperimmune immunoglobulin or IVIG) in people who are hospitalized for severe flu.

Detailed Description
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Influenza is responsible for thousands of hospitalizations and deaths each year in the United States and worldwide. One possible new treatment for the flu involves the use of IVIG, a blood product containing antibodies from people who have recovered from the flu or who have had a flu shot. The purpose of this study is to evaluate whether IVIG can reduce the severity and duration of flu in people who are hospitalized with the flu. The study will enroll participants 18 years and older who are hospitalized with the flu. The study will enroll participants over one or more flu seasons. Regardless of the date of enrollment, each participant will be in the study for about 28 days. At study entry (Day 0), participants will be randomly assigned to one of two groups (Arms A and B). Participants in both groups will receive standard of care (SOC) treatment for the flu, but those in Arm A will also receive one dose of IVIG and those in Arm B will receive a placebo for IVIG. Both IVIG and placebo will be given intravenously over at least 2 hours. On Day 0, before receiving IVIG or placebo, participants will undergo a symptoms assessment, blood collection, and a nasopharyngeal (NP) swab to collect a sample of secretions from the nose and throat. Additional study visits will occur on Days 1, 2, 3, 7, 14, and 28. Depending on the visit, participants may take part in the same study procedures that took place on Day 0. On Days 2, 14, and 28, visits for participants who are no longer hospitalized may be conducted over the phone.

Official Title
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Anti-Influenza Hyperimmune Intravenous Immunoglobulin Clinical Outcome Study (INSIGHT 006: FLU-IVIG)

Conditions
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Influenza A, Influenza B

Intervention / Treatment
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* Biological: Intravenous hyperimmune immunoglobulin (IVIG)
* Biological: Placebo for IVIG


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: hIVIG<br>Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. | Biological: Intravenous hyperimmune immunoglobulin (IVIG)<br>* Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)<br>|
| Placebo Comparator: Arm B: Placebo<br>Participants will receive a single infusion of placebo for hIVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu. | Biological: Placebo for IVIG<br>* Administered IV as 500 mL of normal saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients in Each of 6 Clinical Status Categories on Day 7 | This is the primary outcome, a 6-category ordinal outcome ranging from death (worst) to discharged from hospital with resumption of normal activities (best). | Assessed on Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients in Each of 5 Clinical Status Categories on Day 3 | 5-category ordinal outcome assessed on day 3; clinical status ranges from death (worst) to discharged from the hospital (best). | Assessed on Day 3 | 
| Number of Patients in Each of 6 Clinical Status Categories on Day 3 | 6-category ordinal outcome evaluated on Day 3; clinical status ranges from death (worst) to discharged from hospital with resumption of normal activities (best). | Measured on Day 3 | 
| Number of Patients With a Favorable Outcome on Day 7 | Sliding dichotomy defined as non-ICU hospitalization or discharge if enrolled from ICU, and discharge if enrolled from the general ward. | Assessed on Day 7 | 
| Hospital Discharge | Number of participants alive and discharged from the hospital | Measured through Day 7 | 
| Mortality | Number of participants dying through day 28. | Measured through day 28 | 
| Number of Patients Alive and Out of Hospital | Number and percent alive and out of hospital on day 28 | Measured through Day 28 | 
| Change in Viral Load | Change in nasopharyngeal viral load from baseline to day 3 | Day 3 | 
| Death or Re-hospitalization | Number and percent of participants who died or were re-hospitalized after initial discharge | Day 28 | 
| Percent of Participants Developing Complications | Number and percent of participants developing respiratory distress syndrome, acute renal failure, sepsis, pneumonia, enteritis, or bronchitis | Measured through Day 28 | 
| Number of Patients in Each of 6 Clinical Status Categories on Day 14 | 6-category ordinal outcome measured on day 14 | Measured on day 14 | 
| Number of Patients Alive and Out of Hospital on Day 14 | Number and percentage of participants alive and out of the hospital on Day 14 | day 14 | 
| Resumption of Normal Activities by Day 14 | Participants reporting resumption of normal daily activities by Day 14 | day 14 | 
| Number of Patients in Each of 6 Clinical Status Categories on Day 28 | 6-category ordinal outcome corresponding to clinical status on day 28 | day 28 | 
| Number of Influenza A-Infected Patients in Each of 6 Clinical Status Categories on Day 7 | Primary 6-category ordinal outcome for participants infected with Influenza A | Day 7 | 
| Number of Influenza B-Infected Patients in Each of 6 Clinical Status Categories on Day 7 | Primary 6-category ordinal outcome for subgroup of participants infected with influenza B | Day 7 | 
| pH1N1 Titers at Day 7 | pH1N1 hemagglutination inhibition assay (HAI) titers among participants infected with pH1N1 using A/Cal/2009 as reference virus | Day 7 | 
| H3N2 Titers at Day 7 | H3N2 HAI titers among participants infected with H3N2 using A/HongKong/2014 as reference virus | Day 7 | 
| Influenza B Titers at Day 7 | Flu B HAI titers among participants infected with influenza B using B/Phuket/2013 as reference virus | Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antiviral, IVIG, Hemagglutination inhibition (HAI), Antibody