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

• ClinicalTrials.gov Identifier: NCT02287467
• Recruitment Status: Completed
• First Posted: November 10, 2014
• Results First Posted: November 14, 2019
• Last Update Posted: November 14, 2019
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: University of Minnesota; International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information

• First Submitted Date: November 6, 2014
• First Posted Date: November 10, 2014
• Results First Submitted Date: September 20, 2019
• Results First Posted Date: November 14, 2019
• Last Update Posted Date: November 14, 2019
• Study Start Date: January 2015
• Actual Primary Completion Date: June 7, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 11, 2019)

Number of Patients in Each of 6 Clinical Status Categories on Day 7 [ Time Frame: Assessed 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).

Original Primary Outcome Measures (submitted: November 6, 2014)

• Percent of participants who die by Day 7 [ Time Frame: Measured through Day 7 ]
• Percent of participants in the intensive care unit (ICU) at Day 7 [ Time Frame: Measured at Day 7 ]
• Percent of non-ICU hospitalized participants requiring supplemental oxygen at Day 7 [ Time Frame: Measured at Day 7 ]
• Percent of non-ICU hospitalized participants not requiring supplemental oxygen at Day 7 [ Time Frame: Measured at Day 7 ]
• Percent of participants who are not hospitalized, but who are unable to resume normal activities at Day 7 [ Time Frame: Measured at Day 7 ]
• Percent of participants who are not hospitalized and have fully resumed normal activities at Day 7 [ Time Frame: Measured at Day 7 ]

Current Secondary Outcome Measures (submitted: November 11, 2019)

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

Original Secondary Outcome Measures (submitted: November 6, 2014)

• Change in National Early Warning (NEW) score from baseline to Day 3 [ Time Frame: Measured at Day 3 ]
• Number of days participants hospitalized [ Time Frame: Measured through Day 28 ]
• Composite of mortality or hospitalization at Days 7, 14, and 28 [ Time Frame: Measured through Day 28 ]
• Among participants not enrolled in the ICU, number who require invasive mechanical ventilation or admission to the ICU [ Time Frame: Measured through Day 28 ]
• Percent of participants shedding virus at Day 3 [ Time Frame: Measured at Day 3 ]
• Hemagglutination inhibition (HAI) antibody level changes through Day 7 [ Time Frame: Measured through Day 7 ]
• Number of Grade 3 and 4 adverse events [ Time Frame: Measured through Day 28 ]
• Number of serious adverse events [ Time Frame: Measured through Day 28 ]
• Percent of participants developing bronchitis, pneumonia, or other complications through Day 28 [ Time Frame: Measured through Day 28 ]
• Number of participants who die [ Time Frame: Measured through Day 28 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluating the Safety and Efficacy of Anti-Influenza Intravenous Hyperimmune Immunoglobulin (IVIG) in Adults Hospitalized With Influenza
• Official Title: Anti-Influenza Hyperimmune Intravenous Immunoglobulin Clinical Outcome Study (INSIGHT 006: FLU-IVIG)
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Influenza A
• Influenza B

Intervention

• Biological: Intravenous hyperimmune immunoglobulin (IVIG)
  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)
• Biological: Placebo for IVIG
  Administered IV as 500 mL of normal saline

Study Arms

• Experimental: Arm A: hIVIG
  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.
  Intervention: Biological: Intravenous hyperimmune immunoglobulin (IVIG)
• Placebo Comparator: Arm B: Placebo
  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.
  Intervention: Biological: Placebo for IVIG

• Publications *: Davey RT Jr, Fernandez-Cruz E, Markowitz N, Pett S, Babiker AG, Wentworth D, Khurana S, Engen N, Gordin F, Jain MK, Kan V, Polizzotto MN, Riska P, Ruxrungtham K, Temesgen Z, Lundgren J, Beigel JH, Lane HC, Neaton JD; INSIGHT FLU-IVIG Study Group. Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial. Lancet Respir Med. 2019 Nov;7(11):951-963. doi: 10.1016/S2213-2600(19)30253-X. Epub 2019 Sep 30.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 11, 2019): 329
• Original Estimated Enrollment (submitted: November 6, 2014): 320
• Actual Study Completion Date: June 7, 2018
• Actual Primary Completion Date: June 7, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Denmark, United Kingdom, United States

Administrative Information

• NCT Number: NCT02287467
• Other Study ID Numbers: INSIGHT 006: FLU-IVIG
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Original Study Sponsor: Same as current

Collaborators

• University of Minnesota
• International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)

Investigators

• Study Chair: Richard T. Davey, Jr., MD; National Institute of Allergy and Infectious Diseases (NIAID)
• Study Chair: Eduardo Fernández-Cruz, MD, PhD; Hospital General Universitario Gregorio Marañón
• Study Chair: Norman P. Markowitz, MD; The Henry Ford Hospital
• Study Chair: Sarah L. Pett, MD, MBBS, DTM, MRCP (UK); University College, London

• PRS Account: National Institute of Allergy and Infectious Diseases (NIAID)
• Verification Date: November 2019