Influenza Treatment Project Groups 7 and 8 Among patients hospitalized with influenza, does intravenous immunoglobulin (FLU IVIG) + standard of care (SOC) reduce the 60-day morbidity and mortality associated with influenza as compared to placebo + SOC?

Background and Rationale n Morbidity and mortality associated with influenza is substantial – estimated at 500,000 deaths worldwide. n A recent meta-analysis of observational studies found that neuraminidase inhibitor treatment was associated with significant reduction in mortality among hospitalized patients if treatment was given within 48 hours of onset. n Many patients are not hospitalized within 48 hours of symptoms. n Preliminary studies with hyperimmune intravenous immunoglobulin (IVIG) suggest there may be benefit associated with their use.

Figure 7. Age distribution of projected global and regional respiratory mortality, for both pandemic and seasonal influenza mortality estimates. Simonsen L, Spreeuwenberg P, Lustig R, Taylor RJ, et al. (2013) Global Mortality Estimates for the 2009 Influenza Pandemic from the GLaMOR Project: A Modeling Study. PLoS Med 10(11): e doi: /journal.pmed

Date of download: 11/29/2013 Copyright © The American College of Physicians. All rights reserved. From: Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment? Ann Intern Med. 2006;145(8): doi: /

Date of download: 11/29/2013 Copyright © The American College of Physicians. All rights reserved. From: Meta-Analysis: Convalescent Blood Products for Spanish Influenza Pneumonia: A Future H5N1 Treatment? Ann Intern Med. 2006;145(8): doi: /

Influenza IVIG: Recent Studies 35 ICU patients at 5 hospitals in Hong Kong with severe A(H1N1)pdm09 infection on standard antiviral treatment requiring ventilatory support: randomized to receive H-IVIG (17 pts) or normal IVIG (18 pts) Overall mortality was similar: 5 (29.4%) H-IVIG participants died 4 (23.5%) IVIG participants died. H-IVIG treatment was associated with significantly lower day 5 (p=0.04) and 7 (p=0.02) post-treatment viral load compared to IVIG. Subgroup analysis: ? beneficial effect of H-IVIG on mortality among participants treated within 5 days of symptom onset (0/12 deaths on H-IVIG versus 4/10 deaths on IVIG) Safety: no adverse safety signals of H-IVIG treatment reported.

Influenza IVIG: Unknowns Influenza mortality due to ongoing viral replication versus host inflammation? Ability of antibodies to favorably mediate disease pathogenesis? Optimal dose of hyperimmune plasma/IVIG? Is an HAI titer of ≥ 1:40 sufficient? Optimal timing of hyperimmune plasma/IVIG treatment? Does a therapeutic window close “x” days after symptom onset? Possibility of therapeutic harm? Does hyperimmune plasma/IVIG have any role in “complicated” influenza with secondary infections (e.g. bacterial pneumonia)?

Infusion Procedure - 1 n Storage of IVIG and Timing of Infusion u Store IVIG at -20º C and thaw immediately before use. u After thawing IVIG, it is added to saline based on weight to obtain desired 500 mL volume u Begin infusion within 4 hours of preparation of study treatment and soon as possible after randomization u Infusion of study treatment must be completed within 8 hours of preparation

Infusion Procedure - 2 n Considerations in blinding u IVIG has a different color than placebo so use an sleeve over the infusion bag u Do not shake the infusion bag as IVIG will bubble n Infusion administration u Infuse at room temperature over a minimum of 2 hours F Can vary administration rate as per local guidelines

Questions To Consider n Location of sites – both Northern and Southern Hemisphere would permit enrollment year round. Need many sites because it not clear where influenza will strike. n Feasibility of maintaining double-blind n Primary endpoint definition; definition of secondary endpoints, including safety. n Inclusion criteria, e.g., duration of symptoms and confirmation of influenza.