Anti-Influenza Hyperimmune Intravenous Immunoglobulin Clinical Outcome Study (INSIGHT 006: FLU-IVIG)
Phase: PHASE3
Conditions: Influenza A, Influenza B
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
 
 
 
 
 
 
 
Anti-Influenza Hyperimmune Intravenous Immunoglobulin 
 Clinical Outcome Study  
(INSIGHT 006: FLU-IVIG) 
 
A Multicenter Study of the 
International Network for Strategic Initiatives in Global HIV Trials 
(INSIGHT) 
 
 
 
Sponsored by: University of Minnesota 
 
IND #15771 held by Regulatory Compliance and Human Subjects Protection Branch 
(RCHSPB), National Institute of Allergy and Infectious Diseases (NIAID) 
 
 
 
Protocol Co-Chairs:   
Richard T. Davey, Jr., MD 
 
 
Eduardo Fernández-Cruz, MD 
 
 
Norman P. Markowitz, MD 
 
 
Sarah L. Pett, MD 
 
 
 
 
 
 
INSIGHT 006:  FLU-IVIG  
 
 
Version: 2.0 
Date:  May 31, 2016 
 
 

INSIGHT 006:  FLU-IVIG 
 
Version 2.0 IND #15771 
 
 
 
31 May 2016 
 
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TABLE OF CONTENTS 
1  SYNOPSIS ........................................................................................................6 
2  BACKGROUND AND RATIONALE .................................................................9 
2.1  Influenza ............................................................................................................ 9 
2.2  Immunotherapy .............................................................................................. 10 
2.3  IVIG Pilot Study .............................................................................................. 12 
2.4  Potential Risks ................................................................................................ 13 
2.4.1 
Risks of IVIG ........................................................................................ 13 
2.4.2 
Risks Associated with Procedures ....................................................... 14 
2.5  Clinical Endpoint Considerations ................................................................. 14 
2.6  Study Product ................................................................................................. 15 
3  METHODOLOGY ........................................................................................... 17 
3.1  Study Design .................................................................................................. 17 
3.2  Treatment ........................................................................................................ 17 
3.3  Study Objectives ............................................................................................ 18 
3.3.1 
Primary Objective ................................................................................ 18 
3.3.2 
Secondary Objectives .......................................................................... 18 
3.4  Endpoints ........................................................................................................ 19 
3.5  Randomization ................................................................................................ 19 
3.6  Sample Size and Statistical Considerations ................................................ 19 
3.7  Availability of IVIG Lots ................................................................................. 21 
3.8  Participant Selection ...................................................................................... 21 
3.8.1 
Inclusion Criteria .................................................................................. 22 
3.8.2 
Exclusion Criteria ................................................................................. 22 
3.9  Study Plan ....................................................................................................... 23 
3.9.1 
Screening and Baseline ....................................................................... 23 
3.9.2 
Randomization and Blinding Procedures ............................................. 24 
3.9.3 
Storage and Administration of Study Treatment .................................. 24 
3.9.4 
Participant Follow-up ........................................................................... 24 
4  ASSESSMENT OF SAFETY ......................................................................... 27 

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4.1  Documenting, Recording, and Reporting Adverse Events and 
Unanticipated Problems ................................................................................ 27 
4.2  Investigator Assessment and Reporting of Adverse Events and 
Unanticipated Problems ................................................................................ 27 
4.2.1 
Adverse Event ..................................................................................... 27 
4.2.2 
Serious Adverse Event (SAE) .............................................................. 27 
4.2.3 
Unanticipated Problems ...................................................................... 27 
4.2.4 
Assessment of Severity and Causality for Adverse Events and 
Unanticipated Problems ...................................................................... 28 
4.2.5 
Reporting of Adverse Events ............................................................... 29 
4.3  Reporting Responsibilities ............................................................................ 29 
4.3.1 
Adverse Events ................................................................................... 29 
4.3.2 
Serious Adverse Events ...................................................................... 29 
4.3.3 
Unanticipated Problems ...................................................................... 29 
4.3.4 
Investigator Reporting Responsibilities to Local IRB(s) and Ethics 
Committees (ECs) ............................................................................... 30 
4.3.5 
Follow-up of Serious Adverse Events .................................................. 30 
4.3.6 
Serious Adverse Event Reporting Required by the European Union ... 30 
4.4  Study Deviations and Violations ................................................................... 30 
4.5.1 
Medical Monitor ................................................................................... 30 
4.5.2 
Data and Safety Monitoring Board (DSMB) ......................................... 30 
5  CLINICAL MANAGEMENT ISSUES ............................................................. 30 
5.1  Early Discontinuation of Study Treatment ................................................... 31 
5.2  Study Withdrawal ........................................................................................... 31 
5.3  Prohibited Medications .................................................................................. 31 
5.4  Live Virus Vaccines ........................................................................................ 31 
5.5  Pregnancy and Breastfeeding ....................................................................... 31 
5.6  Children31 
6  EVALUATION ................................................................................................ 31 
6.1  Data Analysis .................................................................................................. 31 
6.2  Data Monitoring .............................................................................................. 33 
7  PROTECTION OF HUMAN SUBJECTS & OTHER ETHICAL 
CONSIDERATIONS ............................................................................................ 34 

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7.1  Participating Clinical Sites and Local Review of Protocol and Informed 
Consent  .......................................................................................................... 34 
7.2  Ethical Conduct of the Study ........................................................................ 34 
7.3  Informed Consent of Study Participants ...................................................... 34 
7.4  Confidentiality of Study Participants ............................................................ 34 
7.5  Remuneration of Study Participants ............................................................ 34 
8  OTHER IMPORTANT DOCUMENTS AND POLICIES ................................. 35 
8.1  Reference Documents.................................................................................... 35 
8.2  Data Monitoring .............................................................................................. 35 
8.3  Storage and Use of Specimens ..................................................................... 35 
8.4  Record Retention ........................................................................................... 35 
8.5  Publications and Presentations .................................................................... 36 
 
APPENDIX A:  Sample Consent Form 
 
APPENDIX B:  Time and Events Schedules 
 
APPENDIX C:  FLU-IVIG Protocol Team 
 
APPENDIX D:  References on INSIGHT Website 
 
APPENDIX E:  List of Acronyms 
 
APPENDIX F:  Policies for Specimen Storage and Use 

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LIST OF TABLES 
 
Table 1:  Status of 333 Participants on Day 7 in FLU 003…………………..….……….12 
Table 2:  Difference that Can Be Detected in the Day 7 Ordinal Outcome …...……..21 
Table 3:  National Early Warning Score (NEWS)………………………….…………....23 
Table 4:  Generic AE Grading Scale………………………………..……….……………28 
 
LIST OF FIGURES 
 
Figure 1:  FLU-IVIG Design……………………………………………..………….……….5 
Figure 2:  Study Flow Sheet………………………………………………..……….……..26 
 

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1 Synopsis 
Purpose 
The purpose of this randomized, double-blind, placebo-controlled trial of intravenous 
hyperimmune immunoglobulin (IVIG) in individuals with influenza A or B is to 
determine whether, when added to standard of care (SOC) treatment, administration 
of IVIG is superior to placebo in terms of reducing disease severity and duration.   
 
Rationale 
Influenza is responsible for 226,000 excess hospitalizations and 30,000-50,000 deaths 
each year in the United States alone. The number of deaths is estimated to exceed 
500,000 worldwide.  Despite treatment with currently available antivirals, considerable 
morbidity and mortality occur due to influenza.   IVIG has demonstrated promising 
efficacy in several preliminary studies.   
 
Design 
FLU-IVIG is a randomized, double blind, placebo-controlled, multicenter, international 
clinical trial.  Hospitalized patients with a National Early Warning1 (NEW) score of 2 or 
greater will be randomized in a 1:1 allocation to receive either IVIG plus standard of 
care (SOC) therapy or placebo for IVIG (a comparable volume of normal saline) plus 
SOC, and will then be followed for 28 days. A total of 320 adult patients will be 
randomized over multiple influenza seasons. 
  
Figure 1:  FLU-IVIG Design 
 
 
 
 
IVIG + SOC 
 
N=160 
Hospitalized Adults with Influenza A or B  
Placebo for IVIG + SOC 
N=160  

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Endpoints 
The primary endpoint is an ordinal outcome at Day 7 that has 6 mutually exclusive 
categories:  
1. death; 
2. hospitalization in the intensive care unit (ICU); 
3. non-ICU hospitalization, requiring supplemental oxygen; 
4. non-ICU hospitalization, not requiring supplemental oxygen; 
5. not hospitalized, but unable to resume normal activities; or 
6. not hospitalized with full resumption of normal activities. 
 
Other endpoints include: 
 Change from baseline to Day 3 in NEW score 
 The ordinal primary outcome assessed at Days 1-7, 14 and 28 
 Number of days hospitalized 
 Composite of mortality or hospitalization at Days 7, 14 and 28 
 Requirement for invasive mechanical ventilation or admission to the ICU (among 
those not enrolled from the ICU) 
 Percent of patients shedding virus at Day 3 
 Hemagglutination Inhibition (HAI) antibody titer changes through Day 7 
 Grade 3 and 4 adverse events 
 Serious adverse events 
 Percent of patients developing bronchitis, pneumonia or other complications 
through Day 28 
 Mortality 
 
Inclusion Criteria 
1. Signed informed consent  
2. Age ≥ 18 years of age  
3. Locally determined positive influenza test (by PCR or other nucleic acid testing, or 
by rapid Ag) from a specimen obtained within 2 days prior to randomization  
4. Onset of illness no more than 7 days before randomization, defined as when the 
patient first experienced at least one respiratory symptom or fever 
5. Hospitalized (or in observation unit) with influenza, with anticipated hospitalization 
for more than 24 hours.   
6. For women of child-bearing potential: willingness to abstain from sexual intercourse 
or use at least 1 form of hormonal or barrier contraception through Day 28 of the 
study  
7. Willingness to have blood and respiratory samples obtained and stored 
8. NEW score ≥ 2 at screening (see Table 3) 
 
Exclusion Criteria 
1. Women who are pregnant or breast-feeding 
2. Prior treatment with any investigational drug therapy within 30 days prior to 
screening 
3. History of allergic reaction to blood or plasma products (as judged by the site 
investigator) 
4. Known IgA deficiency 

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5. A pre-existing condition or use of a medication that, in the opinion of the site 
investigator, may place the individual at a substantially increased risk of thrombosis 
(e.g., cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically 
significant monoclonal gammopathy) 
6. Presence of any pre-existing illness that, in the opinion of the site investigator, would 
place the individual at an unreasonably increased risk through participation in this 
study 
7. Patients who, in the judgment of the site investigator, will be unlikely to comply with 
the requirements of this protocol 
8. Medical conditions for which receipt of a 500 mL volume of intravenous fluid may be 
dangerous to the patient (e.g., decompensated congestive heart failure) 
9. Receiving extracorporeal membrane oxygenation (ECMO) 
10. Suspicion that infection is due to an influenza strain or subtype other than 
A(H1N1)pdm09, H3N2, or influenza B (e.g., H5N1, H7N9) 
 
Procedures 
Hospitalized patients with a locally determined positive influenza test will be assessed 
for their eligibility. Eligible patients who consent to the trial will be randomized. 
Administration of the assigned treatment will commence on the day of randomization.  
Participants will be given a single infusion of IVIG or matching placebo at a dose of 0.25 
g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body 
weight) in a total volume of 500 mL over a period of approximately 2 hours.   
 
Nasopharyngeal swabs will be obtained on Days 0 and 3 for central determination of 
molecular influenza viral loads by reverse transcription polymerase chain reaction (RT-
PCR).  Blood will be drawn prior to infusion and on Days 1, 3 and 7 for measurement of 
HAI titer levels and for storage. 
 
The primary clinical outcome will be assessed on Day 7.  Participants will be followed 
for other clinical outcomes through Day 28.   

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2 Background and Rationale 
2.1 
Influenza 
Despite vaccines and antivirals such as oseltamivir, influenza is responsible for 
226,000 excess hospitalizations and 30,000-50,000 deaths each year in the United 
States alone. The number of deaths is estimated to be over 500,000 worldwide.2  
These complications occur against an even wider spectrum of acute self-limited illness 
that annually accounts for substantial morbidity (e.g., days lost from school or 
employment) in both the developed and the developing world. Better treatments for 
influenza at all stages of severity are needed. 
 
Following the sudden and unexpected emergence of A(H1N1)pdm09 influenza virus, 
initial reports suggested a high mortality rate.3,4  More recent statistics suggest a 
mortality rate that is similar to seasonal influenza.  In 2009, the International Network 
for Strategic Initiatives in Global HIV Trials (INSIGHT), taking advantage of the 
geographic location of its sites and expertise in conducting international trials, 
launched 2 international protocols for observational cohort studies to estimate rates of 
morbidity and mortality and to examine predictors of the severity of A(H1N1)pdm09 
infection.5  One of these protocols, FLU 003, initially enrolled patients hospitalized with 
a presumptive or definitive diagnosis of A(H1N1)pdm09; in the other study (FLU 002), 
patients seen as outpatients who had influenza-like illness were enrolled.  In 2010, 
when it became clear that A(H1N1)pdm09 was not always the dominant virus in many 
locations, the protocols were modified to enroll individuals with all subtypes of 
seasonal influenza A virus no matter what the dominating subtype was.  In 2011, the 
protocols were further expanded to include influenza B. This INSIGHT cohort study 
provides some of the best data available to estimate rates of morbidity and mortality 
from influenza among patients in many different geographic locations around the 
world. 
 
Data from FLU 003 were used to inform the design of the proposed study.  Among 
participants enrolled in FLU 003, 333 with confirmed influenza by central PCR testing 
were enrolled within 7 days after the onset of influenza symptoms and had a baseline 
NEW score of at least 2.  The status of these 333 participants on Day 7 following 
enrollment was as follows: 
 
Table 1:  Status of 333 Participants on Day 7 in FLU 003 
 
 
 
Status on Day 7  
No. 
Percent 
Died 
6 
1.8 
Intubated or on ECMO 
12 
3.6 
Hospitalized, on supplemental oxygen 
52 
15.6 
Hospitalized, not on supplemental oxygen 
47 
14.1 
Out of hospital, not returned to normal 
130 
39.0 
Out of hospital, returned to normal activities 
86 
25.8 
 

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2.2 
Immunotherapy 
The statistics from the INSIGHT FLU 003 study confirm the substantial morbidity and 
health care burden associated with influenza, and the need for better treatments.  One 
potential therapeutic strategy involves the use of hyperimmune intravenous 
immunoglobulin (IVIG) that is prepared either from convalescent plasma from patients 
with documented influenza or from volunteers previously vaccinated for influenza.   
 
Influenza-convalescent human blood products were used to treat Spanish influenza.  
Luke et al described the results of 8 studies of transfusion of influenza-convalescent 
blood products conducted in 1918-1919.6  None of the studies were randomized trials. 
Overall, 336 seriously ill patients were treated with convalescent serum, plasma or 
whole blood and 1,219 patients served as controls.  Pooled mortality for treated 
patients and controls was 16% and 37%, a 57% relative difference.  Absolute 
differences in mortality ranged from 8% to 26% among the 8 studies. Of the 8 studies, 
two compared early (within 4 days of pneumonia complications) and late treatment 
(more than 4 days after pneumonia complications) with controls.  In both studies the 
benefit was restricted to those treated early (32% vs. 60% vs. 43% mortality for early, 
late and control patients in one study and 14% vs. 40% vs. 43% in the other study). 
The studies lacked methodological rigor but suggested that mortality could be 
substantially reduced with convalescent serum if introduced relatively early in the 
course of disease. 
 
A non-randomized study was conducted in Hong Kong; 93 patients, aged >18 years 
with severe A(H1N1)pdm09 infection requiring intensive care, were recruited by 7 
hospitals.7  All participants were offered treatment with 500 mL convalescent plasma 
that was collected from patients recovering from influenza, and that had a neutralizing 
A(H1N1)pdm09 antibody titer of >1:160. Twenty individuals (21.5%) agreed to receive 
the plasma treatment, and 73 declined.  All participants received standard antiviral 
treatment and other supportive medical care. Clinical outcomes were compared in the 
patients treated with plasma with those who declined plasma treatment as the 
“untreated” controls. Mortality in the treatment group was significantly lower than in the 
control group (20.0% vs. 54.8%; P = .01). The adjusted odds ratio (OR) for death was 
0.20 (95% CI: 0.06-0.69).  No adverse effects to the treatment were reported. 
 
A multi-center prospective double-blind randomized controlled trial of a hyperimmune 
intravenous immunoglobulin (H-IVIG) versus normal IVIG was also conducted in Hong 
Kong.8  Convalescent plasma from patients who recovered from the 2009 pandemic 
influenza infection was made into an immunoglobulin product (H-IVIG). Patients with 
severe A(H1N1)pdm09 infection on standard antiviral treatment requiring intensive 
care and ventilatory support were randomized at 5 hospitals in Hong Kong to receive 
H-IVIG or normal IVIG.  Thirty-five individuals were randomized to receive H-IVIG (17 
patients) or IVIG (18 patients). One of the participants assigned H-IVIG was excluded 
because of refusal to provide serial nasopharyngeal sampling and blood taking.  
Overall mortality was similar: 5 (29.4%) participants assigned H-IVIG died and 4 
(23.5%) participants assigned IVIG died.  However, H-IVIG treatment was associated 
with significantly lower day 5 and 7 post-treatment viral load when compared to the 
control (p=0.04 and p=0.02 respectively). A subgroup analysis suggested that there 
was a beneficial effect of H-IVIG on mortality among participants treated within 5 days 

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of symptom onset (0/12 deaths on H-IVIG versus 4/10 deaths on IVIG), although the 
opposite was suggested for those with symptoms for more than 5 days (5/5 deaths on 
H-IVIG and 0/7 deaths on IVIG). The authors indicated that no adverse effects related 
to treatment were reported. 
 
Over the years various case reports and small case series of the use of IVIG and 
convalescent plasma for the treatment of influenza have been reported.  Gordon et al 
report the results for 5 patients with A(H1N1)pdm09 infection treated with IVIG as 
potential salvage therapy.  In 3 of the 5 patients IVIG therapy was associated with 
improvement; the other 2 patients had significant respiratory deterioration.9  Zhou et al 
reported the use of convalescent plasma for the treatment of H5N1 influenza in a 
single patient who recovered.10  In the absence of any controls, it is difficult to attribute 
any benefit or risk to the treatments used in these investigations. 
 
Multiple studies in animals and humans conducted in the Soviet Union reported that 
convalescent plasma, serum and intravenous immune globulin were efficacious in the 
treatment of influenza pneumonia; however, these studies were small, often not 
randomized, and had other methodological concerns.11,12,13,14,15,16  A recent study of 
immunodeficient mice homozygous for the scid mutation found that prophylactic 
passive administration of hyperimmune IVIG increased survival of mice that were 
challenged with pH1N1.17   
 
A number of other viral diseases have also been treated with antibody preparations 
with variable results. These antibody preparations are generally given as IVIG. 
Curative treatment with IVIG is rare. Red blood cell aplasia caused by parvovirus B19 
infection is the only recognized viral infection for which treatment with IVIG may 
eradicate the infection.18,19 However, there is considerable evidence that immune 
globulin preparations may modify the natural history of viral diseases. These are 
summarized below. 
 
 Cytomegalovirus (CMV): CMV enriched immune globulin preparations have 
shown benefit when used in combination with ganciclovir in the treatment of CMV 
pneumonia.20  This immune globulin preparation is also utilized in the treatment 
of ganciclovir-resistant CMV infections.  
 
 Respiratory Syncytial Virus (RSV): In adult bone marrow transplant (BMT) 
patients with RSV pneumonia, combination therapy using aerosolized ribavirin 
and standard IVIG (500 mg/kg every other day for 12 days) for the treatment had 
a 22% mortality rate, compared to a historical mortality rate of 70%.21  In pediatric 
BMT patients with RSV pneumonia, patients treated with combination 
aerosolized ribavirin and RSV antibody enriched IVIG (RespiGam®) had a 9.1% 
mortality rate, compared with a historical 50-70% mortality rate of such patients 
given ribavirin alone.22 
 
 Vaccinia Virus: Certain complications of vaccination with the vaccinia virus 
(smallpox vaccine) are treated with vaccinia immune globulin (VIG). These 
included generalized vaccinia, eczema vaccinatum, and progressive vaccinia. 
There have been no controlled trials of the efficacy of VIG. However, anecdotal 

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experience suggests that treatment with VIG for these conditions is beneficial, 
and is now considered the standard of care (SOC).23 
 
 Hepatitis A: IVIG has also been shown useful in hepatitis A. Persons who have 
been recently exposed to hepatitis A and who have not been previously 
vaccinated with hepatitis A are recommended to receive standard IVIG as post-
exposure prophylaxis. This is based on data that showed IVIG, when 
administered within 2 weeks following an exposure to hepatitis A, is greater than 
85% effective in preventing hepatitis A.24  IVIG can also attenuate the clinical 
expression of hepatitis A infection when given later in the incubation period.25 
Standard IVIG is used because it does contain sufficient anti-hepatitis A 
antibodies.  
 
 Hepatitis B: For patients with hepatitis B and cirrhosis undergoing orthotopic liver 
transplant, hepatitis B hyperimmune IgG is given pre-operatively and post-
operatively to prevent reinfection with hepatitis B. This has been shown to be 50-
85% effective in preventing recurrence of hepatitis B in the transplanted liver.26  
 
 Rabies: Rabies hyperimmune IgG is the standard recommended therapy after 
exposure to the rabies virus/rabid animal.27 
 
 Argentine Hemorrhagic Fever: Convalescent plasma from survivors is the SOC 
and has been shown to reduce mortality from 50% to 4% if therapy is initiated 
within 8 days after disease onset.28 
 
 Severe Acute Respiratory Syndrome (SARS): Convalescent human plasma may 
have efficacy in the treatment of SARS.29 
 
 In a recent overview of studies of convalescent plasma and hyperimmune 
immunoglobulin convalescent plasma appeared to be safe and reduced mortality 
when used to treat severe respiratory infections of viral aetiology.30   
2.3 
IVIG Pilot Study 
A pilot study (INSIGHT 005: FLU-IVIG Pilot) was conducted to inform the dosing 
requirements in this study.31  The primary purpose of the randomized, double-blind 
pilot study was to determine the pharmacokinetic (PK) profile of an anti-influenza IVIG 
preparation and to assess whether antibody levels observed following IVIG transfusion 
were similar to those predicted.  In the pilot study, randomization, blinding and study 
procedures were also evaluated.  Thirty-one patients were randomized in the FLU-
IVIG Pilot, 16 to IVIG and 15 to placebo for IVIG.  Key findings are: 
 
 At one hour post-infusion, targeted HAI titer levels were achieved in 100% of 
patients for A/California/07/2009 H1N1pdm09 (1:64), 100% of patients for 
A/Texas/50/2012/ H3N2 (1:32), and 94% of patients for 
B/Massachusetts/02/2012 (1:16). 
 

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 HAI titer levels for patients with H1N1pdm09 (55% of patients), differed 
significantly between the IVIG and placebo groups through Day 3 of follow-up.  
Due to natural immunity treatment differences in HAI titer levels diminished with 
longer follow-up.  There was no between-group difference in HAI titer levels after 
Day 3. 
 
 Increases in HAI titers were smaller for influenza B than influenza A. 
 
 Two of 31 patients did not receive the full dose of IVIG/placebo.  One patient 
refused the infusion following randomization, and the infusion for a second 
patient was interrupted due to anxiety and a subjective feeling of dyspnea.  No 
safety concerns were identified in the study. 
 
 Blinding appears to have been maintained.  At the end of the trial, patients and 
clinical staff who assessed outcomes were asked to guess their assignment and 
this indicated that the blinding had been achieved. 
 
The FLU-IVIG Pilot study included outpatients and other patients who did not meet the 
strict eligibility criteria of this study.  Of the 31 patients randomized, 16 (52%) would 
meet the eligibility criteria of the proposed study.  Since the data collection plans for 
this study and the FLU-IVIG Pilot studies are similar, the clinical and virologic 
outcomes for these 16 patients will remain blinded and will be used to supplement the 
newly enrolled patients in INSIGHT 006.    
2.4 
Potential Risks 
2.4.1 
Risks of IVIG 
Like the FLU-IVIG Pilot, the IVIG used in this study will be manufactured in the same 
manner and to the same standards as commercially available (non-influenza antibody 
enriched) IVIG.  This includes screening for blood-borne pathogens and manufacturing 
steps that include solvents/detergents to inactivate any viruses.  There are no 
anticipated unique risks to an anti-influenza antibody enriched IVIG; therefore the risks 
are anticipated to be the risks of standard IVIG preparations. Common risks include 
fever, rash, hives, or headache.  Other more serious risks are rare and include serious 
allergic reactions including anaphylaxis, hemolysis, and aseptic meningitis.  As IVIG is 
made from human plasma, transmittable viral infections such as hepatitis B, hepatitis 
C, and human immunodeficiency virus (HIV) are a potential risk, although steps are 
taken to screen for and inactivate such pathogens. In addition, there is a theoretical 
risk, although low, that IVIG administration may be capable of transmitting other 
known or unknown infectious agents other than viruses, such as infectious prions 
(e.g., the agent of Creutzfeldt-Jakob disease). 
 
Immune globulin administration may impair the efficacy of live attenuated virus 
vaccines such as measles, rubella, mumps and varicella.  Renal dysfunction, acute 
renal failure, and osmotic nephropathy may occur with immune globulin intravenous 
products in predisposed patients. Renal dysfunction and acute failure occur more 

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commonly in patients receiving IVIG products containing sucrose. The influenza IVIG 
preparation used in this study does not contain sucrose. 
 
Although rare, transfusion-related acute lung injury (TRALI) may occur with IVIG 
therapy and is characterized by severe respiratory distress, pulmonary edema, 
hypoxemia, normal left ventricular function, and fever. 
  
There are case reports of pulmonary emboli occurring after administration of IVIG and 
plasma therapy, although definitive studies assessing risk are lacking.32 In one series 
5 of 10 patients critically ill with A(H1N1)pdm09 were shown to have pulmonary 
emboli.33 This high percentage has not been shown in other H1N1 series, and 
pulmonary emboli have been shown to develop in approximately 10-15% of critically ill 
adults.34 However, the potential risk of pulmonary embolism exists.  Other thrombotic 
events, including myocardial infarction, cerebral vascular accident, and deep vein 
thrombosis may also occur. 
2.4.2 
Risks Associated with Procedures 
The primary risk of nasopharyngeal (NP) swabs is local discomfort or gagging. Rarely, 
there can be local bleeding from the nasal mucosa, which is controlled with local 
measures such as pressure or packing with gauze.  
 
The risks of having blood taken typically include short-lasting pain, bleeding, bruising, 
lightheadedness, fainting and, rarely, infection or a blood clot where the needle enters 
the body.   
2.5 
Clinical Endpoint Considerations 
There are no established clinical endpoints for evaluating the clinical efficacy of 
influenza treatments.  Furthermore, as noted in a guidance document from the Food 
and Drug Administration (FDA), no study has definitively demonstrated substantial 
clinical efficacy in patients with serious influenza who are hospitalized.35 A number of 
possible clinical and virologic endpoints have been proposed for antiviral treatments.36  
These include death, progression to respiratory failure, continued clinical instability, 
prolonged hospitalization, and return to premorbid status.  Each of these outcomes will 
be assessed in INSIGHT 006.   
 
As a general requirement, the endpoint for a clinical trial should be clinically relevant, 
ascertainable in an unbiased manner for both treatment groups and occur with 
sufficient frequency to make a study feasible.  For example, mortality is a relevant 
clinical outcome but it occurs in too small a percent of patients to use it as the primary 
endpoint; sample size would be prohibitive.  In FLU 003, mortality after 14 days was 
less than 3% for patients who were enrolled while in the general hospital ward37; for 
potentially eligible patients for this study, mortality was less than 2% at Day 7 in FLU 
003 (see section 2.1).  On the other hand, sample size would be smaller for a virologic 
outcome as compared to a clinical endpoint but viral shedding is not an established 
surrogate marker for clinical disease.  It is important that the outcome used capture 
the patient’s clinical status during follow-up.  
 

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With these considerations, for the primary endpoint of the proposed study, we defined 
an ordinal outcome that is based on the patient’s status at Day 7 of follow-up.  An 
ordinal outcome has been used in other studies of seriously ill patients38; such an 
outcome will likely have greater statistical power than a binary clinical outcome 
assessed at Day 7 since it uses more information.  Day 7 was chosen as a time point 
for the primary comparison because, based on the FLU-IVIG Pilot, differences 
between treatment groups in HAI titer levels are greatest in the first few days after 
treatment with IVIG.  Also, measures of clinical status at later time points could reflect 
the impact of co-morbidities instead of influenza and dilute any treatment difference.  
Because of the uncertainty about the clinical endpoint to use in studies of hospitalized 
patients with influenza, and because of the importance of follow-up for a longer period 
of time than 7 days, multiple other clinical outcomes and a virologic endpoint will also 
be assessed as secondary endpoints over the planned 28 day follow-up period. 
2.6 
Study Product 
For this study, the FLU-IVIG was manufactured by Emergent BioSolutions, Winnipeg, 
Canada (formerly Cangene) under contract to the United States National Institute of 
Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), using high 
titer plasma collected from volunteers.  Emergent BioSolutions also manufactured the 
product used in the pilot study (INSIGHT 005: FLU-IVIG Pilot). The IVIG product used 
in this trial is manufactured according to Good Manufacturing Practices (GMP) from 
human plasma collected under IND at sites that are FDA-registered or licensed to 
perform this function. Based on the current Investigator’s Brochure (Version 5.0), the 
plasma used in this IVIG product meet the following criteria prior to being used for 
manufacture: 
 
 Negative Aniti-HIV 1 / 2 
 Negative Anti-HTLV 1 / 2 
 Negative Anti-HCV 
 Negative HBsAg 
 Negative serologic test for syphilis 
 Negative HIV NAT 
 Negative HCV NAT 
 Negative WNV NAT 
 Negative Hepatitis A virus NAT 
 Negative Hepatitis B virus NAT 
 Negative Parvovirus B19 NAT 
 
Any updates to the criteria will be documented in the next version of the Investigator’s 
Brochure. 
 
All tests are performed by commercially available assays.  
 
The lots of IVIG are tested at manufacture and periodically (at 3, 6, 9, 12, 18, 24, 36, 
and 48 months post-manufacture) for contemporary strains of influenza (as defined by 
the strains recommended by the WHO for the seasonal influenza vaccine). IVIG is 
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strain-specific HAI results by lot are included in the Investigator’s Brochure (IB), 
however, it is anticipated that the IVIG to be used in this study has the following 
average HAI titers: 
 
 A/H1N1 = 1:640  
 A/H3N2 = 1:640  
 B = 1:160  
 
If any new strains of influenza emerge through a season, additional HAI testing will be 
conducted against the new strain, when able, to document expected activity towards 
the new strain. 
 
The anticipated HAI titer levels in participants following infusion were estimated as 
follows.  The Vz (volume of distribution) of IVIG is approximately 0.05 L/kg, which is 
approximately the plasma volume.39  At the proposed dose of 0.25 g/kg, a 70 kg 
subject would receive 350 mL of influenza IVIG (with a minimum HAI titer of 1:640 for 
H3N2 and 1:160 for influenza B based on the above results). Thus, in a plasma 
volume of 3.5 L (0.05 L/kg) the minimum resultant HAI titer is estimated to be 
approximately 1:64 for H3N2 and 1:16 for influenza B. 
  
At the proposed dose, theoretically the following HAI titers would be expected in the 
recipient (assuming no pre-existing immunity): 
 
 A/ H1N1pdm09 = 1:64 
 A/ H3N2 = 1:64 
 B= 1:16 
 
Data from seasonal inactivated vaccines indicate that inducing an HAI titer > 1:40 
(sero-protection) in immunized individuals should be at least 70% effective in 
preventing influenza infection.40,41  An overview of 12 studies by de Jong et al. found 
that the median HAI titer protecting 50% of those vaccinated against the virus was 
1:28.42 However, it must be emphasized that protective pre-exposure prophylactic 
titers and post-exposure disease-modification titers are distinct concepts that do not 
necessarily harmonize, and the HAI titer actually needed for modifying favorably the 
course of an established influenza infection is not clear.   
 
Rockman et al demonstrated in an H5N1 model in ferrets that achieving an HAI titer of 
1:8 with a hyperimmune IVIG without any other antivirals was sufficient in preventing 
death if given early in the illness (during fever), and in delaying death if given at the 
onset of severe disease.43   
 
In the non-randomized plasma treatment study that showed significant mortality 
benefit associated with convalescent plasma infusion, the HAI in recipients was 
estimated to be 1:11.7 
 

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3 Methodology 
3.1 
Study Design 
INSIGHT 006:  FLU-IVIG is a multicenter, double-blind, randomized, placebo-
controlled clinical trial comparing treatment with hyperimmune intravenous 
immunoglobulin (IVIG) versus placebo in hospitalized patients with locally confirmed 
influenza A or B who have a NEW score ≥ 2.  For participants in both assigned 
treatment groups, the randomized treatment will be administered in addition to SOC 
treatment.  The study will be blinded to participants and to clinical staff other than the 
site pharmacist. 
 
Study participants will begin to be enrolled in the 2014-2015 influenza season.  
Enrollment will continue in subsequent influenza seasons until the required sample 
size is achieved.    
3.2 
Treatment 
The dispensing of study medication will be performed by a site pharmacist unblinded 
to the treatment assignment.  The pharmacist at each clinical site will use normal 
saline that is approved by their hospital formulary.   
 
Participants assigned to the placebo arm will receive a 500 mL bag of normal saline 
without any modifications.  For those assigned to IVIG, the pharmacist will prepare a 
bag containing IVIG at a dose of 0.25 g/kg of actual body weight, to a maximum of 
24.75 g IVIG (approximately 100 kg), plus as much saline as is needed to reach a total 
of 500 mL.  Detailed instructions for the pharmacist are in the INSIGHT FLU-IVIG 
Pharmacy Manual and the Investigator’s Brochure (IB) for IVIG.   
 
It is recognized that the presence of IVIG in normal saline will produce a yellowish 
coloration and some turbidity to the saline base that will vary depending upon the 
amount of IVIG product involved.  To knowledgeable staff or participants, this 
appearance could potentially unblind the study medication at the time of 
administration. Nonetheless, a reasonable effort will be undertaken to keep both the 
non-pharmacist staff at the clinical site and the study participant blinded to the 
treatment administered without interfering with safe intravenous infusion policies that 
may exist at a given institution.   
 
Following procedures used in INSIGHT 005: FLU-IVIG Pilot, in which the blind was 
effectively maintained, site pharmacists will be instructed to place a colored sleeve or 
other suitable covering over the 500 ml bag to mask the color of the contents therein, 
a process similar to what is occasionally done to shield photosensitive medications 
from light degradation.  
 
In the case of a medical emergency, at the request of the site investigator, the site’s 
study pharmacy staff can provide the participant’s unblinded treatment assignment. 
 
All participants will receive SOC treatment. This will be determined by their treating 
clinician and will not be dictated by this protocol.  It is anticipated that SOC will include 

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an antiviral effective against the circulating strain of influenza.  It is further anticipated 
that this will be oseltamivir in most cases, but use of other antivirals such as zanamivir 
or peramivir is permitted and will be left to the discretion of the treating clinician. 
3.3 
Study Objectives 
3.3.1 
Primary Objective 
The primary objective is to compare the clinical status of patients in the IVIG and 
placebo groups at 7 days of follow-up using an ordinal outcome with 6 clinical states.  
Specifically, patients will be categorized into one of the following 6 mutually exclusive 
categories on Day 7:  
 
1)   death;  
2)   hospitalization in the intensive care unit (ICU);  
3)   non-ICU hospitalization, requiring supplemental oxygen;  
4)   non-ICU hospitalization, not requiring supplemental oxygen;  
5)   not hospitalized, but unable to resume normal activities; or  
6)   not hospitalized with resumption of normal activities.   
3.3.2 
Secondary Objectives 
a. To compare participants in the IVIG and placebo groups for the following 
secondary outcomes: 
 Change from baseline to Day 3 in NEW score  
 The ordinal primary outcome assessed at Days 1-7, 14 and 28 
 Number of days hospitalized 
 Composite of mortality or hospitalization at Days 7, 14 and 28 
 Requirement for invasive mechanical ventilation or admission to the ICU 
(among those not enrolled from the ICU) 
 Mortality 
 Complications of influenza such as bronchitis and pneumonia 
 Percent of patients shedding virus at Day 3 
 
b. To compare the IVIG and placebo groups for HAI titer levels at Days 1, 3 and 7. 
 
c. To compare the IVIG and placebo groups for major clinical outcomes in 
subgroups defined by the following characteristics measured at baseline: 
 Age 
 Gender 
 Race/ethnicity 
 Geographic region (United States, Europe, South America, Australasia)  
 Duration of symptoms prior to enrollment 
 Influenza subtype 
 Type of hospital ward at time of enrollment 
 Production lot of IVIG 
d.  To compare the safety and tolerability of the FLU-IVIG and placebo group for: 

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 Number and percent with grade 3 or 4 adverse events (AEs) 
 Number and percent with serious adverse events (SAEs) 
 Number and percent with early termination of study treatment 
e. To relate viral load and HAI changes to clinical outcomes and assess whether 
these potential surrogate markers explain any clinical endpoint difference found. 
3.4 
Endpoints 
The primary endpoint is an ordinal outcome at Day 7 that has 6 mutually exclusive 
categories:  
1. death; 
2. hospitalization in the intensive care unit (ICU); 
3. non-ICU hospitalizion, requiring supplemental oxygen; 
4. non-ICU hospitalization, not requiring supplemental oxygen; 
5. not hospitalized, but unable to resume normal activities; or 
6. not hospitalized with full resumption of normal activities. 
 
Other endpoints include: 
 Change from baseline to Day 3 in NEW score 
 The ordinal primary outcome assessed at Days 1-7, 14 and 28 
 Number of days hospitalized 
 Composite of mortality or hospitalization at Days 7, 14 and 28 
 Among those not enrolled in the ICU, requirement for invasive mechanical 
ventilation or admission to the ICU 
 Percent of patients shedding virus at Day 3 
 HAI antibody titer changes through Day 7 
 Grade 3 and 4 adverse events 
 Serious adverse events 
 Percent of patients developing bronchitis, pneumonia or other complications 
through Day 28 
 Mortality 
3.5 
Randomization 
Eligible patients will be randomized in a 1:1 ratio to receive either IVIG + SOC or 
placebo + SOC.  Randomization will be stratified by clinical site. 
3.6 
Sample Size and Statistical Considerations 
The planned sample size for the trial is 320 randomized patients.  Sixteen of these 320 
patients will come from the FLU-IVIG Pilot.  A sample size re-estimation will be made 
after approximately 150 patients have been enrolled.  
 
The following assumptions were made in estimating the required sample size for the 
trial: 
 
a. The primary analysis will be intention to treat with a proportional odds model 
that includes indicators for treatment group and indicators for whether the 
patient was enrolled in the ICU and required oxygen at the time of 

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randomization.  The model will be stratified by geographic region (United 
States, Europe, South America and Australasia). 
 
b. Type 1 error is 0.05 (2-sided) and power =0.80. 
 
c. Patients will be equally allocated to IVIG or placebo. 
 
d. The clinical status of patients in the control arm at Day 7 will be similar to 
patients enrolled in the hospital in FLU 003 (see section 2.1 and table below).  
The estimates from FLU 003 are based on 333 hospitalized patients who 
were enrolled 7 or fewer days after onset of influenza symptoms and who had 
a NEW score of 2 or greater at the time of enrollment. 
 
e. In FLU 003, approximately 64-65% of patients were out of the hospital on Day 
7 (sum of 39.0% and 25.8% in table).  We assumed that for patients given 
IVIG this percent could be increased to 74% (about 10 percentage points).  
We assumed this same proportional improvement (an odds ratio of 
approximately 1.6) would apply to other category cutpoints on the ordinal 
scale (an underlying assumption of the proportional odds model).  If that were 
the case, the percentages in each clinical state in the IVIG group that would 
be realized are shown Table 2.44 
 
f. Based on the FLU-IVIG Pilot, we expect minimal non-adherence to IVIG and 
missing data at Day 7.  
 
 

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 Table 2:  Difference that Can Be Detected in the Day 7 Ordinal Outcome  
 
Power = 80%, Alpha = .05 (2-sided) and Sample Size = 320 
 
 
Day 7 Outcome (%) 
Hierarchical Outcome 
 
Placebo 
 
IVIG 
 
Death 
 
1.8 
 
1.0 
 
In ICU 
 
3.6 
 
2.1 
 
Non-ICU hospitalization, on O2 
 
15.6 
 
9.9 
 
Non-ICU hospitalization, not on O2  
 
14.1 
 
10.3 
 
Not back to normal activities 
 
39.0 
 
38.4 
 
Resumed normal activities 
 
25.8 
 
38.2 
 
Odds ratio  
 
 
 
1.77 
 
 
In summary, 320 patients (160 assigned IVIG and 160 assigned placebo) will be 
randomized.  An odds ratio will be computed as a summary measure of the treatment 
effect.  For the above table, this odds ratio is 1.77.  This can be interpreted as the 
average shift over the entire ordinal outcome scale caused by IVIG.  An odds ratio 
greater than one corresponds to a more favorable response for treatment with IVIG as 
compared to placebo.  With the proportional odds model this odds ratio is assumed to 
be the same for all possible ways of collapsing the 6-category scale into a better 
versus worse category (e.g., the odds ratio is 1.77 for out of hospital versus in 
hospital, not in ICU or death versus death or in ICU, etc).   
3.7 
Availability of IVIG Lots 
Study product will come from at least 4 lots of IVIG.  The first lot, the IVIG remaining in 
inventory from the FLU-IVIG Pilot study, is sufficient for approximately 10-15 patients 
assigned to IVIG.  The second lot became available for use in September 2014, and it 
is estimated that it will provide sufficient IVIG to treat 55 patients with IVIG (i.e., to 
randomize approximately 110 patients) at the same dose used in the FLU-IVIG Pilot.  
The third lot became available in September 2015.   
 
A fourth lot of IVIG is being prepared and is expected to become available in 
September 2016, allowing approximately 470 patients to be enrolled if necessary.  
This will be determined following a sample size re-estimation that is carried out after 
approximately 150 participants have been enrolled.  A decision on the need for 
additional lots will consider the time requirements for collecting plasma and 
manufacturing IVIG.  
3.8 
Participant Selection 
As a general guideline, individuals who are considered for enrollment should be able, in 
the clinician's opinion, to adhere to the protocol (i.e., be willing to accept and adhere to 
the data and specimen collection schedule and the assigned treatment).   

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3.8.1 
Inclusion Criteria 
1. Signed informed consent  
2. Age ≥ 18 years of age  
3. Locally determined positive influenza test (by PCR or other nucleic acid test, or by 
rapid Ag) from a specimen obtained within 2 days prior to randomization  
4. Onset of illness no more than 7 days before randomization, defined as when the 
patient first experienced at least one respiratory symptom or fever 
5. Hospitalized (or in observation unit) with influenza, with anticipated hospitalization 
for more than 24 hours.   
6. For women of child-bearing potential: willingness to abstain from sexual intercourse 
or use at least 1 form of hormonal or barrier contraception through Day 28 of the 
study  
7. Willingness to have blood and respiratory samples obtained and stored 
8. NEW score ≥ 2 at screening (see Table 3) 
3.8.2 
Exclusion Criteria 
1. Women who are pregnant or breast-feeding 
2. Prior treatment with any investigational drug therapy within 30 days prior to 
screening 
3. History of allergic reaction to blood or plasma products (as judged by the site 
investigator) 
4. Known IgA deficiency 
5. A pre-existing condition or use of a medication that, in the opinion of the site 
investigator, may place the individual at a substantially increased risk of thrombosis 
(e.g., cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically 
significant monoclonal gammopathy)  
6. Presence of any pre-existing illness that, in the opinion of the site investigator, would 
place the individual at an unreasonably increased risk through participation in this 
study 
7. Patients who, in the judgment of the site investigator, will be unlikely to comply with 
the requirements of this protocol 
8. Medical conditions for which receipt of a 500 mL volume of intravenous fluid may be 
dangerous to the patient (e.g., decompensated congestive heart failure) 
9. Receiving extracorporeal membrane oxygenation (ECMO) 
10. Suspicion that infection is due to an influenza strain or subtype other than 
A(H1N1)pdm09, H3N2, or influenza B (e.g., H5N1, H7N9) 
 
 
 

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Table 3:  National Early Warning Score (NEWS) 
 
3.9 
Study Plan 
3.9.1 
Screening and Baseline 
Consenting participants will have the following screening/baseline information and 
measurements collected. 
 
 
Within 2 days prior to randomization 
 Demographics and medical history 
 For women of child-bearing potential, a pregnancy test 
 Assessment of NEW score  
 Use of antiviral treatment 
 Laboratory confirmation of influenza 
 Clinical data  
 Local labs: 
o CBC with differential white cell count, hemoglobin, hematocrit, platelets 
o Blood chemistries:  sodium, potassium, serum bicarbonate, BUN, 
creatinine, glucose, albumin, ALT/GPT, AST/GOT, total bilirubin,  
PTT, PT, INR 
 
 

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On the day of randomization (Day 0) 
 Targeted symptoms 
 Assessment of NEW score (if not already performed for screening on Day 0) 
 Serum specimen for central lab (sufficient for 4 1-mL transport tubes, for 
serology testing and stored sample)  
 Plasma specimen for central lab (sufficient for 4 1-mL transport tubes, for 
stored sample) 
 Nasopharyngeal (NP) swab for quantitative PCR  (1 swab in 3mL VTM) 
 
Screening and baseline data and specimen collection requirements are summarized in 
tabular form in Appendix B: FLU-IVIG Time and Events Schedule.  Details of 
specimen handling can be found in the INSIGHT FLU-IVIG Laboratory Manual. 
 
For participants who consent to the separate INSIGHT Genomics study (INSIGHT  
004), a whole blood sample will be obtained for DNA extraction to study 
polymorphisms in immune response genes and other genetic variants that may be 
associated with an increased risk of respiratory diseases due to influenza. 
3.9.2 
Randomization and Blinding Procedures 
This study uses a placebo (normal saline) that is prepared and labeled to resemble 
active treatment (IVIG) by site pharmacists who are unblinded to the treatment 
assignment.  Randomization will be performed by study personnel using procedures 
outlined in the INSIGHT FLU-IVIG Protocol Instructions Manual.   
 
Blinding of the participant and clinical site staff will be achieved by placing a colored 
sleeve over the 500 mL bag that contains the IVIG plus normal saline or normal saline 
alone.  In the event that the blind is broken for reasons of safety, this will be recorded 
and the study team will be notified.  In that situation, every attempt will be made to 
minimize the number of people unblinded. 
 
Blinding is important for assessing safety and other outcomes planned for the clinical 
efficacy study; therefore procedures and the ability to maintain the blind will be 
evaluated at the end of follow-up for each participant.   
3.9.3 
Storage and Administration of Study Treatment 
After a site is opened for enrollment, a supply of IVIG will be provided to the clinical 
site pharmacy.  Details for storing, labeling, and dispensing study treatment are 
detailed in the INSIGHT FLU-IVIG Pharmacy Manual. 
 
Administration of blinded study treatment will commence as soon as possible after 
randomization on the day of randomization (Day 0).  The study treatment will be 
administered in a single infusion with a total volume of 500 mL over approximately 2 
hours.  
3.9.4 
Participant Follow-up 
Participants will be followed through Day 28 following randomization for collection of 
study data. Clinical data will be collected on Days 1-3, 7, 14, and 28.  For participants 

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who are not hospitalized, contact with the participant for the purpose of study data 
collection may be performed by telephone on Days 2, 14 and 28.  
 
An NP swab for central RT-PCR testing will be obtained on Day 3.  On Day 7, a local 
CBC and chemistry panel will be obtained.  On Days 1, 3, and 7, serum and plasma 
samples (sufficient for 4 1-mL transport tubes of each) will be obtained for central 
testing of the immune response to influenza and for storage for future influenza-related 
research. 
 
Follow-up data and specimen collection requirements are summarized in tabular form 
in Appendix B: FLU-IVIG Time and Events Schedule.  Details of specimen handling 
can be found in the INSIGHT FLU-IVIG Laboratory Manual. 
 
 

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Figure 2:  Study Flow Sheet 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Placebo + 
SOC 
IVIG + 
SOC 
Day -2 to Day 0 
 
Informed consent 
 
Screening & baseline data collection 
 
Local labs  

Confirmation of influenza
Day 1 
 
Clinical assessment, NEW score* 
* NEW score twice daily while hospitalized 
 
Serum & plasma specimen 
Day 0 
 
Targeted symptoms 
 
Randomization 
 
Serum, plasma, & NP swab collection 
 
Infusion 
Day 3 
 
Clinical assessment & NEW score* 
* NEW score twice daily while hospitalized 
 
NP swab for central PCR 
 
Serum, plasma, & NP swab collection 
 
Targeted symptoms 
Day 7 
 
Clinical assessment 
 
Local labs 
 
Serum & plasma specimen 
 
Targeted symptoms  
Day 14 
 
Clinical assessment 
Day 28 
 
Clinical assessment 
Day 2 
 
Clinical assessment, NEW score* 
* NEW score twice daily while hospitalized 

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4 Assessment of Safety 
4.1 
Documenting, Recording, and Reporting Adverse Events and 
Unanticipated Problems 
At each contact with the participant, information regarding adverse events and 
Unanticipated Problems will be elicited by appropriate questioning and examinations 
and will be: 
 Immediately documented in the participant’s medical record/source document 
 Recorded on the appropriate case report form 
 Reported as outlined below (e.g., IND holder, IRB, FDA) 
4.2 
Investigator Assessment and Reporting of Adverse Events and 
Unanticipated Problems 
4.2.1 
Adverse Event 
An adverse event is any untoward or unfavorable medical occurrence in a study 
participant, including any abnormal sign (e.g., abnormal physical exam or laboratory 
finding), symptom, or disease, temporally associated with their participation in research, 
whether or not considered related to the research.   If a diagnosis is clinically evident (or 
subsequently determined), the diagnosis, rather than the individual signs and symptoms 
or lab abnormalities, will be recorded as the AE. 
4.2.2 
Serious Adverse Event (SAE) 
An SAE is an AE that results in one or more of the following outcomes:   
 
 Death 
 Events that are life-threatening (i.e., an immediate threat to life)  
 Events requiring hospitalization or prolongation of hospitalization 
 Events resulting in a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions  
 Congenital abnormalities/birth defects  
 Other important medical events that may jeopardize the participant and may require 
intervention to prevent one of the outcomes listed above  
 
All events meeting the above criteria are reportable as SAEs.  In addition, all 
occurrences of TRALI (see section 2.4.1), regardless of grade, are also defined as 
medically important events for the purposes of this protocol, and are therefore to be 
reported as SAEs. 
 
Additional details on reporting SAEs are found in the INSIGHT FLU-IVIG Protocol 
Instructions Manual. 
4.2.3 
Unanticipated Problems 
An Unanticipated Problem (UP) is any incident, experience or outcome that is: 
 
1. Unexpected in terms of nature, severity, or frequency in relation to: 

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a. the research risks that are described in the IRB-approved research 
protocol and informed consent document; Investigator’s Brochure or other 
study documents; and 
b. the characteristics of the population being studied; and 
2. Possibly, probably, or definitely related to participation in the research; and 
3. Places study participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or 
recognized. 
 
Furthermore, a UP could be an expected event that occurs at a greater frequency in the 
IVIG group than placebo group.  The Data and Safety Monitoring Board (DSMB) 
providing oversight to the study may make such an assessment based on an aggregate 
analysis of events.  In that case, they will notify the sponsor who will in turn notify 
clinical site investigators who will be asked to submit the written DSMB summary report 
to IRBs. 
4.2.4 
Assessment of Severity and Causality for Adverse Events and 
Unanticipated Problems 
The investigator will evaluate all AEs with respect to seriousness as above (see section 
4.2.2) and severity (intensity or grade).  AEs will be graded for severity according to the 
DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, (also 
known as the DAIDS AE Grading Table; see Appendix D for the URL link).  
AEs will be reported irrespective of perceived relationship to the study agent.  
 
For specific events that are not included in the DAIDS AE Grading Table, the following 
generic scale is to be used: 
 
Table 4:  Generic AE Grading Scale 
 
Grade 1 
Symptoms causing no or minimal interference with usual social and 
functional activities 
Grade 2 
Symptoms causing greater than minimal interference with usual social 
and functional activities 
Grade 3 
Symptoms causing inability to perform usual social and functional 
activities 
Grade 4 
Symptoms causing inability to perform basic self-care functions, or 
medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death 
Grade 5 
Events resulting in death 
 
Causality (likelihood that the event is related to the study agent) will be assessed for 
SAEs and UPs.  For the purposes of IND safety reporting, ‘reasonable possibility’ of 
relationship means there is evidence to suggest a causal relationship between the drug 
and the adverse event.  Such evidence includes temporal relationship between study 

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agent administration and event, a known or suspected response pattern based on 
similar agents, and the likelihood (or lack thereof) of an alternative etiology. 
 
Note:  Causality assessment is based on available information at the time of the 
assessment of the event.  The investigator may revise the causality assessment as 
additional information becomes available. 
4.2.5 
Reporting of Adverse Events 
As noted in section 2.4.1 there are potential risks associated with taking IVIG.  These 
risks include fever, rash, hives, headache, allergic reactions, transmitted infections, 
renal dysfunction/failure, TRALI and pulmonary embolism.  The risk of transmitted 
infections is considered low because of the screening of the plasma used to make the 
IVIG. 
 
Some of these risks are similar to symptoms associated with influenza.  Also, it is 
expected that many participants will have co-morbid conditions that are associated with 
signs, symptoms and laboratory abnormalities that are similar to possible risks of IVIG.  
Thus, AEs will be collected irrespective of perceived relationship to treatment in order to 
compare differences between the IVIG and placebo groups. 
 
Through 28 days of follow-up, AE data collection will be restricted to any new grade 3 or 
4 AE, or previously existing AEs which have increased in severity to grade 3 or 4.  
4.3 
Reporting Responsibilities 
4.3.1 
Adverse Events 
Line listings, frequency tables, and other summary AE data will be submitted to 
RCHSPB (via the INSIGHT Safety Office) as required for periodic safety assessments, 
review of IND annual reports, review of IND safety reports, and preparation of final 
study reports.  These summaries will be for both treatment groups combined. 
4.3.2 
Serious Adverse Events 
All SAEs must be reported immediately (within 24 hours of awareness) by sites to the 
sponsor via the INSIGHT Safety Office.  Suspected unexpected serious adverse 
reactions (SUSARs) that result in death or are immediately life-threatening will be 
reported from the INSIGHT Safety Office to the NIAID Office of Clinical Research 
Policy and Regulatory operations (OCRPRO) and applicable regulators within 7 
calendar days of receipt.  All other SUSARs will be reported to OCRPRO and 
regulators within 15 calendar days. 
4.3.3 
Unanticipated Problems 
Non-serious AEs that are considered UPs must also be reported on CRFs and sent to 
the Safety Office no later than 7 calendar days after site awareness of the event.   

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4.3.4 
Investigator Reporting Responsibilities to Local IRB(s) and Ethics 
Committees (ECs) 
Investigators are responsible for submitting IND Safety Reports and UP summaries 
that are received from the IND holder to their local IRB/EC.  Investigators must also 
comply with all local IRB/EC reporting requirements. 
4.3.5 
Follow-up of Serious Adverse Events 
Participants who experience SAEs are followed until the final outcome is known, even 
if this occurs after the end of the study follow-up at 28 days. 
4.3.6 
Serious Adverse Event Reporting Required by the European Union 
In accordance with the EU Directive 2001/20/EC (http://eur-
lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2001:121:0034:0044:en:PDF), 
2011/C 172/01 (CT-3) (http://ec.europa.eu/health/files/eudralex/vol-
10/2011_c172_01/2011_c172_01_en.pdf),  UK SI 2004 1031 
(http://www.legislation.gov.uk/uksi/2004/1031/pdfs/uksi_20041031_en.pdf), and 
subsequent revisions, and member state requirements, the sponsor, through its legal 
representative in Europe, will ensure that all relevant information about serious adverse 
events including suspected unexpected serious adverse reactions (SUSARs) is 
recorded and reported to the central and/or concerned member state authorities and 
IECs as appropriate and in compliance with requirements for expedited reporting.  The 
study data collected will be used to construct the required reports to European 
authorities. 
4.4 
Study Deviations and Violations 
Protocol deviations will be reported on a CRF and these deviations will be summarized 
for the protocol team and the DSMB.  The protocol team will work with the site to 
promptly develop corrective actions as warranted. 
4.5 
Safety Oversight  
4.5.1 
Medical Monitor 
A Medical Monitor will participate on the study team (see Appendix C).  The Medical 
Monitor will be responsible for performing safety assessments as outlined above and 
communicate, as needed, with the IND holder.  
4.5.2 
Data and Safety Monitoring Board (DSMB) 
A DSMB will review the study data to evaluate the safety, efficacy, study progress, and 
conduct of the study (see Section 6.2).  Written DSMB summary reports with 
recommendations will be submitted to IRBs. 
  
5 Clinical Management Issues 
The following clinical management guidelines apply to both treatment groups. 

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5.1 
Early Discontinuation of Study Treatment 
Case report forms will be used to capture both the intended total dosage of study 
treatment as well as the dosage actually received.  Reasons for early termination of 
study treatment will be recorded.  
5.2 
Study Withdrawal 
A participant may be withdrawn if: 
 He/she is imprisoned or involuntarily incarcerated for medical reasons 
 The study is discontinued. 
 
All patients should otherwise be followed according to protocol.   
 
Participants may withdraw from the study at any time at their request and resume 
participation at any time upon re-consent.  Even if a participant did not receive all or 
any of the assigned study treatment, or some required data or specimens cannot be 
collected, every effort should be made to follow participants for clinical outcomes until 
the end of the study.   
5.3 
Prohibited Medications 
Participants may not receive other investigational medications during the first 7 days of 
follow-up.   
5.4 
Live Virus Vaccines 
As mentioned in section 2.4.1, immune globulin administration may impair the efficacy 
of live attenuated virus vaccines such as measles, rubella, mumps and varicella. 
Whenever possible, vaccination with live virus vaccines should be deferred until at 
least three months after administration of the IVIG. 
5.5 
Pregnancy and Breastfeeding 
Given the lack of known efficacy, and unknown potential toxicities, women are not 
eligible for enrollment into the study during their pregnancy or while they are 
breastfeeding. For women of child-bearing potential, a serum or urine pregnancy test 
must be performed before randomization.  
5.6 
Children 
Given the lack of known efficacy, and unknown potential toxicities, individuals < 18 
years of age are not eligible for enrollment into the study.  
 
6 Evaluation 
6.1 
Data Analysis 
The primary analysis will be intention to treat, comparing the outcomes of patients 
assigned IVIG with those assigned placebo.  For the primary endpoint, the percent of 
patients in the following 6 categories will be compared: 1) death; 2) ICU; 3) non-ICU 
ward, on supplemental oxygen; 4) non-ICU ward, not on supplemental oxygen; 5) out 
of the hospital but normal activities have not been resumed; and 6) out of the hospital 

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and normal activities resumed.  Patients discharged from the hospital to a 
rehabilitation facility will be included in category 5) above.  Patients discharged from 
the hospital to a nursing home will also be included in category 5), unless the patient 
lived in a nursing home prior to admission to the hospital, in which case the patient will 
be characterized based on resumption of normal activities. 
 
A proportional odds model will be used to estimate a summary odds ratio.  The model 
will include an indicator for treatment and indicators for the patient’s clinical state at 
entry (ICU, general ward on supplemental oxygen, general ward not on supplemental 
oxygen).  The model will be stratified by geographic region (United States, Europe, 
South America and Australasia). 
 
To supplement the overall summary odds ratio, separate odds ratios will be estimated 
for each dichotomized definition of improvement that can be formulated from the 
components of the ordinal outcome.  A test for the proportionality assumption will also 
be made. 
 
The following clinical secondary outcomes are of interest: 1) percent alive and out of 
the hospital at Day 14; 2) change in NEW score at Day 3; and 3) resumption of normal 
activities at Day 14.  It is expected that IVIG will have a favorable effect on each of 
these outcomes as well as the ordinal primary outcome.  Since the primary endpoint 
and these secondary endpoints are related and expected to be correlated, before 
examining each secondary endpoint separately, a single global test will be carried out 
using the method described by O’Brien and Pocock. 45,46  With this approach, the 
endpoints will be equally weighted and a single global test statistic will be determined.  
This single global test is expected to have greater power than the test for each 
endpoint separately. For example, for a common correlation among the four outcomes 
of 0.50, the average Z value must be 1.55 (instead of 1.96) to achieve a significance 
level of 0.05. The combined evidence using all four outcomes does not have to be as 
extreme as for a single outcome.  
 
Time to death and time to hospital discharge will be summarized with Kaplan-Meier 
plots and Cox models. For time-to-event analyses, time will be measured from 
randomization. The comparison of NEW scores and HAI titers will be compared using 
analysis of covariance with the baseline score or titer as a covariate. HAI titer levels 
will be log-transformed and the data at each time point will be summarized as the ratio 
of geometric means for those assigned IVIG and placebo. 
 
Longitudinal random effects models will also be used to summarize repeated 
assessments of the ordinal outcome, HAI titers and the NEW score. By collecting 
specific dates when patients are removed from the ICU and oxygen, discharged and 
resume normal activities, the ordinal outcome can be defined for a patient on each day 
of follow-up. 
 
Symptoms reported and AEs will be compared for the IVIG and placebo groups and 
summarized using chi-square statistics.  Laboratory measurements will be 
summarized as changes from baseline to Day 7.    
 

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Subgroup analyses for the primary and secondary outcomes will be performed to 
determine whether the treatment effect (IVIG versus placebo) differs qualitatively across 
baseline-defined subgroups.  The following subgroups will be considered: age, gender, 
race/ethnicity, geographic region, duration of symptoms prior to enrollment, influenza 
subtype, enrollment in ICU versus general ward and production lot of IVIG used.  For 
each subgroup considered, an overall test of heterogeneity of treatment effect will be 
constructed to assess how strong the evidence is that the treatment effect varies across 
the baseline subgroups. 
6.2 
Data Monitoring 
The trial will be conducted under the direction of the FLU-IVIG study protocol team.  
Members of the protocol team are listed in Appendix C.  The protocol team (except 
those who prepare the confidential analyses) and all participating investigators will be 
blinded to interim results.  The protocol team will monitor enrollment, follow-up, and 
adherence to the assigned treatment as determined by the number and percent of 
participants who complete the infusion of blinded treatment.  Follow-up data will be 
summarized for both treatment groups combined.  The protocol team will carry out a 
sample size re-estimation after approximately one-half of the patients have been 
enrolled.  For this sample size re-estimation, pooled data for the primary endpoint will 
be used. 
 
The DSMB will review the study prior to initiation and every 6 months thereafter.  The 
DSMB may convene additional reviews as necessary.  After each meeting they will 
recommend continuing the study as planned, modifying the study, or terminating the 
study.   
 
The DSMB will be asked to recommend early termination or modification only when 
there is clear and substantial evidence of a treatment difference.  As a guideline, the 
Lan-DeMets spending function analog of the O’Brien-Fleming boundaries will be used 
to monitor the primary endpoint comparison.47,48  
 
After approximately 50% of patients are enrolled, futility analyses will be presented to 
the DSMB by the unblinded statisticians based on conditional power estimates.  
Conditional power incorporates the observed results by treatment group thus far (and 
uses the originally assumed treatment effect for future data) to calculate the 
conditional probability of obtaining a significant result by the end of the trial.  If 
conditional power, given the observed data and assuming the originally hypothesized 
treatment effect thereafter, is less than 10%, consideration should be given to stopping 
the trial.   
 
 

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7 Protection of Human Subjects & Other Ethical 
Considerations 
7.1 
Participating Clinical Sites and Local Review of Protocol and Informed 
Consent 
This study will be conducted by major medical centers participating in the International 
Network of Strategic Initiatives in Global HIV Trials (INSIGHT).  It is anticipated that 
potential participants will be recruited by the site investigators and/or that positive 
influenza laboratory testing will be used to enquire about potential enrollment.   
Information about this study will be disseminated to health care providers in these 
settings. 
 
Prior to the initiation of the study at each clinical research site, the protocol, informed 
consent form and any participant information materials will be submitted to and 
approved by the site’s Institutional Review Board (IRB) or Institutional Ethics Committee 
(EC).  Likewise, any future amendments to the study protocol will be submitted and 
approved by each site’s IRB or EC.  After IRB/EC approval, sites must register for this 
study before screening potential participants, and must register for any protocol 
amendments.  Protocol registration procedures are described in the FLU-IVIG Protocol 
Instructions Manual. 
7.2 
Ethical Conduct of the Study  
The study will be conducted according to the Declaration of Helsinki in its current 
version; the requirements of Good Clinical Practice (GCP) as defined in Guidelines, EU 
Clinical Trials Directive (2001/20/EC), and EU GCP Directive (2005/28/EC); 
International Conference on Harmonization (ICH) Guidelines; Human Subject Protection 
and Data Protection Acts; the US Office for Human Research Protections (OHRP); or 
with the local law and regulation, whichever affords greater protection of human 
subjects. 
7.3 
Informed Consent of Study Participants  
Informed consent must be obtained (see sample in Appendix A) prior to conducting any 
study-related procedures. 
7.4 
Confidentiality of Study Participants  
The confidentiality of all study participants will be protected in accordance with GCP 
Guidelines and national regulations.  
7.5 
Remuneration of Study Participants 
INSIGHT will provide funds to sites to permit compensation of enrolled study 
participants for the time and inconvenience associated with their study participation. The 
ceiling for this remuneration will be fixed and should be provided by the site to each 
participant on a pro-rated basis depending upon the number of study visits they 
successfully complete. However, it is anticipated that each participating site may have 
differing institutional policies or standards in regards to the types and amount of total 
compensation that can be offered to research participants and that the site IRB/EC will 
review and approve this compensation on a site-specific basis. 

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8 Other Important Documents and Policies 
8.1 
Reference Documents 
Study procedures are described in detail in the FLU-IVIG Protocol Instructions Manual.  
Instructions for handling, storing, and shipping specimens are found in the INSIGHT 
FLU-IVIG Laboratory Manual.  Procedures for the pharmacist are described in detail in 
the FLU-IVIG Pharmacy Manual. 
8.2 
Data Monitoring 
Study data will be made available to site monitoring personnel.  Monitoring may be 
performed by staff from INSIGHT International Coordinating Centers (ICC), by 
contractors of the primary funder, or by the Food and Drug Administration (FDA). 
 
At a minimum, all items referenced in the protocol as being relevant to the research 
study will be recorded in the participant's research record in accordance with standard 
procedures.   
8.3 
Storage and Use of Specimens 
Study participants consenting to this study consent to all study procedures, including 
collection of specimens.  A participant may withdraw consent from the study at any 
time.  If a participant requests that their specimens collected to date be destroyed, this 
request would be honored.  Upon being informed that a participant has withdrawn 
consent for storage of specimens, the study database will be updated to indicate this, 
the specimen repository will be notified, and every effort will be made to have the 
specimens destroyed.  
 
Stored respiratory specimens in this study will be used for RT-PCR testing for 
influenza and additional virological characterization, which may include but is not 
limited to subtype, antigenic and genetic analyses of the virus.  The serum specimens 
collected at baseline and during follow-up will be used for measurement of 
hemagglutination inhibition (HAI) antibody titers.  Future research using serum and 
plasma specimens may include, but is not limited to, the determination of biomarkers 
that could be associated with specific clinical outcomes.   
 
Proposed research utilizing stored samples will be reviewed and approved by the 
Protocol team, the INSIGHT Scientific Steering Committee, and NIAID.  Samples will 
not be sold to third parties or used directly to produce commercial products.   
 
Further information regarding the use of stored specimens can be found in Appendix 
F. 
8.4 
Record Retention 
The investigator is responsible for retaining all essential documents listed in the ICH 
Good Clinical Practice Guideline.  The FDA requires study records to be retained for 
up to two years after marketing approval or disapproval (21 CFR 312.62), or until at 
least 2 years have elapsed since the formal discontinuation of clinical development of 
the investigational agent for a specific indication. These records are also to be 

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maintained in compliance with IRB/EC, state, and federal medical records retention 
requirements, whichever is longest. All stored records are to be kept confidential to the 
extent required by federal, state, and local law.  
 
Should the investigator wish to assign the study records to another party and/or move 
them to another location, the investigator must provide written notification of such 
intent to the sponsor with the name of the person who will accept responsibility for the 
transferred records and/or their new location. NIAID must be notified in writing and 
written permission must be received by the site prior to destruction or relocation of 
research records. 
8.5 
Publications and Presentations 
Publications and presentations related to data obtained from this study will adhere to 
the INSIGHT Publications and Presentations Policy on the INSIGHT website. 

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APPENDIX A: Sample Consent Form Documents 
 
None of the changes to the FLU-IVIG protocol from Version 1.0 to Version 2.0 
necessitated a change in the existing consent template.  However, the protocol 
revision was seen as an opportunity to use the findings of the START Informed 
Consent substudy (as yet unpublished), that a more readable consent did not reduce 
comprehension of important consent information and was well-received by 
participants.   
 
Along with the original sample informed consent (unchanged from Version 1.0), a 
simplified sample informed consent is also included in this version of the FLU-IVIG 
protocol.  Readability statistics generated by Microsoft Word for the two versions are 
presented below.  Both templates contain all of the required elements of consent 
according to ICH GCP. 
 
Original consent 
 
 
Simplified consent 
 
Counts 
 
 
Counts 
 
Words 
2,180 
 
Words 
2,386 
Characters 
9,833 
 
Characters 
10,503 
Paragraphs 
69 
 
Paragraphs 
140 
Sentences 
119 
 
Sentences 
162 
Averages 
 
 
Averages 
 
Sentences per paragraph 
2.1 
 
Sentences per paragraph 
1.6 
Words per sentence 
17.4 
 
Words per sentence 
12.8 
Characters per word 
4.3 
 
Characters per word 
4.2 
Readability 
 
 
Readability 
 
Passive sentences 
26% 
 
Passive sentences 
20% 
Flesch Reading Ease 
65.9 
 
Flesch Reading Ease 
75.0 
Flesch-Kincaid Grade 
Level 
8.3 
 
Flesch-Kincaid Grade 
Level 
5.9 
 
At this time, the simplified consent template is not being translated into 
languages other than English.  English-speaking sites may choose to use either 
one of these samples as the basis for their site-specific informed consent 
document, but should use the same consent for all participants.  Should the 
simplified consent be translated in the future, any site may choose to use it in place of 
the standard consent. 
 
 

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APPENDIX A.1: Standard Sample Consent Form  
Protocol Title: 
Anti-Influenza Hyperimmune Intravenous Immunoglobulin Clinical 
Outcome Study (INSIGHT 006) 
Sponsored by: 
The University of Minnesota  
A Multicenter Study of the 
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)  
Short Title of the Study: FLU-IVIG Study  
CONSENT FOR PARTICIPATING IN AN NIH-FUNDED RESEARCH TRIAL  
SITE INVESTIGATOR: ________________________________ PHONE: __________  
ALL SITE INSTRUCTION THAT IS INCLUDED IN A TEXT BOX SHOULD BE 
REMOVED FROM THE SITE’S INFORMED CONSENT FOR PARTICIPANTS  
 
 
 
 
 
 
 
 
We are asking you to join the INSIGHT 006 research study (the FLU-IVIG Study) 
because you are in the hospital with influenza (the “flu”). It is up to you whether or not 
you want to join this study; your participation is voluntary. 
WHY ARE WE DOING THIS RESEARCH?  
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. There are not many good 
treatments available for severe flu. One possibility for a new treatment is to use 
OHRP Requirements to be read by the sites: 
 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL 
IRB/EC REVIEW AND APPROVAL.  INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL 
IRB/EC WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH THE LANGUAGE INTENDED 
FOR LOCAL USE.  LOCAL IRBs/ECs ARE REQUIRED TO WEIGH THE UNIQUE RISKS, 
CONSTRAINTS, AND POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  
ANY DELETION OR SUBSTANTIVE CHANGE OF INFORMATION CONCERNING RISKS OR 
ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY THE INVESTIGATOR, APPROVED BY 
THE LOCAL IRB/EC, AND NOTED IN THE IRB/EC MINUTES.  JUSTIFICATION AND IRB/EC 
APPROVAL OF SUCH CHANGES MUST BE FORWARDED TO THE INTERNATIONAL 
COORDINATING CENTER.  SPONSOR-APPROVED CHANGES IN THE PROTOCOL MUST BE 
APPROVED BY THE LOCAL IRB/EC BEFORE USE UNLESS INTENDED FOR THE ELIMINATION 
OF APPARENT IMMEDIATE HAZARD.  NEW INFORMATION SHALL BE SHARED WITH 
EXISTING SUBJECTS AT NEXT ENCOUNTER, WITH ALL NEW SUBJECTS PRIOR TO 
INVOLVEMENT, OR AS THE LOCAL IRB/EC MAY OTHERWISE ADDITIONALLY REQUIRE. 
 

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antibodies collected from people who have recovered from the flu or who have had a flu 
shot. Antibodies are made by the body to fight infection. They stick to the germ that 
causes the infection and make it easier for your immune system to find the germ and 
destroy it. These antibodies (also called intravenous immunoglobulin or “IVIG”) may 
work to treat the flu. In this study we are using IVIG made by Emergent Biosolutions, a 
company very experienced in making this type of medication. IVIG is not currently 
approved for treating the flu. We are testing it in this study. 
We are doing this study to find out if giving IVIG to people who are in the hospital for the 
flu will help them get better sooner, get out of the hospital sooner, and have fewer bad 
effects from the flu. We plan to enroll about 320 patients in different countries over one 
or more flu seasons. It is possible we might need more people to answer the study 
question, and, if so, we might enroll up to 470 patients.  
HOW LONG WILL YOU BE IN THE STUDY?  
You will be in the study for about 28 days.  
WHAT WILL HAPPEN DURING THE RESEARCH?  
Before you join this study:  
  We will ask you questions about your medical history, medicines and treatments. 
We may get some of this information from looking at your chart.  
  We will take 1-2 tablespoons (15-30 mL) of blood from a vein in your arm by using 
a needle. We will use this blood for normal medical tests to check your health. 
If you are able to join this study, you will get the usual care for someone with the flu, 
which includes anti-flu medicines taken by mouth (like Tamiflu®) or by inhaling (like 
Relenza®). You will also get 1 of 2 study treatments decided by chance (like by flipping 
a coin). You will have an equal chance (50/50) of getting either treatment. The study 
treatments are:  
1. IVIG mixed with normal saline (a salt solution). The amount of IVIG mixed in 
will depend on your weight.  
2. Normal saline alone (no IVIG)  
Both treatments are given one time intravenously (dripped through a tube attached to a 
needle in a vein in your arm). You will get about 2 1⁄4 cups (half a liter) of the study 
treatment. Neither you nor your doctor or nurse will know which of the 2 treatments you 
will receive. The treatment will be given over at least 2 hours. The antibodies from the 
IVIG will last for several weeks in your body.  

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At certain times during the study, we will draw about 1- 2 tablespoons (15-30 mL) of 
blood and send it to a central laboratory for tests. This will help us understand how high 
the level of antibodies gets within your blood. Neither you nor your doctor will receive 
the results of these tests.  
We will see you while you are in the hospital. When you go home, we will give you a 
diary and ask you to record symptoms you have at home.  
We will collect additional information or samples at the following times:  
1. On the day of study enrollment, before you are given your study treatment:  
 We will draw 1-2 tablespoons (15-30 mL) of blood to be sent to a central 
laboratory. 
 
We will take a sample from your nose and throat using a swab (like a Q-tip) to do 
tests that will tell us how much flu virus is in your body and what type of flu you 
have.  
2. At 1 day after enrollment, we will draw 1-2 tablespoons (15-30 mL) of blood to be 
sent to a central laboratory.  
3. For the 3 days after enrollment, we will check with you daily to see how you are 
feeling.  
4. At 3 days after enrollment: 
 We will take another sample from your nose and throat using a swab (like a Q-
tip) to do tests that will tell us how much flu virus is still in your body.  
 We will draw 1-2 tablespoons (15-30 mL) of blood, to be sent to a central 
laboratory.  
5. At about 7 days after enrollment:  
 We will draw 3-4 tablespoons (45-60 mL) of blood. We will use about half of this 
blood for normal medical tests, to see how the study treatment is affecting you.  
 We will send the rest of this blood sample to a central laboratory.  
 We will ask you questions about how you are feeling. 
6. At about 14 days after enrollment, we will check with you to find out how you are 
feeling. This will probably be done by telephone. 
7. At about 28 days after enrollment, we will check with you to find out how you are 
feeling. This will probably be done by telephone. This will be the last study visit.  
We may need to get some of the study information from your medical record. By signing 
this consent you also agree to let us get information that is related to this study from 
your medical record.  
WHAT HAPPENS TO THE SAMPLES?  

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The swab samples from your nose and throat will be sent to a central laboratory in the 
United States to test the amount and type of flu virus in your body.  Neither you nor your 
doctor will get the results of these tests. 
Some of the blood samples will be sent to a local laboratory for normal medical tests to 
check your health and see how the treatment is affecting you. Your doctor will get the 
results of these tests and may share these results with you. Other blood samples will be 
sent to the same central laboratory in the United States as the swab samples. These 
blood samples will be tested to see how many flu antibodies are in your blood – how 
your immune system responded to your illness. Neither you nor your doctor will get the 
results of these tests.  
Part of the samples will be stored at the central laboratory and may be used in the 
future by members of the study team to answer other questions about the flu. The 
samples will not be used for commercial use, and no human genetic testing will be 
done. No additional tests are planned at this time. There is no time limit on how long 
your samples will be stored. 
WHAT ARE THE RISKS AND/OR DISCOMFORTS OF BEING IN THIS STUDY?  
There are some possible side effects of getting IVIG. Some of the more common side 
effects are fever, rash, hives, or headache.  
Serious and potentially fatal side effects are rare. These include serious allergic 
reactions, kidney problems, a lung injury that makes it hard to breathe, a higher risk of 
blood clots, meningitis (a type of brain swelling), and a condition called hemolysis, 
where red blood cells open up and spill their contents into surrounding fluid (plasma).  
Because IVIG is made from the blood of other people, it is possible that the blood could 
contain a virus. Although all blood that is used for making the IVIG is carefully checked 
for infections and is treated to kill any known viruses, we cannot be absolutely sure that 
using IVIG will not give you other types of infections.  
You should wait three months or more after having the study treatment before you get 
live attenuated (weakened) virus vaccines like those for measles, rubella, mumps and 
varicella (chickenpox or shingles). This is because the IVIG may temporarily make your 
body unable to respond to the vaccines as well as you would like.  
The risks of having blood taken or having an intravenous line put in your arm include 
short-lasting pain, bleeding, bruising, lightheadedness, fainting and, rarely, infection or a 
blood clot where the needle enters your body. Some people have mild discomfort or gag 
when samples are taken from their throat or nose. Even if you decide not to be in this 
study, you will likely have these sorts of tests done as part of your usual medical care 
for the flu.  

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An independent Data and Safety Monitoring Board (DSMB) will look at results from the 
study at least every six months. The DSMB is made up of doctors and other people with 
a good understanding of influenza and of studies like this one. They will help to try to 
keep the study safe for all participants.  
WHAT ARE THE BENEFITS OF BEING IN THIS STUDY?  
We do not know whether being in the study will help you. About half of the people in this 
study will actually get IVIG. We think that adding IVIG to the usual anti-flu medicines 
may help you get over your flu faster, but we do not know that for sure. What we learn 
from this study will help decide if IVIG should be recommended for treating flu in the 
future.  About half the people in the study will get a salt water solution and will not get 
IVIG, and we do not expect any benefit at all for those people.  The chance of getting 
IVIG or getting salt water solution is random, like flipping a coin. 
WHAT ARE THE COSTS TO YOU?  
The study treatment will be provided at no cost to you. We will provide all clinical 
services, lab work, and other tests that are part of this study. You, your insurance 
company, or some other third-party payer must pay for all other medicines and any 
required hospital stay. 
WHAT IF YOU ARE INJURED AS PART OF THIS STUDY?  
If you are injured because of being in this study, [insert the name of the clinic] will give 
you immediate necessary treatment for your injuries. The cost for this treatment will be 
charged to you or your insurance company. The study cannot pay you or pay for any 
care for study-related injuries or for your illness.  
WHAT ABOUT PREGNANCY AND BREASTFEEDING?  
Women who are pregnant or breastfeeding cannot join this study. If you are a woman 
who can get pregnant, you will have a blood or urine test to see if you are pregnant 
before you can join the study. If you are in this study, you must agree to either not have 
sex that could make you pregnant while you are in the study, or to use at least one type 
of birth control, either a barrier type (condom, diaphragm, IUD, etc.) or a hormonal type 
(birth control pills, Depo-Provera, etc.). 
WHAT CHOICES DO YOU HAVE OTHER THAN BEING IN THIS STUDY?  
You do not have to join this research study if you do not want to. If you join, you may 
decide to quit at any time. If you choose not to join or to quit, it will not change your 
regular medical care. If any new information becomes available that might change your 
decision about joining or staying in the study, we will tell you about it right away. 
WHAT ARE ALTERNATIVE TREATMENTS?  

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If you do not want to be in this study, you can get the usual medicines to treat the flu. 
However, you cannot get the experimental IVIG treatment.  
HOW IS YOUR PRIVACY PROTECTED?  
We will protect the privacy of your medical information as much as legally possible, and 
release your records only with your written permission.  We will label your study records with a 
code number and three letters, and you will not be identified in any publications about this 
research.   However, your records may be seen by: 
 
People in the U.S. government agencies that fund or oversee this research, for example, 
the U.S. National Institutes of Health (NIH) and the Food and Drug Administration (FDA). 
 
Study monitors who make sure the study is being conducted correctly.  
 
Independent groups such as institutional review boards (IRBs) or ethics committees (ECs) 
that make sure the study is ethical (fair).   
 
COMPENSATION  
Compensation will be offered for your time and inconvenience participating in the study. 
[additional details to be completed by site]  
WHO CAN I TALK TO ABOUT THIS STUDY?  
For questions about this study, or about the storage or use of your samples, and in case 
of any research-related injury, contact:  
• [name of the investigator or other study staff] • [telephone number of above]  
For questions about your rights as a research participant contact: 
• [name or title of person on the ethics committee (Institutional Review Board, IRB) or 
other organization appropriate for the site] 
• [telephone number of above]  
 
 

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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE INSIGHT 006 STUDY  
If you have read the consent (or if you have had it explained to you) and understand the 
information, and you voluntarily agree to join this study, please sign your name below.  
I agree to participation in the INSIGHT 006 study (FLU-IVIG Efficacy) as described 
in this consent document.  
 
 
________________________________________________________ 
Participant’s name (typed or printed) 
 
 
____________________________________________________ 
______________ 
Signature of participant or legal representative 
Date 
 
 
________________________________________________________ 
*Witness’s name (typed or printed) 
 
 
____________________________________________________ 
______________ 
Witness’s signature 
Date 
 
 
 
 
________________________________________________________ 
Name of staff member conducting consent process (typed or printed) 
 
 
____________________________________________________ 
______________ 
Staff member’s signature 
Date 
*A witness to the participant’s signature is strongly encouraged.  
NOTE: This consent form, with the original signatures, MUST be retained on file 
by the Investigator of Record. A copy must be given to the participant. A copy 
should be placed in the participant’s medical record, if applicable.  
 
 
 
 

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APPENDIX A.2: Simplified Sample Consent Form  
Study Title: Flu Treatment Study (FLU-IVIG) 
Sponsored by: 
The University of Minnesota  
A Multicenter Study of the 
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)  
Full Title of the Study: Anti-Influenza Hyperimmune Intravenous 
Immunoglobulin Clinical Outcome Study (INSIGHT 006) – Version 2.0, 
31-May-2016 
CONSENT FOR PARTICIPATING IN AN NIH-FUNDED RESEARCH STUDY  
SITE INVESTIGATOR: ________________________________ PHONE: __________  
  
 
 
 
 
 
 
 
 
 
INTRODUCTION 
This information is about a study for treating the flu (influenza). 
WHY HAVE I BEEN GIVEN THIS INFORMATION? 
You have been given this information in case you want to join the study. 
OHRP Requirements to be read by the sites: 
 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL 
IRB/EC REVIEW AND APPROVAL.  INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL 
IRB/EC WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH THE LANGUAGE INTENDED 
FOR LOCAL USE.  LOCAL IRBs/ECs ARE REQUIRED TO WEIGH THE UNIQUE RISKS, 
CONSTRAINTS, AND POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  
ANY DELETION OR SUBSTANTIVE CHANGE OF INFORMATION CONCERNING RISKS OR 
ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY THE INVESTIGATOR, APPROVED BY 
THE LOCAL IRB/EC, AND NOTED IN THE IRB/EC MINUTES.  JUSTIFICATION AND IRB/EC 
APPROVAL OF SUCH CHANGES MUST BE FORWARDED TO THE INTERNATIONAL 
COORDINATING CENTER.  SPONSOR-APPROVED CHANGES IN THE PROTOCOL MUST BE 
APPROVED BY THE LOCAL IRB/EC BEFORE USE UNLESS INTENDED FOR THE ELIMINATION 
OF APPARENT IMMEDIATE HAZARD.  NEW INFORMATION SHALL BE SHARED WITH 
EXISTING SUBJECTS AT NEXT ENCOUNTER, WITH ALL NEW SUBJECTS PRIOR TO 
INVOLVEMENT, OR AS THE LOCAL IRB/EC MAY OTHERWISE ADDITIONALLY REQUIRE. 
 
ALL SITE INSTRUCTION THAT IS INCLUDED IN A TEXT BOX SHOULD BE 
REMOVED FROM THE SITE’S INFORMED CONSENT FOR PARTICIPANTS 

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You are being asked to join because you are in the hospital with the flu.  
WHAT IS INVOLVED IF I WANT TO JOIN? 
 
Before you can decide whether or not to take part, you will need to know: 
 
•  Why the study is being done. 
 
•  What is involved. 
 
•  Whether there are advantages to your health. 
 
•  Whether there are any risks. 
 
You can also talk to your doctor or other health provider about the study.  You can 
also discuss it with your family and friends. 
 
If you have questions, please ask your doctor or other health worker to answer these 
until you are happy with the answers, 
 
DO I HAVE TO JOIN THE STUDY? 
No.  Taking part is voluntary.  This means: 
 Whether or not you decide to take part is your choice. 
 If you join the study and then change your mind, you can stop later. 
 If you decide not to take part, it will not affect your health care in the future. 
 
 
WHAT HAPPENS IF I DECIDE TO TAKE PART? 
 
If you agree to take part, you will be asked to sign this consent form.   
 
You will be given a copy of the signed consent form to keep. 
 
If someone is representing you, they will be asked to sign this form.  
 
WHY ARE WE DOING THIS STUDY?  
The flu is a common illness that usually occurs in fall (autumn) and winter.  For most 
people the flu is usually mild. In some cases it can cause serious illness or death.  

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There are very few treatments for severe flu.  
One possible new treatment is to use immune responses (called antibodies). 
This study uses antibodies taken from people who had the flu and got better, or who 
had a good response to a flu vaccine.  
Antibodies are made by the body to fight infection. They stick to the flu virus that causes 
the infection.  This makes it easier for your immune system to find the flu virus and kill it. 
Giving people these antibodies may help to treat the flu.  
The antibodies used are called intravenous immunoglobulin or IVIG. This is pronounced 
“I.V.I.G.” 
This study is to find out if IVIG helps people who are in the hospital for the flu. 
We want to see whether it will help in three ways. 
1. To help get better sooner. 
2. To be able to get out of the hospital sooner 
3. To have fewer bad effects from the flu.  
In this study we are using IVIG made by Emergent BioSolutions.  Emergent is very 
experienced in making IVIG. IVIG is not approved for treating the flu. We are testing it in 
this study. 
HOW MANY PEOPLE WILL TAKE PART? 
The study will enroll about 320 participants. 
This will include people in different countries over several flu seasons.   
If more people are needed, the study might enroll up to 470 people.  
 
HOW LONG WILL YOU BE IN THE STUDY?  
You will be in the study for about 28 days.   
After you leave the hospital, you will be contacted by telephone on days 14 and 28 to 
see how you are feeling.  
HOW WILL THE STUDY WORK?  

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Before you can join this study, we want to make sure it will be safe for you to do so:  
   
We will check your medical history and treatments. We may get this from looking 
at your medical records, or may ask you questions.  
   
We will also take 1-2 tablespoons (15-30 mL) of blood.  We will take this blood 
from a vein in your arm using a needle. We will use this blood for routine medical 
tests to check your health. 
If you are able to join this study, you will get the all usual care for someone with the flu.  
This includes oral medicines (like Tamiflu®) or inhaled medicine (that you breath in) (like 
Relenza®).  
Besides your usual care, you will also be randomized to one of two study groups. The 
treatment you get will be decided by chance, like by flipping a coin. You will have an 
equal chance (50/50) of getting either treatment.  
This is called a double-blind study. Neither you nor the doctors and nurses will know 
which group you are in. 
The only person to know which treatment you get will be the pharmacist who makes up 
your treatment. They are not allowed to tell anyone this, even the researchers. 
The study groups are:  
1. To have a single infusion of IVIG mixed with a salt solution. The amount of 
IVIG mixed in will depend on your weight.  This is the experimental treatment. 
2. To have a single infusion of a salt solution (with no IVIG). This is an inactive 
solution or placebo, and is the comparison group. 
No matter which treatment you get, you will only get it once.   
The infusion is given by a drip through a tube attached to a needle in your arm. This is 
called intravenously (IV), The infusion is about 2 1⁄4 cups (half a liter).  
You will get the infusion the same day you join the study, within a few hours after you 
join.  The infusion will take at least two hours. 
 
We will see you while you are in the hospital. When you go home, we will give you a 
diary and ask you to record symptoms you have at home.  
 
 

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WHAT INFORMATION IS COLLECTED AND AT WHAT TIMES? 
The following information will be collected at these times:  
Day 0 (the day you 
join the study) 
Day 1 
Day 3 
Day 7 
 Infusion of study 
treatment 
 Sample from 
your nose or 
throat using a 
swab (like a Q-
tip) 
 Blood for future 
research 
 Blood for future 
research 
 We will check 
how you are 
feeling every day 
through Day 3 
 How you are 
feeling 
 Sample from 
your nose or 
throat using a 
swab (like a Q-
tip) 
 Blood for future 
research 
 How you are 
feeling 
 Blood tests to 
check your 
health 
 Blood for future 
research 
 
At about Day 14 and Day 28 after you join, we will check with you to find out how you 
are feeling. This will probably be done by telephone.  Day 28 is the last study visit. 
We may need to get some information from your medical record. By signing this 
consent you also agree to let us get information for this study from your medical record.  
WHAT HAPPENS TO THE BLOOD AND SWAB SAMPLES?  
Some of the blood samples will be sent to the local laboratory for normal medical tests 
to check your health. Your doctor will get the results of these tests and may tell you the 
results.  
The swab samples from your nose or throat will be sent to a central laboratory in the 
United States.  This is to measure how much flu virus you have.  You and your doctor 
will not get the results of these tests. 
Other blood samples will be sent to the same central laboratory in the United States as 
the swab samples. This is to measure how many flu antibodies are in your blood.  This 
tells us how your immune system responded to your flu. You and your doctor will not 
get the results of these tests.  
Any blood and swab samples that are leftover will be stored at the central laboratory.  
These might be used in the future to answer other questions about the flu.   
We do not know yet what this future research will involve.  You and your doctor will not 
get any results from these tests.  These samples will not be sold or used for commercial 
research.  We will not test your DNA (your genes).  We do not have a time limit for how 
long we keep your samples. 
WHAT ARE THE RISKS AND/OR DISCOMFORTS OF BEING IN THIS STUDY?  

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All treatments can cause side effects.  You may have some side effects from IVIG.  
These are some common side effects that are not usually serious: 
 
Fever 
 
Rash 
 
Hives 
 
Headache.  
It is rare for IVIG to cause serious side effects, but it can happen.  These are some of 
the serious effects that can happen: 
 
Serious allergic reactions 
 
Kidney problems 
 
A lung injury that makes it hard to breathe 
 
Blood clots 
 
A type of brain swelling called meningitis 
 
A condition called hemolysis, where red blood cells open up and spill their 
contents into surrounding fluid.  
IVIG is made from the blood of other people.  All blood that is used for making IVIG is 
carefully checked and is treated to kill any known viruses.  However, we cannot be 
totally sure that you will not get other types of infections from IVIG.  
IVIG may temporarily make you not able to respond to vaccines as well as usual.  You 
should wait at least three months after having the study treatment before you get live 
attenuated (weakened) virus vaccines such as measles, mumps, rubella, and varicella 
(chickenpox or shingles).   Measles, mumps, and rubella vaccines are sometimes given 
in one shot called “MMR.” 
When you have blood taken or have a tube put in your arm for the study treatment, you 
might have short-lasting pain or bleeding.  You might have a bruise or a small wound.  
You could get lightheaded or faint.  You could get an infection or a blood clot where the 
needle enters your body, but this is very rare.  
You might gag or feel uncomfortable when the swab is put in your nose or throat.  
You will likely have these sorts of tests done as part of your care for the flu, even if you 
decide not to be in this study.  
WHAT ARE THE BENEFITS OF BEING IN THIS STUDY?  
We do not know if being in the study will help you. 
About half of the people in this study will actually get IVIG. If you get IVIG, we think that 
adding it to the usual anti-flu medicines may help you get over your flu faster, but we do 
not know for sure.  This is what we are trying to find out in this study.   

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About half the people in the study will get a salt water solution and will not get IVIG.  If 
you do not get IVIG, we do not expect you to have any benefit. 
What we learn from this study will help decide if IVIG should be recommended for 
treating flu in the future.  
WHAT ARE THE COSTS TO YOU?  
We will give you the study treatment at no cost. We will pay for all clinic visits, lab work, 
and other tests that are part of this study.  
 
 
You, your insurance company, or some other third-party payer must pay for all other 
medicines and hospital costs. 
 
 
WHAT ABOUT PREGNANCY AND BREASTFEEDING?  
Women who are pregnant or breastfeeding cannot join this study.  
If you are a woman of child bearing potential, we will test to see if you are pregnant 
before you can join the study.  
If you join this study, you must agree to either not have sex that could make you 
pregnant while you are in the study, or to use at least one type of birth control, either a 
barrier type (condom, diaphragm, IUD, etc.) or a hormonal type (birth control pills, 
Depo-Provera, etc.). 
WHAT IF NEW INFORMATION BECOMES AVAILABLE? 
If we have any new information that might change whether you want to join or stay in 
the study, we will tell you right away. 
WHAT CHOICES DO YOU HAVE OTHER THAN BEING IN THIS STUDY?  
You do not have to join this research study if you do not want to.  
If you join, you may stop at any time. If you choose not to join or to stop, your regular 
medical care will not change.  
THE NEXT PARAGRAPH IS FOR UNITED STATES SITES ONLY.  SITES IN 
OTHER COUNTRIES SHOULD DELETE THE NEXT PARAGRAPH. 
SITES OUTSIDE THE UNITED STATES:  Please replace the paragraph above 
with language appropriate for your location.

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WHAT ARE ALTERNATIVE TREATMENTS?  
If you do not want to be in this study, you will still get the usual medicines and other 
care to treat the flu. However, you cannot get the IVIG treatment, because it is 
experimental.  
WHAT IF YOU ARE HURT AS PART OF THIS STUDY?  
If you are hurt because of being in this study, [insert the name of the clinic] will treat 
your injury right away.  You or your insurance will have to pay for this treatment.  The 
study cannot pay you or pay for any care for study-related injuries or for your illness.  
 
 
HOW IS YOUR PRIVACY PROTECTED?  
We will take every reasonable step to keep your health information private and to 
prevent misuse of it.   
 
Your data (information) and samples (blood and swab) will not be identified by name, or 
in any other way, in anything published about this study.   
 
You will be identified only by a code. We will not release personal information from your 
records without your written permission. 
 
[The following paragraph is for sites outside the US only] 
We will do everything we can to keep your personal information private, but we cannot 
guarantee that nobody will get it.  We may have to release your personal information if 
required by law.  
 
[The following paragraph is for all sites] 
The following people may see your medical and research information:  
 the [insert the name of the site] ethics committee (institutional review board, IRB); 
  the research staff and monitors and their designees.  
 
They are committed to protect your privacy.   
 
As the research staff at [insert the name of the site], we are required to make sure that 
people not involved with this study cannot see your research and medical information 
while collecting personal information about you.   
 
We will keep your files in a locked cabinet in a safe place and will handle your personal 
information very carefully.  This will also help to protect your privacy. 
 
If the above is not true for your site, i.e., if trial insurance covers such cost, 
please replace the sentence with appropriate language. 

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WILL YOU BE PAID TO BE IN THE STUDY? 
We will compensate you for your time and inconvenience participating in the study. 
[specific details to be completed by site]  
WHAT IF YOU HAVE PROBLEMS OR QUESTIONS?  
If you ever have questions about this study, or about the storage or use of your 
samples, or if you are hurt by being in the study, contact:  
• [name of the investigator or other study staff] • [telephone number of above]  
If you have questions about your rights as a research participant, you can call: 
• [name or title of person on the ethics committee (Institutional Review Board, IRB) or 
other organization appropriate for the site] 
• [telephone number of above]  
 
 

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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE INSIGHT 006 STUDY 
(FLU-IVIG Efficacy)  
If you have read the consent (or if you have had it explained to you), you are satisfied 
that you understand the information, and you want to join this study, please sign your 
name below.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
________________________________________________________ 
*Witness’s name (typed or printed) 
 
 
____________________________________________________ 
______________ 
Witness’s signature 
Date 
 
 
________________________________________________________ 
Name of staff member conducting consent process (typed or printed) 
 
 
____________________________________________________ 
______________ 
Staff member’s signature 
Date 
*A witness to the participant’s (or surrogate/representative, if applicable) 
signature is strongly encouraged.  
NOTE: This consent form, with the original signatures, MUST be retained on file 
by the Investigator of Record. A copy must be given to the participant. A copy 
should be placed in the participant’s medical record, if applicable.  
 
 
 
_________________________ 
______________________________ 
__________ 
Participant’s name  
 
Participant’s signature  
 
Date 
(typed or printed) 
 
OR 
 
 
_________________________ 
______________________________ 
__________ 
Surrogate/representative’s name Surrogate/representative’s signature Date 
(typed or printed) 

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Appendix B: Time and Events Schedule  
 
Screening and Baseline 
 
Day -2 to 0 
Day 0 
ELIGIBILITY AND SCREENING 
 
 
Informed consent 
X 
 
Demographics, medical history 
X 
 
Influenza testing  
X 
 
Pregnancy test, if child-bearing potential
X 
 
CBC, Chemistry panel, PTT/PT/INRa
X 
 
NEW score 
X 
 
DAY OF RANDOMIZATION 
 
 
Assessment of targeted symptoms
 
X 
NEW scoreb 
 
X 
Randomize participant 
 
X 
Serum & plasma for storage & serologyc
 
X 
NP swab for virus isolation 
 
X 
IVIG/placebo infusion 
 
X 
 
 
Day 1 Day 2d Day 3 Day 7  
+1 day
Day 14d 
±2 days 
Day 28d 
+7 days
STUDY PROCEDURES 
 
 
 
 
 
 
NEW scoree 
X
X
X
 
 
 
Assessment of targeted symptomsf
 
 
X
X
 
 
Clinical data 
X
X 
X
X
X 
X
Adverse events 
X
X
X
X
X 
X
LOCAL LAB 
 
 
 
 
 
 
CBC, Chemistry panela 
 
 
 
X
 
 
CENTRAL LAB 
 
 
 
 
 
 
NP swab for virus isolation 
 
 
X
 
 
 
Serum & plasma for storage and 
serologyc 
X 
 
X 
X 
 
 
a CBC includes white cell count with differential (neutrophil, lymphocyte, eosinophil percentages), 
hemoglobin, hematocrit, and platelets.  Chemistry panel includes sodium, potassium, serum 
bicarbonate, BUN, creatinine, glucose, albumin, ALT/GPT, AST/GOT, total bilirubin. 
b NEW score must be repeated on day 0 if the score used for screening was from a previous day. The 
NEW score at screening must be ≥ 2. 
c Sufficient for 4 1-mL aliquots of serum and 4 1-mL aliquots of plasma 
d May be assessed via telephone, if not hospitalized. 
e Assessed twice daily, at 8:00 AM and 4:00 PM (±2 hours), while hospitalized. 
f Participants are given a diary at hospital discharge to use for this assessment, and for recording 
resolution of flu symptoms and return to normal activities. 
 
 

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Appendix C: INSIGHT 006:  FLU-IVIG Protocol Team  
 
To oversee the implementation of this randomized clinical trial, membership on the 
broader protocol team will include: 
 
 Protocol co-chairs 
 NIAID representatives 
 INSIGHT International Coordinating Center representatives 
 INSIGHT medical monitor  
 Collaborating laboratory representatives 
 Site investigators 
 INSIGHT infrastructure representatives 
 Study biostatisticians  
 Community representatives 
 
 

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Appendix D:    Reference on INSIGHT Website 
  
The INSIGHT website (www.insight-trials.org) will maintain updated links to the 
following documents referenced in the FLU-IVIG protocol and to other information 
pertinent to the study: 
 
 
The FLU-IVIG Protocol Instructions Manual 
 
 
The FLU-IVIG Laboratory Manual 
 
 
The FLU-IVIG Pharmacy Manual 
 
 
Investigator’s Brochure for IVIG 
 
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 1.0, December 2004 (or “DAIDS AE Grading Table”) 
 
 
INSIGHT Publications and Presentations Policy

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Appendix E:    List of Acronyms 
 
AE 
 
 
Adverse Event 
BMT 
 
 
Bone marrow transplant 
CBC 
 
 
Complete blood count 
CFR 
 
 
Code of Federal Regulations (U.S.) 
CI 
 
 
Confidence interval 
CMAX 
 
 
Maximum concentration 
CMV 
 
 
Cytomegalovirus 
CRF 
 
 
Case Report Form 
CSO 
 
 
Clinical Safety Office 
DHHS 
 
 
Department of Health and Human Services (U.S.) 
DSMB 
 
 
Data and Safety Monitoring Board 
EC 
 
 
Ethics Committee 
ECMO 
 
 
Extracorporeal membrane oxygenation 
EU 
 
 
European Union 
FDA 
 
 
Food and Drug Administration (U.S.) 
g 
 
 
grams  
GCP 
 
 
Good Clinical Practice 
GMP 
 
 
Good Manufacturing Practices 
H-IVIG 
 
 
Hyperimmune intravenous immunoglobulin 
HAI 
 
 
Hemagglutination inhibition 
HAV, HBV, HCV  
Hepatitis A, B, C virus 
HBsAg 
 
 
Hepatitis B surface antigen 
IB 
 
 
Investigators Brochure 
ICU 
 
 
Intensive care unit 
IEC 
 
 
Institutional Ethics Committee 
INR 
 
 
International normalized ratio 
INSIGHT 
 
 
International Network for Strategic Initiatives in Global HIV Trials 
IRB 
 
 
Institutional Review Board 
IVIG 
 
 
Intravenous immunoglobulin 
mL 
 
 
Milliliter 
mm 
 
 
Millimeter 
NAT 
 
 
Nucleic acid testing 
NIAID 
 
 
National Institute of Allergy and Infectious Diseases, NIH (U.S.) 
NIH 
 
 
National Institutes of Health (U.S.) 
NEW 
 
 
National Early Warning 
NEWS 
 
 
National Early Warning Score 
NP 
 
 
Nasopharyngeal 
OHRP 
 
 
Office for Human Research Protections (U.S.) 
PID 
 
 
Participant Identification Number 
PIM 
 
 
Protocol Instructions Manual 
PK 
 
 
Pharmacokinetics 
PT 
 
 
Prothrombin time  
 
 

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PTT 
 
 
Partial thromboplastin time 
RSV 
 
 
Respiratory syncytial virus 
RT-PCR 
 
 
Reverse transcriptase-polymerase-chain-reaction 
SAE 
 
 
Serious adverse event 
SARS 
 
 
Severe acute respiratory syndrome 
SDMC 
 
 
Statistical and Data Management Center 
SOC 
 
 
Standard of care 
SSC 
 
 
Scientific Steering Committee (INSIGHT) 
SUSAR 
 
 
Suspected Unexpected Serious Adverse Reactions 
TRALI 
 
 
Transfusion-related acute lung injury 
UP 
 
 
Unanticipated Problem 
U.S. 
 
 
United States of America 
VIG  
 
 
Vaccinia immune globulin  
Vz 
 
 
Volume distribution 
WBC 
 
 
White Blood Cell Count 
WHO 
 
 
World Health Organization

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APPENDIX F:  Policies for Specimen Storage and Use 
 
Storage and Use of Specimens in INSIGHT Protocol 006: FLU-IVIG  
(02 September 2014) 
 
This document outlines the procedures for storage, acquisition and utilization of stored 
samples collected in the FLU-IVIG Study. 
 
1.  Laboratories and Repository 
 
All participant blood and respiratory specimens collected through this INSIGHT study 
are sent along with specimens for other INSIGHT studies to Advanced BioMedical 
Laboratories (ABML) L.L.C., P.O. Box 2289/1605 Industrial Hwy, Cinnaminson, NJ 
08077-2289, United States for cataloguing.  From there, the specimens from the FLU-
IVIG Study will be sent to Leidos Biomedical Research, Inc. 1066 Boyles Street, 
Second Floor, Room 201, Frederick, MD 21702, United States, for RT-PCR testing 
and long-term storage.  The results of all testing of the stored specimens will be 
transferred to the Statistical and Data Management Center (SDMC) for analysis and 
will become part of the FLU-IVIG Study database. 
 
 
2. Acquisition of specimens 
 
Study participants must have consented to INSIGHT 006 prior to any study 
procedures, including collection of specimens.  A participant may withdraw consent 
from the study at any time.  If a participant requests that their specimens collected to 
date be destroyed, this request would be honored.  Upon being informed that a 
participant has withdrawn consent for storage of specimens, the SDMC database will 
be updated to indicate this, the specimen repository will be notified, and every effort 
will be made to have the specimens destroyed.  In no case will these specimens be 
selected for use in analysis after consent has been withdrawn.  If samples have 
already been tested prior to the revocation of consent, the results of the testing remain 
part of the research.  
 
Participant privacy is protected through labeling specimens with unique codes.  
Specimens that are released to collaborators for approved research are identified only 
by these unique codes.  Personal identifying information is maintained only at the 
participant’s clinical site and is never provided to the SDMC, repository, or 
collaborating researchers. 
 
3. Utilization of stored samples 
 
a. Planned uses for stored blood and respiratory specimens in INSIGHT 006 
 
Respiratory specimens in INSIGHT 006 will be used for RT-PCR testing for influenza.  
The serum specimens collected at baseline and during follow-up will be used for 

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measurement of hemagglutination inhibition (HAI) antibody titers.  Future use of stored 
specimens may include, but is not limited to, antigenic and genetic analyses of the 
virus and determination of biomarkers that could be associated with specific clinical 
outcomes.   
 
Samples will not be sold to third parties or used directly to produce commercial 
products. 
 
b. Approval of proposed research using specimens 
1) Scientific approval 
Specimens are requested by preparing a Research Proposal available on the 
INSIGHT website, www.insight-trials.org, under “New Science” on the home page.  
The INSIGHT Scientific Steering Committee (SSC) reviews all research proposals 
for use of the stored specimens.  The evaluation of every request entails 
consideration of its scientific merit in the context of other investigators’ requests 
and the limited availability of specimens.  The INSIGHT 006 Protocol Team will 
assist the SSC with the scientific evaluation of specimen proposals.  At the 
discretion of the SSC, additional review of a given proposal may also be solicited 
from an INSIGHT Interest Group whose field of interest is of most relevance to that 
request. 
 
2) Ethical approval 
An application will be submitted to the University of Minnesota Health and 
Medical/Biological Institutional Review Board (U of M IRB) requesting a Category 4 
IRB determination that the specific uses of specimens collected in INSIGHT 006 
are exempt from IRB Committee review for a period of five years.  This 
determination is usually granted if: 
 All of the specimens were obtained from participants who consented to the 
specimen collection using a local IRB/EC approved informed consent, and 
 All specimens are de-identified and confidentiality is assured. 
 
If local IRBs request notification of proposals that have been approved to move 
forward, this will be provided to them.  If they do not approve the research using 
stored samples from patients under their jurisdiction, they are to notify the 
INSIGHT Executive Committee (EC).  Upon receiving this notification, the SDMC 
will note in the database that these samples are not to be used in the research 
proposal. 
 
c. Publication of research using specimens 
1) Collaborating investigators agree to the Publications & Presentations Policy on 
the INSIGHT website (www.insight-trials.org) > Publications & Presentations> 
Resources> “Publications & Presentations Policy”. 
1. The INSIGHT funders are acknowledged in all such publications and 
presentations. 
2. Abstracts and manuscripts must be submitted to the INSIGHT 006 Protocol 
Team and the INSIGHT SSC for review and approval prior to submission to a 

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conference or journal.  This will ensure that safety concerns or policy implications 
can be addressed and that all parties involved are appropriately recognized. 
 
Summary 
The stored specimens in INSIGHT 006 (FLU-IVIG) are a valuable resource for better 
characterizing predictors of outcomes for individuals with influenza infections.  The 
availability of the repository may facilitate the discovery and validation of new 
biomarkers that may correlate with specific disease outcomes.  These stored 
specimens will be made available to researchers with excellent research ideas so that 
the knowledge gained from the data and specimens provided by the participants can 
be maximized. 
 
 

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31 INSIGHT FLU005 IVIG Pilot Study Group. INSIGHT FLU005: an anti-influenza hyperimmune 
iIntravenous immunoglobulin pilot study. J Infect Dis 2015; pii: jiv453. 
 

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