Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
Phase: PHASE4
Conditions: Inflammatory Bowel Disease (IBD)
Sponsor: University of Wisconsin, Madison

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
Bowel Disease Patients 
 
 
 
1.0 Background  
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract 
which includes Crohn’s disease (CD) and ulcerative colitis (UC).  1 A recent epidemiological 
investigation estimates that nearly 4 million people worldwide are affected and approximately 
1.4 million of these cases occur in the United States. 2  IBD can lead to debilitating symptoms, 
hospitalizations, decreased quality of life, frequent procedures and/or surgery. Treatment options 
consist of immunosuppressive therapy, such as systemic corticosteroids, immunomodulators 
(thiopurines and methotrexate) and/or biologics, such as tumor necrosis factor alpha (TNF) 
agents or an integrin inhibitor, vedolizumab.  They can achieve clinical remission and decrease 
the risk of complications, but also increase the risk for infections, including influenza. 3 4  
 
Influenza is a common respiratory illness that can lead to complications and hospitalizations. 
Those with chronic medical conditions or who are immunosuppressed, including patients being 
treated for IBD, are at particularly high risk of complications and mortality from influenza 
infection. 7    Patients with IBD who develop influenza may require hospitalization, including 
intensive care and interruption of their therapy.   Additionally, disease flares have been reported 
with influenza infection.7 Annual seasonal influenza vaccine is recommended for all IBD 
patients. However, immunosuppressed IBD patients are at risk of a blunted vaccine response and 
decreased clinical protection from infection. 
 
Multiple studies have shown lower influenza vaccine responses in patients with IBD compared 
to healthy individuals; IBD patients treated with TNF agents or combination therapy (TNF 
inhibitors and immunomodulators) are very likely to mount a poor immune response. 8-10  
Influenza serum antibody concentration correlates with protection from infection following 
vaccination. 11 Therefore, increasing influenza antibody responses in patients with IBD would 
appear to be critical to improving protection from influenza. A high dose (HD) influenza vaccine 
containing four times more hemagglutinin was licensed based on its ability to induce higher 
antibody concentrations compared to standard dose (SD) in adults 65 years or older. 12 Based on 
this information, we propose the following two specific aims:  
 
Specific Aim #1:  Determine whether HD influenza vaccine induces higher antibody 
concentrations and sustained response in immunosuppressed IBD patients compared to 
SD.   We hypothesize that IBD patients who receive HD influenza vaccine will mount higher 
antibody concentrations to at least two of the influenza vaccine viruses.  
 
Specific Aim #2:  Evaluate the influenza vaccine response in IBD patients treated with 
vedolizumab, a new gut selective immunosuppressant.    We hypothesize that patients on 
vedolizumab will mount a normal immune response since vedolizumab affects only gut 
lymphocyte trafficking and does not induce systemic immunosuppression. 13 
 
We will test our hypotheses by performing a single center double blind randomized controlled 
trial in IBD patients receiving influenza vaccination during one season.  At the completion of this 
project, we will have determined the most effective influenza vaccine for immunosuppressed 

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
Bowel Disease Patients 
 
 
IBD patients and determine if patients on vedolizumab mount a normal response. This study 
could provide influenza vaccination protocols for other immunosuppressed populations. 
 
 
2. Objectives  
 
2.1 Primary Objective 
 
To evaluate if vaccination with HD influenza vaccine induces higher antibody concentration in 
IBD patients on TNF inhibitors.  
 
2.11 Primary objective aim #1:  Antibody response  
We will evaluate if the HDIV induces higher antibody concentrations in IBD patients compared 
to SDIV by comparing the week 3 antibody concentrations between the two groups 
 
Specific aim #2 
To evaluate the influenza vaccine response in IBD patients treated with vedolizumab, a new gut 
selective immunosuppressant 
 
2.12 Primary Objective aim #2:  Antibody Response We will compare influenza antibody 
concentrations after vaccination in patients with IBD treated with vedolizumab to healthy 
individuals using the 3 week post immunization time point. 
 
 
2.2  Secondary Objectives  
 
2.21 Secondary outcomes #1 aim #1: Sustained response  
A subsequent titer will be done in 6 months post vaccination to assess sustainability of antibody 
concentration through the season. We will compare antibody concentrations 6 months post 
vaccination between HD and SD groups and post-immunization to the 6 month post vaccination 
time point in each group. 
 
2.22 Secondary outcomes #2 aim #1: Vaccine response rates  
We will compare seroprotection and seroconversion rates between the HDIV and SDIV groups. 
 
2.23 Secondary outcomes #3 aim #1: Vaccine safety   
Study participants will be given a diary card to record symptoms following influenza vaccine 
administration.  We anticipate that the HDIV will cause more injection site reactions12 than the 
SDIV but will otherwise be well-tolerated.  
 
 
2.31 Secondary outcomes #1 Specific aim #2: Sustained response  
A subsequent titer will be done in 6 months to assess sustainability of antibody concentration 
through the season.  
 

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
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2.32 Secondary outcomes #2 Specific aim #2: Vaccine response rates  
We will compare seroprotection and seroconversion rates between the vedolizumab treated and 
healthy groups.   
 
 
3. Selection of Subjects  
 
The subject population will consist of individuals with inflammatory bowel disease and healthy 
controls.  All IBD patients will meet the inclusion criteria but not the exclusion criteria outlined 
in the section below: 
CASES Specific Aim# 1 
3.1  
Inclusion Criteria 
3.11  A history of chronic (greater than 3 month) ulcerative colitis or Crohn’s disease 
diagnosed and documented by the standard clinical, radiographic, endoscopic and 
histopathologic criteria.  
3.12 
Ages 18-64 
3.13 
Currently taking anti-TNF therapy (infliximab, golilumab, adalimumab, or certolizumab) 
for at least 3 months  
3.2 
Exclusion Criteria 
3.21 
Received season’s influenza vaccine 
3.22   Allergy to eggs or influenza vaccine 
3.23 
Current use of systemic steroids  (oral budensonide and rectal steroids allowed) 
3.24 
Other autoimmune condition(s) (e.g. Rheumatoid arthritis, autoimmune hepatitis) 
Specific Aim #2  
 
3.3  
Inclusion criteria  
 
3.31 
A history of chronic (greater than 3 month) ulcerative colitis or Crohn’s disease 
diagnosed and documented by the standard clinical, radiographic, endoscopic and 
histopathologic criteria.  
 
3.32 
Ages 18-64 
 
3.33 
Currently on vedolizumab therapy  
 

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
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3.4 
Exclusion Criteria 
 
3.41 
Received season’s influenza vaccine 
 
3.42   Allergy to eggs or influenza vaccine 
 
3.43 
Currently use of systemic steroids  (oral budesonide or rectal steroids allowed) 
 
3.44  Other autoimmune condition(s) (e.g. Rheumatoid arthritis, autoimmune hepatitis) 
 
 
 
Control group 
 
The control group with consist of 20 individuals who meet the following inclusion and exclusion 
criteria. 
Individuals will be obtained from patients without an IBD diagnosis, chronic liver disease, celiac 
disease or other chronic health condition coming to Digestive Health Center for endoscopic 
procedures or clinic visits.  
3.5 
Inclusion criteria 
 
 
3.51 
Age 18-64 
 
3.52 
Willing to participate in study  
 
3.6 
Exclusion criteria 
 
 
3.61  Currently on immunosuppressive therapy  
 
3.62 
Has a chronic health condition that may have an impact on vaccine antibody 
concentrations as deemed by the investigators, including chronic liver disease, celiac 
disease, history of solid organ or bone marrow transplantation. 
 
3.63 
Older than age 65 years 
 
3.64  Patients in whom venipuncture are not feasible due to poor tolerability or lack of easy 
access.   
 
3.65    Vulnerable groups will be excluded from the study (pregnant, lacking consent capacity,  
 
Non-english speaking) 
 
3.7  
Patient Discontinuation  

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
Bowel Disease Patients 
 
 
Discontinuation is a patient who is enrolled in the study and who terminated from the study prior 
to completion of study.  
 
The patient is free to withdraw from the study for any reason and at any time without giving 
reason for doing so and without penalty or prejudice.  The investigator is also free to terminate a 
patient’s involvement in the study at any time if the patient’s clinical condition warrants it.  
Potential discontinuation criteria for individual patients;  
• Adverse Events 
• Withdrawal of consent  
• Patient is lost to follow-up 
 
4.0 Methods 
Specific Aim #1 HD 
We plan a randomized controlled trial of HDIV vs. SDIV for IBD patients on TNF monotherapy.  
Those meeting the inclusion and exclusion criteria will be invited to participate and be 
randomized.    
 
We will enroll approximately 40 patients and randomized them in a 5:3 fashion to HDIV or 
SDIV.   Subjects who enroll and do not complete 3 week blood draw will be discontinued and 
another subject will be enrolled. Randomization will generated by a random number generator 
and investigator will be blinded to randomization scheme.  
  
Both groups will have blood drawn prior to immunization, 3 weeks, and 6 months post 
vaccination .   Participants will be invited to enroll when the seasonal influenza vaccine becomes 
available, typically about the middle of August until March. 
 
4.1  Control Group 
A third group of 20 healthy individuals without IBD, other chronic diseases, or 
immunosuppressive therapy will be enrolled.  All healthy individuals will receive SD influenza 
vaccine. The influenza vaccine formulation changes annually.  Therefore, a measure of response 
in healthy individuals is necessary in order to rule out any irregularities that may be due to the 
seasonal vaccine and not IBD or its treatment.   
   
4.2  Vedolizumab group  
A prospective study of IBD patients receiving vedolizumab therapy will be conducted.  
We will enroll approximately 20 patients who are currently on vedolizumab. Subjects who enroll 
and do not complete 3 week blood draw will be discontinued and another subject will be 
enrolled.All individuals in this group will receive SDIV and have blood drawn for influenza 
antibody concentrations prior to immunization, 3 weeks, and 6 months post vaccination.  
 
 The study will also be conducted during the influenza season in conjunction with the HDIV 
study.  We will use the healthy control group in the HDIV study to compare the vedolizumab 
patients.  
 
 

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
Bowel Disease Patients 
 
 
5.0  
PRIOR TO RANDOMIZATION EVALAUTION 
 
5.1 
Initial Evaluation 
Patients coming to the University of Wisconsin for care of their inflammatory bowel disease will 
be invited to participate.    This will include the Digestive Health Center and UW Infusion 
Center. A member of their health team will give patients information about the study.  The 
research coordinator will further review information and invite patients to participate in the 
study. 
 
 Patients with UC or CD who meet the inclusion criteria and are in the GI-Hep registry (HSC# 
2011-0168) will be invited to participate via re-contact letter (previously IRB approved).   The 
study coordinator will review all the patient information to make sure that the patient qualifies 
for the study. 
 
5.2  
Consent    
The patient will be told about the purpose of the study and informed consent will be obtained.  
Patients 18 years old and older will provide written informed consent prior to randomization.   
 
5.3  
Demographic information 
Once the patient is enrolled in the study the following information will be collected prior to 
randomization.   
 
 
Baseline Data Collected  
a. Age  
b. Sex 
c. Race  
d. Influenza vaccine in prior season (patient report) 
e. Type of Inflammatory Bowel Disease 
a. Ulcerative Colitis 
b. Crohns Disease 
c. Indeterminate Colitis 
 
f. Type of ulcerative colitis  
a. Proctitis 
b. Proctosigmoiditis 
c. Left sided disease 
d. Pancolitis 
g. Crohns Subtype per Montreal Criteria (12) 
a. A1/A2 
b. L1, L2, L3, L4 
c. B1, B2, B3 
d. Perianal disease 
h. Length of disease (as official diagnosis in months.)  
i. Current Medications, doses, and duration 
a. Mesalamine 

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
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b. Azathioprine or 6MP 
c. Biologic (infliximab, adalimumab, or certalizumab) 
d. Combination biologic and azathioprine or 6MP 
e. Corticosteroids 
j. Other Comorbid Illness 
a. Cardiovascular Disease 
b. Diabetes  
c. Chronic Obstructive Pulmonary Disease  
d. Cerebrovascular Disease 
e. Solid Organ Malignancy  
f. Leukemia or Lymphoma 
 
The baseline data listed above will be collected by the study coordinator interviewing the subject 
to get the information and/or collecting this information from the medical record. The 
demographic data collection sheet will be used.  
 
 
5.4  
Study summary  
 
Start of study. 
After all the baseline demographic information is collected the patient will have blood drawn for 
a serum antibody measurement, randomized to SD or HD, and the influenza vaccine dose will be 
administered.   Patients will also be given a contact phone number to call and discuss any 
adverse events that might have occurred.  Patients will also be provided with an adverse event 
dairy.   The diary will allow patients to enter any potential adverse events for 7 days after 
vaccine administration.   The diary will be a paper copy consisting of the adverse events reported 
in the package insert for influenza vaccine.  
 
Participants will be randomly assigned in a 5:3 fashion to HDIV or SDIV. 
 
Those in the vedolizumab group will not be randomized and will receive SDIV.  
   
5.41   Visit 2 
At the 3 week study visit all participants will undergo phlebotomy for post vaccination serum 
antibody measurement.   
 
5.42   Visit 3  
At the 6 month study visit all participants will have phlebotomy for antibody measurement.  
 
 
 
 
 
 
 

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
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SDIV Group  
 
 
 
 
 
 
High Dose Vaccination Group  
 
Month 
6
Week 3
Week 0
Week 0
Baseline  Antibdody 
Measurement
Standard dose vaccine
Antibody Measurement
Antibody Measurement

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
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5.45   Laboratory Assessments 
 
Blood will be collected at week 0, 3, and  month 6 in all subjects.   
 
 
 
6.0  Randomization  
 
6.1  
At the first study visit patients will randomized to the SDIV OR HDIV.    
 
6.2 Randomization 
Randomization will occur at week 0.     
Randomization will be in a 5:3 ratio based on a random number generator.   
 
7.0 Adverse Events and other Safety aspects  
7.1 
Definition of Adverse Event 
An AE is defined as any untoward medical occurrence in a patient administered either of the 
vaccines.    AE will be recorded after administration of the vaccine and will continue to be 
recorded for days 0-6 using the adverse event dairy. Common adverse events (36) that have been 
reported in vaccination studies are the following: 
• Injection-site pain/soreness/tenderness  
• Injection-site swelling/induration  
• Injection-site erythema  
Month 
6
Week 3
Week 0
Week 0
Baseline  Antibdody 
Measurement
High dose vaccine
Antibody Measurement
Antibody Measurement

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
Bowel Disease Patients 
 
 
• Headache  
• Myalgia 
• Fatigue 
• Muscle pain 
• Fever 
Participants will be asked about additional adverse events that may have occurred when they 
return at 3 weeks for a blood draw.  
 
7.2  
Definition of Serious Adverse Events  
An AE is considered serious if, in the view of the investigator results in any of the following 
outcomes: 
• Inpatient hospitalization 
• A life threatening AE (an AE is considered “life threatening” if, in the view of the 
investigator, its occurrence places the patient at immediate risk of death.  It does 
not include an AE that, had it occurred in a more severe form, might have caused 
death). 
• Death  
 
7.3  
Reporting of Adverse Events  
Adverse events will be reported to the HSC IRB as required and to the Vaccine Adverse Event 
Reporting System (VAERS).  https://vaers.hhs.gov/index 
 
7.4  
Follow up to Adverse Events 
All AEs occurring during the study are to be followed up until resolved or judged to be no longer 
clinically significant, or until they become chronic to the extent that they can be fully 
characterized. 
 
 
8.0 Measure of effect  
 
8.1 Influenza antibody concentrations 
Antibody responses following influenza immunization reach maximum concentrations at 2 to 3 
weeks.  Studies suggest that antibody levels at 2 and 4 weeks following immunization are 
indistinguishable. 27,28 Each individual in the trial will be also categorized as either “Yes” or 
“No” in terms of seroconversion.29,30 All three measures (mean fold increase (MFI) in antibody 
concentration pre to post-immunization, seroconversion, and seroprotection) for all of each 
year’s three antigens, will be assessed and statistically analyzed individually. 
 
8.2  Influenza antibody concentration analysis 
Hemagglutination inhibition assay (HIA) will be used to measure influenza antibodies.  HIA will 
be performed in duplicate using standard microtiter techniques and serial dilutions.  Titrated 
influenza antigen is incubated with the serum dilutions for 30 minutes.  Guinea pig red blood 
cells (50 µl of 0.5% in phosphate buffered saline) are added and incubated for 45 minutes. The 
dilution of serum that no longer inhibits hemagglutination is the influenza antibody titer. These 

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
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assays will be performed in Dr. Hayney’s laboratory. Her laboratory has substantial experience 
with these assays.31-34 
 
9.0 Statistical Plan  
 
9.1Data Analysis  
We will compare geometric mean antibody concentrations and mean fold increase in antibody 
concentrations between groups using t-tests.  Seroprotection rates between the groups, defined as 
an antibody titer of at least 1:40 and rates of seroconversion, defined as having a fourfold 
increase in antibody concentrations following immunization, will be compared using chi square 
tests or Fisher’s exact tests.   
 
9.2 Power Calculation 
Forty individuals will be enrolled in the study in a five high dose to three standard dose vaccine 
ratio.  This strategy yields 89% power to detect an A/H3N2 antibody concentration of 80 
hemagglutination inhibition units, which is higher than that reported in patients with IBD treated 
with TNF based therapy who received SDIV. 26  The power to detect differences in A/H1N1 
influenza antibody concentrations is greater than 90%.  However, this sample size yields only a 
60% power to detect the similar difference between groups. The likely reason for this low power 
is that the study upon which we are basing our sample size calculations showed a GMT of 98 for 
influenza B.  It is unrealistic to hypothesize that we can push it much higher, even with HDIV.  
 
10.  Lab Specimens and Future Research 
After we have performed the tests we plan to perform for this study, we will keep any leftover 
blood and use it in future research projects. Data created from the subjects’ participation in this 
study will also be stored. This will be stored and locked in the GI Research Office. Although the 
specific research using your specimens is not known, the research will be related to the study of 
IBD and/or vaccine-related research. Banking of these samples is required for participation, and 
not optional. Dr. Caldera and the GI Research Office staff will have access to the codes links. If 
subjects no longer wish for their sample to be stored they can contact Dr. Caldera or the research 
office and the specimens will be disposed of according to standard medical research procedures. 
If subjects do not make such a request, the specimen will be stored indefinitely. 
 
Specimens will be labeled with the subjects study ID number and date of collection so that data 
collected for this protocol can be linked to the sample. Samples will be stored in Rennebohm Hall 
at the University of Wisconsin. Only investigators and key personnel assigned to the laboratory 
have access to the lab. Samples will be coded (labeled with subject ID and date of collection) 
before they arrive to the lab. All computers used for data storage and analysis are password 
protected and used exclusively by key personnel. 
 
Any future studies that will use these specimens will be done by UW researchers and will be 
submitted for a separate IRB approval. Only coded samples and data will be released for future 
research. The information linking the samples and data to individual subjects will not be released. 
 
11.  Drugs/ Vaccines  

1/27/17 Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory 
Bowel Disease Patients 
 
 
 
11.1  High Dose Influenza  
A high dose (HD) influenza vaccine containing four times more hemagglutinin was licensed 
based on its ability to induce higher antibody concentrations compared to standard dose (SD) in 
adults 65 years or older  (Fluzone High-Dose) trade name.Patients on TNF inhibitors will be 
randomized to this arm of the study. 
 
11.2  Quadrivalent vaccine  
Standard dose flu vaccine (Fluzone Quadrivalent) will be used in the vedolizumab arm, control 
and TNF inhibitors not receiving high dose.  
 
 
 
 
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