Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Completed
• CT.gov ID: NCT02461758
• Collaborator: (none)
• Enrollment: 81
• Location: 1
• Arms: 4
• Duration (Months): 21
• Patients Per Site Per Month: 3.9

Study Details

Study Description

Brief Summary

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract which includes Crohn's disease (CD) and ulcerative colitis (UC). 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. 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 opportunistic infections, including influenza.

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. Influenza serum antibody concentration correlates with protection from infection following vaccination. 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.

Condition or Disease	Intervention/Treatment	Phase
Inflammatory Bowel Disease (IBD)	Biological: Standard dose Influenza vaccine (SDIV); Biological: High dose influenza vaccine (HDIV)	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 81 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Randomized Trial of High Dose vs. Standard Dose Influenza Vaccine in Inflammatory Bowel Disease Patients
• Study Start Date: Oct 1, 2016
• Actual Primary Completion Date: Jun 1, 2018
• Actual Study Completion Date: Jul 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Control Group A group of 20 healthy individuals without IBD, other chronic diseases, or immunosuppressive therapy will be enrolled. All healthy individuals will receive standard dose influenza vaccine SDIV.	Biological: Standard dose Influenza vaccine (SDIV)
Other: Vedolizumab Group + standard dose influenza vaccine (SDIV) A group of 20 patients who are currently on vedolizumab. All individuals in this group will receive SDIV	Biological: Standard dose Influenza vaccine (SDIV)
Other: High dose influenza vaccine (HDIV) This arm will be a double blind randomized controlled trial of High dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	Biological: High dose influenza vaccine (HDIV)
Other: Standard dose influenza vaccine (SDIV) This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	Biological: Standard dose Influenza vaccine (SDIV)

Outcome Measures

Primary Outcome Measures

1. Measure Antibody Concentrations in Immunosuppressed IBD Patients Who Receive High Dose and Standard of Care Dose Influenza Vaccine [Pre-immunization and 2-4 weeks post immunization]

   Influenza vaccine antibody concentration will be measured in immunosuppressed IBD patients who receive high dose and standard of care dose influenza vaccine. Higher antibody concentrations are associated with better protection from infection.

Secondary Outcome Measures

1. Response Rate Against Influenza Vaccine in Patients With Inflammatory Bowel Disease: Number of Participants Positive for Seroconversion [4 weeks]

   Vaccine response rates for influenza vaccines in patients with inflammatory bowel disease will be accessed by number of patients who has shown significant seroconversion. Seroconversion is defined as a four fold increase in antibody concentration from preimmunization to 4 weeks post immunization.

2. Seroprotection: Number of Participants With Antibody Concentration at Least 1:40 at Week 4 Postimmunization [4 weeks]

   Seroprotection is defined as an antibody concentration of at least 1:40 at 4 weeks post-immunization which confers protection from infection in about 50% of individuals

3. Seroprotection: Number of Participants With Antibody Titer of 160 at Week 4 Post-immunization [4 weeks]

   Seroprotection is defined by the FDA as post-immunization concentration of 1:160 that confers protection from infection to 95% of the population.

4. Measure Antibody Concentrations in Immunosuppressed IBD Patients Who Receive High Dose and Standard of Care Dose Influenza Vaccine [6 months post-immunization]

   Influenza vaccine antibody concentration will be measured in immunosuppressed IBD patients who receive high dose and standard of care dose influenza vaccine. Higher antibody concentrations are associated with better protection from infection.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

CASES Specific Aim #1 Inclusion Criteria

• 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.

• Ages 18-64

• Currently taking anti-TNF therapy (infliximab, golilumab, adalimumab, or certolizumab) for at least 3 months

• Exclusion Criteria

• Received season's influenza vaccine

• Allergy to eggs or influenza vaccine

• Currently use of systemic steroids in the past 3 months

Specific Aim #2 Inclusion criteria

• 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.

• Ages 18-64

• Currently on vedolizumab therapy

Exclusion Criteria

• Received season's influenza vaccine

• Allergy to eggs or influenza vaccine

• Currently use of systemic steroids in the past 3 months

Control group Inclusion criteria

• Age 18-64

• Willing to participate in study

Control group Exclusion criteria

• Currently on immunosuppressive therapy

• 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.

• Older than age 65 years

• Unconfirmed Measles, Mumps, and Rubella (MMR) vaccination status

• Patients in whom venipuncture are not feasible due to poor tolerability or lack of easy access.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Wisconsin Hospital & Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• University of Wisconsin, Madison

Investigators

• Principal Investigator: Freddy Caldera, University of Wisconsin School of Medicine and Public Health, Madison

Study Documents (Full-Text)

• Study Protocol - Jan 27, 2017
• Statistical Analysis Plan - Aug 13, 2015

More Information

Publications

None provided.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT02461758
• Other Study ID Numbers: 2015-0813; Influenza in IBD
• First Posted: Jun 3, 2015
• Last Update Posted: Oct 2, 2019
• Last Verified: Sep 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Additional relevant MeSH terms: Intestinal Diseases; Inflammatory Bowel Diseases; Vaccines

Study Results

Participant Flow

Arm/Group Title	Control Group	Vedolizumab Group	High Dose Influenza Vaccine (HDIV)	Standard Dose Influenza Vaccine (SDIV)
Arm/Group Description	A group of 20 healthy individuals without IBD, other chronic diseases, or immunosuppressive therapy will be enrolled. All healthy individuals will receive standard dose influenza vaccine SDIV.	A group of 20 patients who are currently on vedolizumab. All individuals in this group will receive SDIV	This arm will be a double blind randomized controlled trial of High dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.
Period Title: Overall Study
STARTED	20	20	26	15
COMPLETED	20	19	25	15
NOT COMPLETED	0	1	1	0

Baseline Characteristics

Arm/Group Title	Control Group	Vedolizumab Group	High Dose Influenza Vaccine (HDIV)	Standard Dose Influenza Vaccine (SDIV)	Total
Arm/Group Description	A group of 20 healthy individuals without IBD, other chronic diseases, or immunosuppressive therapy will be enrolled. All healthy individuals will receive standard dose influenza vaccine SDIV.	A group of 20 patients who are currently on vedolizumab. All individuals in this group will receive SDIV	This arm will be a double blind randomized controlled trial of high dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	Total of all reporting groups
Overall Participants	20	19	25	15	79
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.35 (9.89)	36.57 (16.16)	34.96 (12.92)	39.35 (11.98)	37.81 (12.74)
Sex: Female, Male (Count of Participants)
Female	10 50%	12 63.2%	9 36%	5 33.3%	36 45.6%
Male	10 50%	7 36.8%	16 64%	10 66.7%	43 54.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 5%	0 0%	0 0%	0 0%	1 1.3%
White	19 95%	19 100%	25 100%	14 93.3%	77 97.5%
More than one race	0 0%	0 0%	0 0%	1 6.7%	1 1.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%	19 100%	25 100%	15 100%	79 100%

Outcome Measures

1. Primary Outcome

Title	Measure Antibody Concentrations in Immunosuppressed IBD Patients Who Receive High Dose and Standard of Care Dose Influenza Vaccine
Description	Influenza vaccine antibody concentration will be measured in immunosuppressed IBD patients who receive high dose and standard of care dose influenza vaccine. Higher antibody concentrations are associated with better protection from infection.
Time Frame	Pre-immunization and 2-4 weeks post immunization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose of Influenza Vaccine (HDIV) Group	Standard Dose Influenza Vaccine (SDIV) Group	Vedolizumab Group	Control Group
Arm/Group Description	This arm will be a double blind randomized controlled trial of high dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	A group of 20 patients who are currently on vedolizumab. All individuals in this group will receive SDIV	A group of 20 healthy individuals without IBD, other chronic diseases, or immunosuppressive therapy will be enrolled. All healthy individuals will receive standard dose influenza vaccine SDIV.
Measure Participants	25	15	19	20
Influenza A H1N1, pre-immunization	160	160	160	160
Influenza A H1N1, 2-4 weeks post immunization	320	160	320	320
Influenza A H3N2, Pre-immunization	80	40	80	80
Influenza A H3N2, 2-4 weeks post immunization	160	80	320	160
Influenza B Victoria,Pre-immunization	10	10	20	20
Influenza B Victoria, 2-4 weeks post immunization	20	20	20	20
Influenza B Yamagata, Pre-immunization	10	10	20	20
Influenza B Yamagata, 2-4 weeks post immunization	10	20	40	20

2. Secondary Outcome

Title	Response Rate Against Influenza Vaccine in Patients With Inflammatory Bowel Disease: Number of Participants Positive for Seroconversion
Description	Vaccine response rates for influenza vaccines in patients with inflammatory bowel disease will be accessed by number of patients who has shown significant seroconversion. Seroconversion is defined as a four fold increase in antibody concentration from preimmunization to 4 weeks post immunization.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Dose Influenza Vaccine (SDIV) Group	High Dose of Influenza Vaccine(HDIV) Group	Vedolizumab Group	Contorl Group
Arm/Group Description	This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	This arm will be a double blind randomized controlled trial of high dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	A group of 20 patients who are currently on vedolizumab. All individuals in this group will receive SDIV	A group of 20 healthy individuals without IBD, other chronic diseases, or immunosuppressive therapy will be enrolled. All healthy individuals will receive standard dose influenza vaccine SDIV.
Measure Participants	15	25	19	20
Influenza A H1N1	1 5%	9 47.4%	4 16%	4 26.7%
Influenza A H3N2	6 30%	11 57.9%	7 28%	6 40%
Influenza B Victoria	1 5%	4 21.1%	2 8%	0 0%
Influenza B Yamagata	0 0%	0 0%	1 4%	0 0%
At least one virus	7 35%	15 78.9%	9 36%	7 46.7%
At least two viruses	1 5%	7 36.8%	3 12%	3 20%
Three viruses	0 0%	2 10.5%	1 4%	0 0%

3. Secondary Outcome

Title	Seroprotection: Number of Participants With Antibody Concentration at Least 1:40 at Week 4 Postimmunization
Description	Seroprotection is defined as an antibody concentration of at least 1:40 at 4 weeks post-immunization which confers protection from infection in about 50% of individuals
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Dose Influenza Vaccine (SDIV) Group	High Dose of Influenza Vaccine(HDIV) Group	Vedolizumab Group	Control Group
Arm/Group Description	This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme. .	This arm will be a double blind randomized controlled trial of high dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	A group of 20 patients who are currently on Vedolizumab. All individuals in this group will receive SDIV	A group of 20 healthy individuals without IBD, other chronic diseases, or immunosuppressive therapy will be enrolled. All healthy individuals will receive standard dose influenza vaccine SDIV.
Measure Participants	15	25	19	20
Influenza A H1N1	15 75%	25 131.6%	19 76%	20 133.3%
Influenza A H3N2	15 75%	25 131.6%	19 76%	20 133.3%
Influenza B Victoria	8 40%	6 31.6%	10 40%	10 66.7%
Influenza B Yamagata	6 30%	6 31.6%	11 44%	8 53.3%
At least one virus	15 75%	25 131.6%	19 76%	20 133.3%
At least two virus	15 75%	25 131.6%	19 76%	20 133.3%
Three viruses	8 40%	9 47.4%	13 52%	11 73.3%

4. Secondary Outcome

Title	Seroprotection: Number of Participants With Antibody Titer of 160 at Week 4 Post-immunization
Description	Seroprotection is defined by the FDA as post-immunization concentration of 1:160 that confers protection from infection to 95% of the population.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Dose Influenza Vaccine (SDIV) Group	High Dose of Influenza Vaccine(HDIV) Group	Vedolizumab Group	Control Group
Arm/Group Description	This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme. .	This arm will be a double blind randomized controlled trial of high dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	A group of 20 patients who are currently on Vedolizumab. All individuals in this group will receive SDIV	A group of 20 healthy individuals without IBD, other chronic diseases, or immunosuppressive therapy will be enrolled. All healthy individuals will receive standard dose influenza vaccine SDIV.
Measure Participants	15	25	19	20
Influenza A H1N1	12 60%	24 126.3%	19 76%	18 120%
Influenza A H3N2	6 30%	21 110.5%	16 64%	17 113.3%
Influenza B Victoria	0 0%	0 0%	0 0%	0 0%
Influenza B Yamagata	0 0%	0 0%	1 4%	0 0%
At least one virus	13 65%	25 131.6%	19 76%	20 133.3%
At least two virus	5 25%	20 105.3%	16 64%	15 100%
Three viruses	0 0%	0 0%	1 4%	0 0%

5. Secondary Outcome

Title	Measure Antibody Concentrations in Immunosuppressed IBD Patients Who Receive High Dose and Standard of Care Dose Influenza Vaccine
Description	Influenza vaccine antibody concentration will be measured in immunosuppressed IBD patients who receive high dose and standard of care dose influenza vaccine. Higher antibody concentrations are associated with better protection from infection.
Time Frame	6 months post-immunization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Dose of Influenza Vaccine (HDIV) Group	Standard Dose Influenza Vaccine (SDIV) Group	Vedolizumab Group	Control Group
Arm/Group Description	This arm will be a double blind randomized controlled trial of high dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.	A group of 20 patients who are currently on vedolizumab. All individuals in this group will receive SDIV	A group of 20 healthy individuals without IBD, other chronic diseases, or immunosuppressive therapy will be enrolled. All healthy individuals will receive standard dose influenza vaccine SDIV.
Measure Participants	25	15	19	20
Influenza A H1N1, 6 months post immunization	160	160	160	160
Influenza A H3N2, 6 months post immunization	80	80	160	80
Influenza B Victoria, 6 months post immunization	20	20	40	20
Influenza B Yamagata, 6 months post immunization	20	20	20	20

Adverse Events

Time Frame	Up to 7 days
Adverse Event Reporting Description	AEs were recorded after administration of the vaccine from days 0-6 using the adverse event dairy. Adverse event data is reported for 24 participants in the HDIV arm as 1 participant did not submit the diary card for adverse event reporting. Adverse event are reported just for anti-TNF monotherapy group HDIV and SDIV since these were the primary outcome.No AEs were collected for vedolizumab group and control group as they were secondary outcomes which were dependent on primary outcomes.
Arm/Group Title	High Dose Influenza Vaccine (HDIV)		Standard Dose Influenza Vaccine (SDIV)
Arm/Group Description	This arm will be a double blind randomized controlled trial of High dose influenza vaccine (HDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.		This arm will be a double blind randomized controlled trial of standard dose influenza vaccine (SDIV) for IBD patients on TNF monotherapy. 40 patients will be enrolled and randomized in a 5:3 fashion to HDIV or SDIV. Randomization will generated by a random number generator and investigator will be blinded to randomization scheme.
All Cause Mortality
	High Dose Influenza Vaccine (HDIV)		Standard Dose Influenza Vaccine (SDIV)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/15 (0%)
Serious Adverse Events
	High Dose Influenza Vaccine (HDIV)		Standard Dose Influenza Vaccine (SDIV)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	High Dose Influenza Vaccine (HDIV)		Standard Dose Influenza Vaccine (SDIV)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/24 (54.2%)		8/15 (53.3%)
General disorders
fever	1/24 (4.2%)	1	0/15 (0%)	0
Headache	9/24 (37.5%)	9	5/15 (33.3%)	5
Muscle Aches	12/24 (50%)	12	8/15 (53.3%)	8
Arthralgia	6/24 (25%)	6	4/15 (26.7%)	4
Fatigue	13/24 (54.2%)	13	7/15 (46.7%)	7
Skin and subcutaneous tissue disorders
Local reactions: Pain	10/24 (41.7%)	10	4/15 (26.7%)	4
Local reaction: Redness	7/24 (29.2%)	7	5/15 (33.3%)	5
Swelling	5/24 (20.8%)	5	5/15 (33.3%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.