Correlation of Infliximab Levels With Outcomes in Ulcerative Colitis
Conditions: Colitis, Ulcerative, Inflammatory Bowel Disease, IBD
Sponsor: Mayo Clinic

 
 
Correlation of Infliximab levels with 
Outcomes in Ulcerative Colitis 
 
NCT02438410 
 
March 17, 2016 

General Study Information 
 
Principal Investigator/ sponsor investigator:       Darrell S.  Pardi 
 
 
 
 
 
 
 
 
Study Title:    Correlation of Infliximab levels with Outcomes in Ulcerative colitis 
 
Protocol version number and date:      Version #3    Thursday, March 17, 2016 
 
List of Abbreviations: TNF (Tumor Necrosis Factor), CRP (C-reactive protein), ESR (Erythrocyte Sedimentation 
Rate), CMV (Cytomegalovirus) and complete blood cell (CBC)  
Research Team, and Study site: 
Sponsor Investigator: Darrell S. Pardi, M.D.  
Co-Investigator/Fellow: P. Grace Dosanjh, M.D., Dr. Michael Van Nordstand,  
 
Study Coordinator: Patricia P. Kammer 
 
Site: Division of Gastroenterology and Hepatology;  
Mayo Clinic 
200 First Street, SW 
Rochester, Minnesota, U.S.A, 55905 
 
Corresponding author:  
Darrell S. Pardi, MD, MS 
Professor of Medicine 
200 First Street SW 
Rochester, MN  55905 
E-mail: pardi.darrell@mayo.edu 
Phone: (507) 284-2407 
Fax: (507) 284-0538 
 
Disclosures: This work will be supported by clinical research funding from Janssen Scientific Affairs LLC.  
 
 
Purpose 
Hypothesis:  
We hypothesize that non responders to infliximab will have lower early drug levels then 
responders thus reflecting an increased risk of colectomy. Additionally, we will estimate an 
optimal day 4 level based on the study results. 
 
 

Aims, purpose, or objectives: 
 
Summary  
There is increasing interest in the pharmacokinetics of biologics such as Infliximab and their clinical relevance. In 
this study we propose to measure infliximab levels during the first week after infusion in adult patients hospitalized 
with severe ulcerative colitis (UC). We will compare those infliximab levels with one and three month outcomes 
including the requirement for colectomy, changes in inflammatory markers, and complications such as intercurrent 
infections and cardiac, renal, or respiratory deterioration  
 
Background and Significance  
Ulcerative colitis is a chronic inflammatory bowel with significant associated morbidity and risk of colectomy.1 . 
Although many environmental risk factors including smoking, medications, childhood hygiene, and infections have 
been implicated and studied, none can fully explain the disease pathogenesis.2 Additionally, genetic susceptibility 
and a complex interplay between the microbiome and the immune system likely lead to the development of this 
inflammatory bowel disease.3 
 
Acute and chronic complications associated with UC include severe bleeding, toxic megacolon, infection and 
colorectal cancer. Hospitalized patients with a flare of moderate- to-severe ulcerative colitis can be especially 
difficult to manage if they do not respond to intravenous corticosteroids. At this point, medical therapy or a total 
proctocolectomy with a two or three stage ileal pouch–anal anastomosis (IPAA) is frequently considered. 4 
Treatment with cyclosporine may only delay colectomy in most patients.5 Additionally, cyclosporine carries a 
substantial risk of toxicity. 6  Increasingly, Infliximab, a TNF alpha inhibitor, is being used a rescue therapy in this 
situation. 7 
 
. Infliximab is approved for induction and maintenance of clinical remission and mucosal healing in patients with moderate to 
severe active ulcerative colitis, in those who have an inadequate response to conventional therapy such as IV steroids. It is 
typically dosed at 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks thereafter The alternative to rescue 
medical therapy with infliximab is proctocolectomy with ileal pouch anastomosis, which carries risks including  
pouchitis, fecal incontinence, pouch failure requiring further surgical procedures and female infertility 8 9, 10 or 
proctocolectomy with permanent end-ileostomy, which many patients wish to avoid.  An induction regimen of 3 
doses of Infliximab followed by a maintenance dose every 8 weeks is used to achieve response in hopes of avoiding 
colectomy. 11  Unfortunately, a large proportion of patients are unable to achieve (primary failure, approximately 
30%) or sustain a clinical response over time (up to 50%, secondary failure) 12 and end up getting a colectomy.”. 12 
 
Potential implicated pathways in non-responders include fecal wasting of infliximab 13 and factors that accelerate 
drug clearance such as a large TNF or CRP burden, anti-infliximab antibodies (ATI), low serum albumin, male sex 
and larger body size. 14 Patients with severe ulcerative colitis who fail corticosteroids and standard dosing with 
infliximab usually proceed to proctocolectomy.  Optimizing infliximab blood levels in patients with moderate-

severe ulcerative colitis would improve the efficacy and further reduce the need for colectomy. However, there is a 
paucity in the literature as this is a relatively new school of thought.  Our study will address this deficit by 
evaluating the relationship between early drug levels of infliximab in ulcerative colitis and colectomy rates at one 
and three months.  
 
Specific Aims 
Primary Aim 
The primary aim of this study is to analyze the relationship between daily infliximab levels and colectomy free 
survival at 1 and 3 months. We hypothesize that non responders will have lower early drug levels and correlate with 
increased colectomy rates. Based on the resulting correlations, we will estimate an optimal drug level to improve 
clinical outcomes and provide data to support future research. If our hypothesis is correct, we intend to pursue a 
second study which will be randomized and involve early infliximab dose stacking (weeks 0 and 1) in patients with 
suboptimal infliximab levels vs standard infliximab administration (weeks 0, 2, 6) to see if the risk of colectomy can 
be decreased. 
 
Secondary Aims 
The secondary aims of this study are to assess relationships between colectomy and other potential biomarkers 
 
Subject Information – charts, records, images, or specimens are considered ‘subjects’ 
 
Target accrual is the proposed number of subjects to be included in your study at your site. 
“Subjects” may include Mayo Clinic charts, records, or specimens, and/or charts, records, or 
specimens received at Mayo Clinic from external sources for collaborating analysis by the 
investigator under this IRB application:    
Target accrual: 25 
 
Subject population:  Patients must be scheduled to receive clinically indicated infliximab 
at the discretion of their treating physician during an acute hospitalization with a 
flare of moderate to severe UC. The study will enroll a total of 25 subjects.” 
 
 
Inclusion Criteria:   
 
1. Adults, ages >18 
2.  Hospitalized, with a moderate-sever flare of Ulcerativa Colitis, based on the Mayo Scoring System 
for Assessment of UC. Mayo score activity score of equal or greater than 6g 
3. Treatment naïve to anti TNF agents  
4. Initiation of infliximab, with or without immunomodulator such as Azathiorpine. 
5. Ongoing use of immunomodulators such as azathioprine or 6MP is acceptable. Their initiation or 
continuation remains at the discretion of the treating physician 
 

Exclusion Criteria 
1. Ongoing or prior treatment with Infliximab or other anti TNF agents 
2. Ongoing or recent (within 1 month) administration of rescue cyclosporine 
a. 
Concomitant immunomodulator therapy is acceptable if on stable dosing for at least 4 weeks 
b. Current medications may be continued at the discretion of the treating physician 
3. Fulminant colitis requiring emergent surgery or toxic megacolon  
4. Pregnancy  
5. Infectious colitis, example Clostridium difficile or CMV colitis  
6. Active infection or abscess  
7. Untreated latent or active tuberculosis (TB). Those with latent TB who are currently undergoing treatment 
can be included. Please refer to appendix 1 for more information on specific inclusion and exclusion 
criteria related to TB testing. Refer to 1.4.2 of appendix 1 for TB screening questions 
8. Active malignancy  
9. Active or history of Congestive Heart failure (CHF) or those who have received treatment for CHF 
10. Active or history of Multiple Sclerosis (MS), or those who have received treatment for MS 
11. Prisoners, institutionalized individuals, and individuals who are not capable of giving informed consent 
12. Judgement of investigator  
 
Will a Certificate of Confidentiality be obtained?  NO. 
 
Study Design  
 
Methods:  
Design  
We propose an open label pilot study of 25 adult moderate-severe ulcerative colitis inpatients. Since existing 
literature on our study hypothesis is scarce, this sample size was chosen based on other pilot studies of biologic 
therapies in patients with IBD.  
 
Study Population 
Included patients must be receiving clinically indicated infliximab at the discretion of their treating physician during 
an acute hospitalization with a flare of moderate to severe UC. We recognize that our patient population will include 
referral amongst those from the local Olmsted County and surrounding areas.  
To identify subjects, the inpatient gastroenterology service list at St Mary’s Hospital in Rochester Minnesota will be 
reviewed daily. Patients will also be enrolled from any Mayo Clinic Health System (MCHS) site LaCrosse,  if they 
meet the inclusion and exclusion criteria and are under the care of Mayo gastroenterologist. To capture those on 
the internal medicine service, the gastroenterology consult service list will also be reviewed daily. As these patients 
will be admitted with a suspected IBD flare, a clinically indicated colonoscopy or flexible sigmoidoscopy will have 
been completed with colon, terminal ileum and/or sigmoid colon biopsies. Endoscopic findings will be noted and 

those deemed to have moderate to severe disease activity will be included based on the Mayo Scoring System for 
Assessment of Ulcerative Colitis Activity will be considered. Subject will participate for a maximum of 3-months and will 
complete the study when the 3-month follow-up phone call is completed.”. Informed Consent Process  
 A member of the study staff will meet with the potential participant with the assent of the hospitalist who is in charge of the 
patient’s care. The study will be explained to the potential subject and the risks and benefits will be discussed the potential 
subject will be given an opportunity to ask questions.  Only subjects who agree and sign an informed consent 
document will be included in this study. A copy of the written consent document will be provided to the potential 
participant. “Infliximab doses and frequency of administration will be at the discretion of the treating physician.” 
Correlation of Infliximab levels with Outcomes in Ulcerative colitis 
Schedule of events 
Study 
procedure 
Enrollment 
visit 
Study 
day 1 
Study 
day 2 
Study 
day 3 
Study 
day 4 
Study 
day 5 
Study 
day 6 
Study 
day 7 
1 
month  
Phone 
call 
3 
month 
phone 
call 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria including 
confirmation of 
appropriate TB 
screening  
x 
 
 
 
 
 
 
 
 
 
 Concomitant meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study stool labs* 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Study blood labs* 
 
x 
x 
x 
x 
x 
x 
x 
 
 
Study 
Questionnaire 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events/ 
SAE 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 *Study labs include CBC with differential, Sedimentation rate, C reactive protein, Creatinine, TNF level, Albumin, Fecal Calprotectin 
Infliximab and antibody to infliximab levels. Blood and stool to research lab. 
 
Data Collection 
As part of the study, subjects will complete a daily questionnaire of clinical symptoms including stool counts, 
presence of blood or mucous, number of nocturnal bowel movements, fever, malaise, weight loss, urgency or 
tenesmus and abdominal pain3. Estimated time to complete a questionnaire is 5 minutes Additionally stool and blood 
laboratory data such as CBC with differential, creatinine, TNF levels, albumin, fecal calprotectin, ESR, CRP, 
infliximab and antibodies to infliximab levels will be obtained daily for a week, following week 0 Infliximab 
infusion. If any of these labs has been performed on the given day for a clinical indication or to guide management 
by the treating physician, they will not be repeated.  If a subject undergoes colectomy within the first 7 days of the 
study we will stop collecting lab data from them.  
 
All samples collected for the study will be deidentified. Sample labels will contain only subjects study ID, visit # 
and date of collection.    Lab test will be requested by the study physician using Mayo standard of practice 

procedure.  Samples will be collected, processed and sent to the lab per Biospecimens Accessioning and Processing 
(BAP) department at Mayo Clinic.  They will be aliquoted per testing instructions and delivered to the appropriate 
lab for analysis.  
 
 
Those subjects who are discharged prior to a week’s time will have blood and stool collected as outpatients at the Mayo 
Clinic outpatient lab area. Similarly, subjects will receive the rest of daily questionnaires and self-addressed envelopes 
Subjects that are unable to return to Mayo Clinic, will receive mail in blood and stool kits that can be mailed to the 
Mayo Clinic lab at the time of discharge. They will be provided instructions regarding venipuncture at outside labs, 
stool sample collection and shipping of samples. The subjects will be given addressed and postage paid mail in kits. 
They will not be responsible for venipuncture or shipping cost.  Subjects will receive remuneration of $25.00 if they 
complete the study or a pro-rated portion of that amount if they complete only a part of the study. Subjects will 
receive a follow up phone call at 1 and 3 months after Inflixambe intitation (+/- 5 days). A followup symptom 
questionnaire also will be completed at these phone calls. to gather information about progression of symptoms.  In 
an effort to minimize any potential risks to subjects, all information will be treated in accordance with Mayo Clinic 
patient confidentiality rules and regulations as well as with HIPAA regulations. Samples will be destroyed at the end of 
the study.” 
 
Endpoints 
Primary Endpoint:  
1. Colectomy free survival at 1 and 3 month 
Secondary Endpoints:    
1. Improvement in variables such as ESR, CRP, TNF levels, hemoglobin and stool counts 
 
Estimated Timeline  
Final protocol to IRB approval: 1 month 
 
IRB approval to First Patient, First Visit: 1 month 
 
First Patient, First Visit to Last Patient, Last Visit: 18 months 
 
Treatment period: 3 months from date of Remicade initiation  
 
Final study report timing after Last Patient, Last Visit: 2 months 
 
Publication submission timing after final study report: 2 months   
                
Safety Events 
Safety events during the course of the study will be monitored. Adverse events will be monitored from date of 
Remicade initiation until the 1 month follow up phone call and serious adverse events will be monitored from date 

of Remicade initiation until the 3 month follow up phone call.  Please refer to appendix 2 for protocol adverse event 
language for investigator-initiated studies.” 
 
Check all that apply. If none apply, leave blank: 
 
  This is a multisite study involving Mayo Clinic and non-Mayo Clinic sites.  
When checked, describe the research procedures/activities being conducted only at Mayo 
Clinic: 
 
  Mayo Clinic staff will be engaged in research activity at a non-Mayo Clinic site.  When 
checked, provide the location and a detailed description of the Mayo Clinic research staff 
involvement. 
 
 
  This study is to establish and/or maintain an ongoing database or registry for research 
purposes only. 
 
x  The research involves contact or interaction with subjects, for example, surveys, 
questionnaires, observation, blood draw.  The study will involve daily blood draws for 
seven days.  We understand this is more draws then normally associated with a 
minimal risk study. Most of the subjects will be hospitalized, with daily blood draws, 
we will not repeat any testing done clinically.  This is why we feel it the study still 
meets the minimal risk category. 
 
  The study involves photographing, audiotaping or videotaping subjects (and guests).  
 
 
 
 
 
Blood Collection 
 
If this study involves prospective blood collection by finger, heel, ear stick or venipuncture, 
complete the following:  
 
 
  From healthy, non pregnant, adult subjects who weigh at least 110 pounds. For a 
minimal risk application, the amount of blood drawn from these subjects may not exceed 
550ml in an 8 week period and collection may not occur more frequently than 2 times per 
week. 
Volume per blood draw: _____ml   
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.) 
_______ 
 
 

X  From other adults and children considering age, weight, and health of subject. 
For a minimal risk application, the amount of blood drawn from these subjects may not 
exceed the lesser of 50 ml or 3 ml per kg in an 8 week period, and collection may not 
occur more frequently than 2 times per week. 
Volume per blood draw: ___3__ml 
Frequency of blood draw (e.g. single draw, time(s) per week, per year, etc.)___7  
 
 
 
Review of Chart, Images, Specimens 
Provide the date range for collection of data and/or specimens that will be included in your 
research dataset.  Example: 01/01/2000 to 12/31/2013 or all records through dd/mon/yyyy.  
Date range:  
 
Check all that apply: 
 
  This study involves only data and/or specimens that exist at the time this application is 
submitted to the IRB (IRB submission date). No data or specimens will be collected beyond this 
date.  
 
 
X This study involves only data and/or specimens that will be collected after submission to the 
IRB. 
 
  The study involves data and/or specimens that exist at the time of submission to the IRB and 
data and/or specimens that will be collected after submission to the IRB, for example a study that 
includes collection of existing data and prospective collection of specimens. 
 
  Data and/or specimens used in this study are collected under another IRB protocol. When 
checked, provide the IRB number(s) from which the research material will be obtained. When 
appropriate,  check the box below to attest that subjects have provided consent for future use of 
their data and/or specimens, as described in this protocol.  
 
 
IRB Number/s - Data Only:  _____________________________________________ 
 
IRB Number/s - Specimens Only: _________________________________________ 
 
IRB Number/s - Data and Specimens:_____________________________________ 
 
 
□ Subjects have provided consent for use of their data and/or specimens, as described in 
this protocol. 
 
  Other data sources will be utilized in this study, e.g. receiving data/specimens from an 
external party. When checked, provide all data sources: