Conditions: Inflammatory Bowel Disease Ulcerative Colitis Crohn's Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
The immunogenicity of anti-tumor necrosis factor alpha (anti-TNF) therapy in inflammatory bowel disease (IBD) is an important cause of loss of response to therapy that may lead to escalation of dose or discontinuation of therapy. Antibodies may develop to infliximab (ATI) or to adalimumab (ATA) and cause this loss of response, also known as a secondary loss of response. An alternative approach is the addition of immunomodulator (IM) therapy to counteract the antibody response and regain efficacy of the biologic medication. The investigators' goal is to treat patients' who have lost response to adalimumab or infliximab with an immunomodulator with the goal of eliminating the circulating antibodies to the anti-TNF and restoring efficacy.

Detailed description:
The immunogenicity of anti-tumor necrosis factor alpha (anti-TNF) therapy in inflammatory bowel disease (IBD) is an important cause of loss of response to therapy that may lead to escalation of dose or discontinuation of therapy. Antibodies may develop to infliximab (ATI) or to adalimumab (ATA) and cause this loss of response, also known as a secondary loss of response. In an attempt to overcome these antibodies, dose escalation can be accomplished either by increasing the dose or shortening the interval between doses. The ability of dose escalation to overcome loss of response due to the presence of ATI or ATA remains controversial. Escalation of dose increases the cost of therapy substantially. If the decision is made to discontinue therapy after a secondary loss of response, a clinician may choose to switch to an alternate anti-TNF therapy of which there are currently only four. Loss of response to one agent predicts a lesser response to other anti-TNF agents and with a limited number of therapeutic options the goal should be to optimize therapy rather than to discontinue therapy.

An alternative approach is the addition of immunomodulator (IM) therapy to counteract the antibody response and regain efficacy of the biologic medication. Three such IMs known to be effective in the treatment of IBD are azathioprine (AZA), 6-mercaptopurine (6MP) and methotrexate (MTX). The SONIC trial showed that patients on infliximab and azathioprine only developed antibodies at 4% of the time as opposed to those on infliximab monotherapy who formed ATI at 13%. The same principal was shown during the COMMIT trial in which patients on infliximab alone had ATI at a rate of 20% versus 4% on methotrexate plus infliximab. Ben-Horin et al. reported five patients treated initially with infliximab monotherapy whom had secondary loss of response based on clinical symptoms. These patients had ATI and all had undetectable troughs of infliximab. In all five patients ATI became undetectable, an adequate trough level was restored and the patients regained clinical response with the addition of an immunomodulator. Combination therapy with azathioprine and infliximab has led to a higher percentage of patients in steroid free remission than either drug alone. Our goal is to treat patients' who have lost response to adalimumab or infliximab with an immunomodulator with the goal of eliminating the circulating antibodies to the anti-TNF and restoring efficacy.

Arms:
arm 1: Azathioprine, 6 mercaptopurine or methotrexate.

Interventions: intervention 1: Azathioprine intervention 2: 6 mercaptopurine intervention 3: Methotrexate
Intervention descriptions: intervention 1: Medication will be given in pill form to patients to take daily as long as the patient has not been intolerant to it in the past. intervention 2: Medication will be given in pill form to patients to take daily as long as the patient has not been intolerant to it in the past as an alternative to imuran intervention 3: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.

Protocol document:
Prot_SAP_000.pdf: 
 10.12.2016 
A Pilot Study to Evaluate if Response to Infliximab or Adalimumab 
May be Regained with the Addition of an Immunomodulator 
 
 
NCT: 02413047 
 
 
 
 
 
Principal Investigator 
Matthew Bohm, DO Assistant Professor of Medicine 
Division of Gastroenterology & Hepatology 
Indiana University Hospital  
550 University Blvd 
Indianapolis, IN 46202 
 
Sub-Investigators 
Monika Fischer, MD Assistant Professor of Medicine 
Sashidhar Sagi, MD, Assistant Professor of Medicine 
Division of Gastroenterology & Hepatology 
Indiana University Hospital  
550 University Blvd 
Indianapolis, IN 46202 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Background 


 10.12.2016 
The immunogenicity of anti-tumor necrosis factor alpha (anti-TNF) therapy in inflammatory bowel 
disease (IBD) is an important cause of loss of response to therapy that may lead to escalation of dose or 
discontinuation of therapy.  Antibodies may develop to infliximab (ATI) or to adalimumab (ATA) and 
cause this loss of response, also known as a secondary loss of response. In an attempt to overcome these 
antibodies, dose escalation can be accomplished either by increasing the dose or shortening the interval 
between doses.  The ability of dose escalation to overcome loss of response due to the presence of ATI or 
ATA remains controversial.   Escalation of dose increases the cost of therapy substantially.  If the 
decision is made to discontinue therapy after a secondary loss of response, a clinician may choose to 
switch to an alternate anti-TNF therapy of which there are currently only four. Loss of response to one 
agent predicts a lesser response to other anti-TNF agents and with a limited number of therapeutic options 
the goal should be to optimize therapy rather than to discontinue therapy.  
 
 
An alternative approach is the addition of immunomodulator (IM) therapy to counteract the 
antibody response and regain efficacy of the biologic medication.  Three such IMs known to be effective 
in the treatment of IBD are azathioprine (AZA), 6-mercaptopurine (6MP) and methotrexate (MTX).  The 
SONIC trial showed that patients on infliximab and azathioprine only developed antibodies at 4% of the 
time as opposed to those on infliximab monotherapy who formed ATI at 13%.  The same principal was 
shown during the COMMIT trial in which patients on infliximab alone had ATI at a rate of 20% versus 
4% on methotrexate plus infliximab.  Ben-Horin et al. reported five patients treated initially with 
infliximab monotherapy whom had secondary loss of response based on clinical symptoms.  These 
patients had ATI and all had undetectable troughs of infliximab.  In all five patients ATI became 
undetectable, an adequate trough level was restored and the patients regained clinical response with the 
addition of an immunomodulator.   Combination therapy with azathioprine and infliximab has led to a 
higher percentage of patients in steroid free remission than either drug alone.  Our goal is to treat patients’ 
who have lost response to adalimumab or infliximab with an immunomodulator with the goal of 
eliminating the circulating antibodies to the anti-TNF and restoring efficacy. 
 
Specific Aims/Hypotheses 
 
Hypotheses : 
 
In patients with loss of response to infliximab or adalimumab who also have detectable ATI or ATA and 
inadequate trough levels of drug, addition of IM will:  
1) improve clinical response, restore trough levels of drug and cause a reduction or resolution of ATI or 
ATA.  
2) normalize inflammatory markers including sedimentation rate, C-reactive protein (CRP) and/or fecal 
calprotectin. 
3) improve or heal mucosal inflammation. 
 
Aims : 
 
Primary: To determine if addition of an IM to anti-TNF, either infliximab or adalimumab, in those 
patients with Crohn’s Disease (CD) or Ulcerative Colitis (UC) who have a secondary loss of response to 
anti-TNF with measurable ATI or ATA and inadequate anti-TNF trough levels: 
• 
Will improve clinical response 
• 
Will restore adequate trough levels of anti-TNF and eliminate or reduce ATI or ATA 


 10.12.2016 
Secondary: To determine if addition of an IM to anti-TNF, either infliximab or adalimumab, in those 
patients with CD or UC who have a secondary loss of response to anti-TNF with measurable ATI or ATA 
and inadequate anti-TNF trough levels: 
• 
Will improve or heal endoscopic appearance of the mucosa 
• 
Will improve or normalize serologic and fecal markers of inflammation 
 
Inclusion/Exclusion Criteria 
• 
Study Subjects 
• 
Inclusion Criteria 
• 
Patients with inflammatory bowel disease who on are stable doses of 
infliximab or adalimumab for at least 3 months who experience a secondary 
loss of response to the medication based on clinical symptoms.  
• 
Presence of at least one objective marker of active disease: active disease 
based on endoscopy, elevated fecal calprotectin or serologic markers of 
inflammation (C-reactive protein or sedimentation rate). 
• 
Crohn’s patients have a Harvey Bradshaw index >5 
• 
Ulcerative colitis patients have a Ulcerative Colitis Clinical Score >  5 
• 
Have adetectable ATI or ADA. 
• 
Oral corticosteroid therapy is allowed. (prednisone at a stable dose ≤30 
mg/day, budesonide at a stable dose ≤9 mg/day, or equivalent steroid) 
provided that the dose has been stable for the 4 weeks immediately prior to 
enrollment if corticosteroids have recently been initiated 
• 
Exclusion Criteria 
• Previous noncompliant with medications 
• < 18 years of age or >80 years of age. 
• Congestive heart failure 
• Abnormal liver tests alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) 2 × the upper limit of normal (ULN) or leucopenia WBC count <3 × 109/L 
• Pregnant or planning on becoming pregnant. 
• Active tuberculosis or hepatitis B infection 
• Any cancer within the past 5 years. (Exception non-melanomatous skin cancer.) 
• Receiving any immunomodulator therapy within the past 3 months 
• Evidence of or treatment for C. difficile infection within 60 days or other intestinal 
pathogen within 30 days prior to enrollment 
• Clinically significant extra-intestinal infection (e.g., pneumonia, pyelonephritis) 
within 30 days of the initial screening visit 
• Any live vaccinations within 30 days prior to study drug administration except for 
the influenza vaccine 
• Any identified congenital or acquired immunodeficiency (e.g., common variable 
immunodeficiency, human immunodeficiency virus [HIV] infection, organ 
transplantation) 
• Any unstable or uncontrolled cardiovascular, pulmonary, hepatic, renal, 
endocrine/metabolic, or other medical disorder that, in the opinion of the 
investigator, would confound the study results or compromise patient safety  
• Unable to give own informed consent 
Study Protocol 
• 
Screening and Enrollment  
• 
Twenty patients will be recruited from the IUHP IBD clinic or at the time of ileo-
colonoscopy. Patients with a history of CD or UC on a stable dose of infliximab or 


 10.12.2016 
adalimumab for 3 months, but with active symptoms (as determined by an expert in IBD) 
and with objective evidence of active disease with either elevated serologic or fecal 
markers of inflammation or endoscopic evidence of active disease will be eligible for 
enrollment as long as they also have measurable ATI (>3.1) or ATA (>1.7) and lack other 
exclusion criteria. 
• 
Informed consent will be obtained from Study Subjects.  
• 
Subjects if enrolled with have a baseline visit and a follow-up visit at 4 months. 
• 
We will add an IM to their current biologic therapy following standard care and clinical 
practice.  IM’s are used in patients who are having ongoing symptoms despite current 
therapy or lost response to their monotherapy.  The choice of IM therapy (azathioprine, 6 
mercaptopurine or methotrexate) will be individualized for each patient based on prior use 
and history of known side effects.  Our first line choice based on prior studies will be to 
use 6 mercaptopurine (1-1.5 mg/kg dosing) or azathioprine (2.5 mg/kg dosing).  We will 
check TPMT (thiopurine methyltransferase) levels and patient has inadequate levels we 
will use methotrexate.  If a patient had side effects to one class of drug the alternative will 
be chosen.  If patients are heterozygotic for TPMT then we will use half dose of the 
AZA/6 MP or can use methotrexate.  The dosing of the methotrexate will be 25 mg 
subcutaneously weekly with weekly folic acid 5 mg the day after the methotrexate.  If 
subcutaneous administration is not tolerated oral methotrexate can be used. 
• 
Patients will remain on same dose of infliximab or adalimumab for entirety of the study 
and no changes of dosing interval will be allowed. 
 
• 
Baseline Visit 
• 
Demographic Data  
• Gender, age, weight, height, ethnicity, duration of disease 
 
• 
Blood work - We will measure:  complete blood count, comprehensive metabolic panel, C 
- reactive protein, sedimentation rate.  Pregnancy test for all females of child bearing age.  
Stool will be checked for inflammation with fecal calprotectin and infection with 
clostridium difficile PCR toxin.  We will check a TPMT level prior to initiating AZA or 
6MP.  
 
 
• 
Baseline and Follow-up visit Clinical History and Symptoms:  The following questionnaires are 
routinely administered to all patients at every clinic visit in our IBD clinic to monitor symptoms 
and quality of life. 
• 
Harvey Bradshaw Index for patients with Crohn’s disease 
• 
Ulcerative Colitis Clinical Score for patients with Ulcerative colitis 
• 
Short Inflammatory Bowel Disease Questionnaire for all patients.  Quality of life scale. 
 
 
• 
Standard-of-Care Procedures at baseline and follow-up visit at 4 months for Study Subjects:  
• 
Ileo-colonoscopy 
• Ileo-colonoscopy at baseline and follow-up examination  
• 
For patient not responding to therapy as determined by their treating 
gastroenterologist under good clinical care we perform an endoscopic 
examination prior to changing therapy.  The endoscopy determines if the 
patient's symptoms are related to active disease, the severity of the 
disease if active or if normal and another cause of their symptoms should 
be evaluated. 


 10.12.2016 
• 
After administering a new therapy, it is acceptable and standard care to 
perform a colonoscopy to assess treatment response 4 months after the 
initiation. 
• 
For those without colonic or terminal ileum disease we will not perform 
a colonoscopy during the study period. 
• During the ileo-colonoscopy mucosal biopsies are taken routinely from abnormal 
areas.  This is done under standard practice and care to examine the histological 
activity of their disease.   Histology is reported by our pathologists as inactive or 
active with mild, moderate or severe activity. 
• Endoscopic activity will be graded by the gastroenterologist using the Simple 
endoscopy score-Crohn’s disease (SES-CD) or the Mayo endoscopic subscale for 
ulcerative colitis. 
• 
Serum sample standard care while taking one of the above IM’s. 
• Follow-up Labs: 
• 
Total WBC and lymphocyte counts will be regularly monitored for all 
patients.  Azathioprine, 6-mercaptopurine, or methotrexate must be 
discontinued, if applicable, for a confirmed absolute lymphocyte count 
<0.5 × 109/L. For an absolute lymphocyte count <0.5 × 109/L, the 
hematology must be repeated in 2 weeks. WBC and lymphocyte counts 
will be followed for these patients until they return to an acceptable 
level. 
• 
Protocol for azathioprine/6-mercaptopurine initiation of WBC 
monitoring will be weekly for 1 month, every 2 weeks for 1 month, 1 
month later then every 3 months as we do in standard practice.  WBC 
will be checked one month after initiation of methotrexate and then every 
2 months as we do in standard practice. 
 
• 
Liver tests will be checked one month after starting methotrexate and 
then every 2 months as we do in standard clinical practice.  Liver tests 
will be checked 1 month after starting azathioprine/6-mercaptopurine.  
Then every 3 months per standard clinical practice.  If ALT/AST in 
patients on methotrexate is >2 Upper limit of normal the medication will 
be discontinued.  If ALT/AST rise in patients on azathioprine/6 MP the 
dose should be lowered and liver tests followed every week until 
normalization.  Clinicians can check metabolites (6-thioguanine and 6-
methylmercaptopurine) to help guide dosing as done in standard practice.  
If liver tests fail to normalize with the above changes the medication will 
be stopped. 
 
• 
C-reactive protein and sedimentation rate will be checked again at 4 
months at the follow-up visit.  In addition, we will check an infliximab or 
adalimumab trough level and ATI or ADA at this visit.  At the 4 month 
visit we will check AZA/6MP metabolites (6-thioguanine and 6-
methylmercaptopurine). 
 
• 
Stool samples 
• At baseline we will check a clostridium difficile PCR of their stool and a fecal 
calprotectin to assess for active inflammation 
• At follow-up visit all patients will give a stool sample to recheck fecal 
calprotectin. 
 


 10.12.2016 
 
Outcomes 
• 
Primary Outcomes 
• 
1. 
To determine if patients with secondary loss of response with infliximab  or 
adalimumab can regain clinical response with the addition of an  immunomodulator: 
azathioprine, 6-mercaptopurine or methotrexate. 
• Endpoint: Change in HBI score, with improvement  defined as a decrease in >3 
points or remission HBI score of <5 
• Endpoint:  Change in UCCS with improvement defines as a decrease in >3 points 
or remission with score < 5 
• Endpoint:  Change in SIBDQ quality of life score 
• 
2. 
To evaluate if the addition of immunomodulator therapy eliminates ATI or 
 
ADA below accepted thresholds and increase trough levels of  
infliximab or 
adalimumab 
• Endpoint:  .   Threshold levels for ATI  is < 3.1and is < 1.7 for ADA. 
 
• 
Secondary Outcome 
• 
1. 
To evaluate endoscopic improvement and mucosal healing from baseline 
 
to follow-up after the addition of an immunomodulator to infliximab or 
 
adalimumab. 
• Endpoint:  Improvement or normalization of Mayo Endoscopy Score for UC 
patients. (scored 0-3) A score of 0 or 1 equivalent to mucosal healing.  
Improvement or normalization of the Simple Endoscopic Score-Crohn’s Disease 
(SES-CD).  Score is 0-15 with 0 indicating mucosal healing. 
• 
2. 
To evaluate if addition of an immunomodulator to infliximab or  adalimumab 
results in improvement of serologic and fecal markers of  
inflammation 
• Endpoint:  Improvement or normalization of C - reactive protein, sedimentation 
rate and fecal calprotectin from baseline to follow-up visits. 
 
Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 
 
Any adverse events or unanticipated problems involving risk to participants or others will be reported to 
the Institutional Review Board.  Physicians will perform adequate work-up and care until event resolves. 
 
Study Withdrawal/Discontinuation 
 
Patient can withdraw from the study at any time without compromising future care. 
 
Follow-up and Record Retention 
 
Patients will continue to follow-up with their gastroenterologist for regular care after the completion of 
the study.  Their records will be in our medical record system:  Cerner. 
 
 
Statistics 
 
Correlation kappa statistics, chi square, analysis of variances will be used.   Wilcoxon rank sum test for 
non-parametric comparison of before-after values for CRP, ESR pre- vs. post immunomodulator 
treatment.  
 
 


 10.12.2016 
Appendix 
 
Simple Endoscopic Score for Crohn's Disease 
 
Simple Endoscopic 
Score for Crohn's 
Disease values  
 
 
 
 
Variable 
0 
1 
2 
3 
Size of ulcers 
None 
Aphthous ulcers 
Large ulcers 
Very large ulcers 
 
 
(Ø 0.1 to 0.5 cm) 
(Ø 0.5 to 2 cm) 
(Ø >2 cm) 
Ulcerated surface 
None 
<10% 
10-30% 
>30% 
Affected surface 
Unaffected segment <50% 
50-75% 
>75% 
Presence of narrowings 
None 
Single, can be passed 
Multiple, can be passed 
Cannot be passed 
 
 
Mayo Endoscopy Subscale 
Findings of flexible procto-sigmoidoscopy or colonoscopy 
0= Normal or inactive 
1= Mild disease (erythema, decreased vascular pattern, mild friability) 
2= Moderate (marked erythema, abscent vascular pattern, friability, erosions) 
3= Severe disease (spontaneous bleeding, ulceration) 
 
 
THE INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE (SIBDQ) 
 
This questionnaire is designed to find out how you have been feeling during the last 2 weeks. You will be asked 
about symptoms you are having as a result of your inflammatory bowel disease, the way you have been feeling in 
general, and how you mood has been. 
 
• 
How often is the feeling of fatigue or being tired and worn out been a problem for you during the 
last 2 weeks? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 
• 
How often during the last 2 weeks have you had to delay or cancel a social engagement because of 
you bowel problems? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 


 10.12.2016 
• 
How much difficulty have you had, as a result of your bowel problems, doing leisure or sports 
activities you have liked to have done over the last 2 weeks? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 
• 
How often during the last 2 weeks have you been troubled by pain in the abdomen? 
All of the time 
Most of the time A good bit of time 
Some of the time A little of the 
time  
Hardly any time        
    Never 
• 
How often during the last 2 weeks have you felt depressed or discouraged? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 
• 
How much of a problem have you had passing large amounts of gas, in the last 2 weeks? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 
• 
Overall, in the last 2 weeks, how much of a problem have you had maintaining or getting to the 
weight you would like to be? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 
• 
How often, during the last 2 weeks, have you felt relaxed or free of tension? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 
• 
How much of the time during the last 2 weeks have you been troubled by a feeling of having to go 
to the toilet even though your bowels were empty? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 
• 
How much of the time, during the last 2 weeks, have you felt angry as a result of your bowel 
problems? 
All of the time 
Most of the time A good bit of time 
Some of the time 
 
A little of the time 
 
Hardly any time        
    Never 
 
 
 


 10.12.2016 
Harvey Bradshaw Index (HBI) 
• 
How did you feel overall last week? 
Very well   Slightly sub-par     Poor           Very poor      Terrible 
      0 
 
      1                    2     
      3 
 
    4 
 
• 
Do you have pain in your stomach? 
 
Very well   Slightly sub-par     Poor           Very poor      Terrible 
      0 
 
      1                    2     
      3 
 
    4 
 
• 
How many liquid bowel movements have you had, on average, per day over the last week? 
 
_______ / day 
 
• 
Do you have an actively draining fistula/pus at the anus? 
Yes 
No 
 
• 
Do you have swollen, tender, stiff joints? 
Yes 
No 
 
• 
Do you have pain and redness, inflammation in the eyes? 
Yes 
No 
 
• 
Do you have ulcers in the mouth or on your skin or tender rashes? 
Yes 
No 
 
MD only below this line: 
• 
Abdominal mass 
 
None 
 
Dubious  
Definite  
Definite and Tender 
    0                       1                              2                                        3 
 
• 
Complications (score 1/item) 
 
• 
Erythema nodosum, arthralgia, uveitis, aphthous ulcers, pyoderma 
• 
Anal fissure or active fistula, abscess 
Scoring 
<5 remission 
5-7 mild disease 
8-16 moderate disease 
>16 severe disease 
 
 
 
ULCERATIVE COLITIS ACTIVITY SCORE (UCCS) 
 
• 
How many loose bowel movements per day have you had, on average, during the last week? 
 
None 
 
1-2 over normal 3-4 over normal 5 or more over normal 
    0                          1                                2                                  3 
 
• 
Do you see blood in the stool? 
 


 10.12.2016 
No 
Streaks, sometimes 
      Obvious blood, most times 
Frank blood by itself 
 0                    1                                               2                                       3 
 
• 
Do you have pain in your stomach/abdomen? 
 
No 
 
Mild 
 
Moderate 
 
Severe 
 0                     1                        2                             3 
 
• 
How did you feel in general last week? 
 
Generally well 
 
Fair 
 
Poor 
 
Terrible 
          0                                  1                    2                     3 
 
• 
Do you have swollen, tender, stiff joints?  
Yes 
No 
• 
Do you have pain and redness, inflammation in the eyes? Yes 
No 
• 
Do you have ulcers in the mouth or on your skin or tender rashes?  Yes  No 
 
MD only below this line: 
 
• 
Global assessment: 
 
Quiescent 
 
Mild 
 
Moderate 
 
Severe 
       0                          1                        2                            3