Evaluate if Response to Infliximab or Adalimumab May be Regained With an Immunomodulator

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.

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 an undetectable or inadequate trough level of infliximab or adalimumab and
detectable 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