Clinical trial NCT02413047: Evaluate if Response to Infliximab or Adalimumab May be Regained With an Immunomodulator
Official title: A Pilot Study to Evaluate if Response to Infliximab or Adalimumab May be Regained With the Addition of an Immunomodulator
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Inflammatory Bowel Disease
Ulcerative Colitis
Crohn's Disease
Lead sponsor: Indiana University
Sponsor class: OTHER
First posted: 2015-04-09
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Harvey Bradshaw Index HBI: Decrease >3 Points or Remission Score<5
timeFrame: 4 months
measure: Therapeutic Trough Level for Infliximab is Defined as >3 and as > 5 for Adalimumab.
timeFrame: 4 months
measure: Ulcerative Colitis Clinical Score UCCS Decrease >3 Points or Remission Score <3
timeFrame: 4 months
measure: Change Inflammatory Bowel Disease Questionnaire SIBDQ
timeFrame: 4 months
measure: Eliminate Antibodies: Threshold Levels for ATI is < 3.1and is < 1.7 for ADA.
timeFrame: 4 months
Secondary outcomes:
measure: Improvement or Normalization of Mayo Endoscopy Score for UC Patients
timeFrame: 4 months
measure: Improvement or Normalization of C-reactive Protein, Sedimentation Rate and Fecal Calprotectin
timeFrame: 4 months
measure: Improvement or Normalization of the Simple Endoscopic Score-Crohn's Disease (SES-CD)
timeFrame: 4 months
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University Hospital
state: Indiana
Study officials:
affiliation: IndianaU IRB
name: Matthew Bohm, DO
role: PRINCIPAL_INVESTIGATOR
References: