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

• Sponsor: Indiana University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02413047
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arm: 1
• Actual Duration (Months): 33.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Inflammatory Bowel Disease; Ulcerative Colitis; Crohn's Disease	Drug: Azathioprine; Drug: 6 mercaptopurine; Drug: Methotrexate	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study to Evaluate if Response to Infliximab or Adalimumab May be Regained With the Addition of an Immunomodulator
• Actual Study Start Date: May 1, 2015
• Actual Primary Completion Date: Feb 1, 2018
• Actual Study Completion Date: Feb 1, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Immunomodulator Azathioprine, 6 mercaptopurine or methotrexate.

Drug: Azathioprine; 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.; Other Names: Imuran ; Drug: 6 mercaptopurine; 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; Drug: Methotrexate; Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.

Outcome Measures

Primary Outcome Measures

1. Harvey Bradshaw Index HBI: Decrease >3 Points or Remission Score<5 [4 months]

   The Harvey-Bradshaw index (HBI) is a simplified version of the CDAI to foster a systematic collection of clinical data related to Crohn's disease. The index considers five parameters, exclusively clinical; patient well-being, abdominal pain, number of liquid or soft stools, abdominal mass, and complications.

2. Therapeutic Trough Level for Infliximab is Defined as >3 and as > 5 for Adalimumab. [4 months]

   Trough level is the lowest level of drug detected in a subject prior to next dose of medication

3. Ulcerative Colitis Clinical Score UCCS Decrease >3 Points or Remission Score <3 [4 months]

   UCCS is the ulcerative colitis clinical score which is based on disease activity. The score is based on bowel movements, blood in stool, overall well being, and global assessment.

4. Change Inflammatory Bowel Disease Questionnaire SIBDQ [4 months]

   SIBDQ is the short inflammatory bowel disease questionnaire which is a health-related quality of life tool measuring physical, social, and emotional status.

5. Eliminate Antibodies: Threshold Levels for ATI is < 3.1and is < 1.7 for ADA. [4 months]

   unwanted immunogenicity is an immune response by an organism against a therapeutic antigen. This reaction leads to production of anti-drug antibodies inactivating the therapeutic effects of the treatment.

Secondary Outcome Measures

1. Improvement or Normalization of Mayo Endoscopy Score for UC Patients [4 months]

   Mayo endoscopy score is scoring completed during the endoscopy to evaluate disease activity. Scoring is based on stool frequency, rectal bleeding, mucosal appearance at endoscopy, and physician rating of disease activity

2. Improvement or Normalization of C-reactive Protein, Sedimentation Rate and Fecal Calprotectin [4 months]

   c-reactive protein, sedimentation rate, and fecal calprotectin were collected to monitor the level of inflammation in the subject. Improvement was determined if inflammation level was reduced.

3. Improvement or Normalization of the Simple Endoscopic Score-Crohn's Disease (SES-CD) [4 months]

   SESCD is the simple endoscopic score for crohn's disease patients scored during endoscopy. The scoring is based on appearance of ulcers/sizing, % of ulcerative surface, % of affected surface, and if there were any narrowings or strictures found.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Indiana University Hospital	Indianapolis	Indiana	United States	46062

Sponsors and Collaborators

• Indiana University

Investigators

• Principal Investigator: Matthew Bohm, DO, IndianaU IRB

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 12, 2016

More Information

Publications

None provided.

• Responsible Party: Matthew Bohm, Assistant Professor of Medicine, Indiana University
• ClinicalTrials.gov Identifier: NCT02413047
• Other Study ID Numbers: 1502834262
• First Posted: Apr 9, 2015
• Last Update Posted: Nov 4, 2019
• Last Verified: Oct 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Crohn Disease; Inflammatory Bowel Diseases; Methotrexate; Mercaptopurine; Azathioprine

Study Results

Participant Flow

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Period Title: Overall Study
STARTED	3
Participants on Infliximab	2
Participants on Adalimumab	1
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48 (14)
Sex: Female, Male (Count of Participants)
Female	2 66.7%
Male	1 33.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	3 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	3 100%
Duration of Disease (years) [Mean (Full Range) ]
Mean (Full Range) [years]	16.66666667
White Blood Cell Count (WBC) (x 10^3 cells/mm^3) [Mean (Full Range) ]
Mean (Full Range) [x 10^3 cells/mm^3]	6.566666667
Hemoglobin (gm/dL) [Mean (Full Range) ]
Mean (Full Range) [gm/dL]	13.63
Platelet Count (x 10^3 cells/mm^3) [Mean (Full Range) ]
Mean (Full Range) [x 10^3 cells/mm^3]	256.00
Aspartate Aminotransferase (units/L) [Mean (Full Range) ]
Mean (Full Range) [units/L]	21.00
ALT (units/L) [Mean (Full Range) ]
Mean (Full Range) [units/L]	23.67
Bilirubin (mg/dL) [Mean (Full Range) ]
Mean (Full Range) [mg/dL]	0.67
Albumin (gm/dL) [Mean (Full Range) ]
Mean (Full Range) [gm/dL]	4.37
Alkaline Phosphatase (units/L) [Mean (Full Range) ]
Mean (Full Range) [units/L]	93.33
Above-Normal C-Reactive Protein (mg/dL) [Number]
Number [mg/dL]	2.0
Erythrocyte Sedimentation Rate (mm/hr) [Mean (Full Range) ]
Mean (Full Range) [mm/hr]	23.67
Calprotectin (mCg/gm) [Mean (Full Range) ]
Mean (Full Range) [mCg/gm]	331.50
Simple Endoscopic Score for Crohn's Disease (points) [Mean (Full Range) ]
Mean (Full Range) [points]	6.67
Harvey Bradshaw Index (HBI) Score (points) [Mean (Full Range) ]
Mean (Full Range) [points]	4.67
Short Inflammatory Bowel Disease Questionnaire (points) [Mean (Full Range) ]
Mean (Full Range) [points]	46.00
Serum Infliximab concentration (ug/mL) [Number]
Number [ug/mL]	6.3
Antibodies to Infliximab concentration (units/mL) [Mean (Full Range) ]
Mean (Full Range) [units/mL]	20.70
Serum Adalimumab concentration (ug/mL) [Number]
Number [ug/mL]	2
Antibodies to Adalimumab concentration (units/mL) [Number]
Number [units/mL]	2.8

Outcome Measures

1. Primary Outcome

Title	Harvey Bradshaw Index HBI: Decrease >3 Points or Remission Score<5
Description	The Harvey-Bradshaw index (HBI) is a simplified version of the CDAI to foster a systematic collection of clinical data related to Crohn's disease. The index considers five parameters, exclusively clinical; patient well-being, abdominal pain, number of liquid or soft stools, abdominal mass, and complications.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Not enough subjects for analysis

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Measure Participants	0

2. Primary Outcome

Title	Therapeutic Trough Level for Infliximab is Defined as >3 and as > 5 for Adalimumab.
Description	Trough level is the lowest level of drug detected in a subject prior to next dose of medication
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Not enough subjects for analysis

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Measure Participants	0

3. Primary Outcome

Title	Ulcerative Colitis Clinical Score UCCS Decrease >3 Points or Remission Score <3
Description	UCCS is the ulcerative colitis clinical score which is based on disease activity. The score is based on bowel movements, blood in stool, overall well being, and global assessment.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Not enough subjects for analysis

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Measure Participants	0

4. Primary Outcome

Title	Change Inflammatory Bowel Disease Questionnaire SIBDQ
Description	SIBDQ is the short inflammatory bowel disease questionnaire which is a health-related quality of life tool measuring physical, social, and emotional status.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Not enough subjects for analysis

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Measure Participants	0

5. Primary Outcome

Title	Eliminate Antibodies: Threshold Levels for ATI is < 3.1and is < 1.7 for ADA.
Description	unwanted immunogenicity is an immune response by an organism against a therapeutic antigen. This reaction leads to production of anti-drug antibodies inactivating the therapeutic effects of the treatment.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Not enough subjects for analysis

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Measure Participants	0

6. Secondary Outcome

Title	Improvement or Normalization of Mayo Endoscopy Score for UC Patients
Description	Mayo endoscopy score is scoring completed during the endoscopy to evaluate disease activity. Scoring is based on stool frequency, rectal bleeding, mucosal appearance at endoscopy, and physician rating of disease activity
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Not enough subjects for analysis

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Measure Participants	0

7. Secondary Outcome

Title	Improvement or Normalization of C-reactive Protein, Sedimentation Rate and Fecal Calprotectin
Description	c-reactive protein, sedimentation rate, and fecal calprotectin were collected to monitor the level of inflammation in the subject. Improvement was determined if inflammation level was reduced.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Not enough subjects for analysis

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Measure Participants	0

8. Secondary Outcome

Title	Improvement or Normalization of the Simple Endoscopic Score-Crohn's Disease (SES-CD)
Description	SESCD is the simple endoscopic score for crohn's disease patients scored during endoscopy. The scoring is based on appearance of ulcers/sizing, % of ulcerative surface, % of affected surface, and if there were any narrowings or strictures found.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Not enough subjects for analysis

Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
Measure Participants	0

Adverse Events

Time Frame	Enrollment to 16 weeks
Arm/Group Title	Immunomodulator
Arm/Group Description	Azathioprine, 6 mercaptopurine or methotrexate. Azathioprine: 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. 6 mercaptopurine: 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 Methotrexate: Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
All Cause Mortality
	Immunomodulator
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	Immunomodulator
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Other (Not Including Serious) Adverse Events
	Immunomodulator
	Affected / at Risk (%)	# Events
Total	0/3 (0%)

Limitations/Caveats

The study terminated early due to low subject enrollment. Since only 3 patients were enrolled, study analysis was not possible for measurable outcomes.

More Information

Certain Agreements

Principal Investigators are NOT 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.