Inflammatory Bowel DiseaseNCT02413047
Evaluate if Response to Infliximab or Adalimumab May be Regained With an Immunomodulator
A study testing Azathioprine, 6 mercaptopurine and Methotrexate in people with Inflammatory Bowel Disease and Ulcerative Colitis, run by Indiana University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Inflammatory Bowel Disease, Ulcerative Colitis, Crohn's Disease
- What is being tested?
- Azathioprine, 6 mercaptopurine and Methotrexate
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteUnited States
- Study dates
- May 2015to Feb 2018
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Indiana University Hospital
Indianapolis, Indiana, 46062
About this study
Official title: A Pilot Study to Evaluate if Response to Infliximab or Adalimumab May be Regained With the Addition of 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. 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.
Read the 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.
- Being tested
- Azathioprine, 6 mercaptopurine, Methotrexate
- Medical subject headings
- Inflammatory Bowel Diseases, Colitis, Ulcerative, Crohn Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzathioprineDrug
Also called Imuran
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 mercaptopurineDrug
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
MethotrexateDrug
Medication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine.
| Study group | Role | What they receive |
|---|---|---|
| Immunomodulator | Experimental | Azathioprine, 6 mercaptopurine or methotrexate. Receives: Drug: Azathioprine; Drug: 6 mercaptopurine; Drug: Methotrexate |
What is being measured
The primary outcome is the main question the study is designed to answer.
Harvey Bradshaw Index HBI: Decrease >3 Points or Remission Score<5
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.
Measured: 4 months
Therapeutic Trough Level for Infliximab is Defined as >3 and as > 5 for Adalimumab.
Trough level is the lowest level of drug detected in a subject prior to next dose of medication
Measured: 4 months
Ulcerative Colitis Clinical Score UCCS Decrease >3 Points or Remission Score <3
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.
Measured: 4 months
Change Inflammatory Bowel Disease Questionnaire SIBDQ
SIBDQ is the short inflammatory bowel disease questionnaire which is a health-related quality of life tool measuring physical, social, and emotional status.
Measured: 4 months
Eliminate Antibodies: Threshold Levels for ATI is < 3.1and is < 1.7 for ADA.
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.
Measured: 4 months
Secondary outcomes (3)
Improvement or Normalization of Mayo Endoscopy Score for UC Patients
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
Measured: 4 months
Improvement or Normalization of C-reactive Protein, Sedimentation Rate and Fecal Calprotectin
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.
Measured: 4 months
Improvement or Normalization of the Simple Endoscopic Score-Crohn's Disease (SES-CD)
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.
Measured: 4 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2015 (estimated)
- Study startMay 2015
- Primary completionFeb 2018
- Study completionFeb 2018
Why it stopped: physician decision to stop study early due to low enrollment
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Inflammatory Bowel DiseaseStudies of the same condition, open and under way.
- More trials run by Indiana UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Indiana University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Matthew Bohm, Indiana University
- Investigators
- Matthew Bohm, DO, Principal investigator, IndianaU IRB
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02413047
- Sponsor's protocol ID
- 1502834262
- Status last verified
- Oct 2019
- First submitted
- 6 Mar 2015
- Last updated
- 4 Nov 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No: No individual participant data was analyzed
Study at a glance
From the registry record, last updated by the sponsor on 4 Nov 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study to Evaluate if Response to Infliximab or Adalimumab May be Regained With the Addition of an Immunomodulator
- ClinicalTrials.gov ID
- NCT02413047
- Acronym / sponsor ID
- 1502834262
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: physician decision to stop study early due to low enrollment
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Indiana UniversityUniversity, hospital or other
- Study start
- May 2015 (actual)
- Primary completion
- Feb 2018 (actual)
- Study completion
- Feb 2018 (actual)
- First posted
- 9 Apr 2015 (estimated)
- Results
- Posted 4 Nov 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Immunomodulator | Experimental | Drug: Azathioprine, Drug: 6 mercaptopurine, Drug: MethotrexateAzathioprine, 6 mercaptopurine or methotrexate. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (14 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AzathioprineAlso: ImuranMedication 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. | Drug | Immunomodulator |
| 6 mercaptopurineMedication 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 | Immunomodulator |
| MethotrexateMedication will be given in subcutaneous injection form once a week if the patient cannot take imuran or 6 mercaptopurine. | Drug | Immunomodulator |
Primary outcome
Harvey Bradshaw Index HBI: Decrease >3 Points or Remission Score<5
Time frame: 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.
Therapeutic Trough Level for Infliximab is Defined as >3 and as > 5 for Adalimumab.
Time frame: 4 months
Trough level is the lowest level of drug detected in a subject prior to next dose of medication
Ulcerative Colitis Clinical Score UCCS Decrease >3 Points or Remission Score <3
Time frame: 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.
Change Inflammatory Bowel Disease Questionnaire SIBDQ
Time frame: 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.
Eliminate Antibodies: Threshold Levels for ATI is < 3.1and is < 1.7 for ADA.
Time frame: 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.
3 secondary outcomes
Improvement or Normalization of Mayo Endoscopy Score for UC Patients
Time frame: 4 months
Improvement or Normalization of C-reactive Protein, Sedimentation Rate and Fecal Calprotectin
Time frame: 4 months
Improvement or Normalization of the Simple Endoscopic Score-Crohn's Disease (SES-CD)
Time frame: 4 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Nov 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No. No individual participant data was analyzed
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Matthew Bohm, DO principal investigator
IndianaU IRB
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Azathioprine, 6 mercaptopurine and Methotrexate in people with Inflammatory Bowel Disease and Ulcerative Colitis, run by Indiana University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 4 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Nov 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Harvey Bradshaw Index HBI: Decrease >3 Points or Remission Score<5 (time frame: 4 months). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Nov 2019.