Imuran Dosing in Crohn's Disease Study

A Multi-site Trial of Azathioprine Dosing in Crohn's Disease

This study will compare two different dosing methods of azathioprine (IMURAN) in participants with Crohn's disease who are currently taking steroids (e.g. prednisone or budesonide)or who have just started steroids. The study can be up to 54 weeks long. All participants enrolled will receive active drug. Participants will take doses either based upon weight or based on the patient's ability to breakdown the drug (monitored by 6-thioguanine nucleotides (6-TGN) metabolite levels in the blood). All patients enrolled in the study will receive active study drug.

Study Overview

• Status: Terminated
• Conditions: Crohn's Disease
• Intervention / Treatment: Drug: Azathioprine weight-based dose; Drug: Azathioprine individualised dose

Detailed Description

This multi-center, double blind (patients and doctors do not know treatment group assignment), randomized (patients are put in 1 of 2 groups) clinical trial which will compare two 52-week-long azathioprine(AZA) dosing methods.

The patients enrolled will all be taking steroids (prednisone or budesonide)or have just been prescribed a steroid. The patients will be either in remission on steroids, but cannot taper off without a flare, patients who are on steroids and are still having Crohn's symptoms, or patients who need to start taking steroids.

After a two week screening period, patients fitting enrollment criteria will be begin taking study drug. Patients will begin to taper steroids per a set schedule, and taper off steroids completely by week 13. Patients who need to go back on steroids because of returned symptoms are allowed to, per a set schedule in the protocol. Patients will have monthly visits that include physical exams, blood tests and a quality of life questionnaire. Patients will be required to keep a diary of abdominal pain, liquid or soft stools and general well being.

After 6 months, only patients in remission (patients not on steroids, and not having active symptoms) will be allowed to continue for last 6 months of the study. Study visits during the last 6 months will be every 2 months, and include physical exams and blood tests, and a quality of life questionnaire.

Patients in the study may receive dose changes, and this will require additional blood tests for safety.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G2X8
      • University of Alberta
  • Ontario
    • London, Ontario, Canada, N6A5A5
      • London Health Sciences Centre
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Atlanta Gastroenterology Associates, LLC
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Chicago, Illinois, United States, 60637
      • University of Chicago Pediatric Gastroenterology
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • Duluth Clinic
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • Great Neck, New York, United States, 11021
      • Long Island Clinical Research Assoc.
    • New York, New York, United States, 10029
      • Mt. Sinai Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 70 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 10-70 years-old., Weigh 20-100 kg (44-220 lbs).
• CD of the ileum, colon or ileocolon, verified by colonoscopy, barium enema, or small bowel series performed within 36 months
• Perianal fistulae will be eligible provided that the perianal disease does not account for the preponderance of symptoms.

• Have steroid-dependent, steroid-refractory or steroid naive CD.

  • Steroid-dependent CD: CDAI or mCDAI of < 150 while receiving prednisone 10-40 mg/day or budesonide 3-9 mg/day for at least 12 weeks prior to screening, but unable to taper prednisone below 10 mg/day or budesonide below 3 mg/day without experiencing a flare within the previous 6 months. Steroids must be at a stable dose for 2 weeks prior to screening (week #-2), prednisone at a dose of 10-40 mg/day and budesonide at a dose of 3-9 mg/day.
  • Steroid-refractory CD: currently moderately active CD (CDAI or mCDAI 200 - 450) despite treatment with 40 kg) or 0.5 mg/kg/day (if weighing 20 mg/day (if weighing prednisone <40 9 mg/day for the previous 4 weeks prior to the screening kg), or budesonide evaluation. Prednisone or budesonide must be at a stable dose for 2 weeks prior to screening (week #-2).

  • Steroid-naïve CD: currently moderately active CD, (CDAI or mCDAI 200 - 450) and one of the following:

    1. Despite treatment with aminosalicylates and/or antibiotics for the previous 4 weeks prior to the screening evaluation, who are candidates for prednisone or budesonide.
    2. Not currently on therapy, who are candidates for prednisone or budesonide
    3. Patients with prior exposure to steroids, who have not been treated with steroids for 4 weeks prior to screening, and are candidates for prednisone or budesonide Prednisone or budesonide will be started at the screening visit, at a dose of 40 mg/day or 9 mg/day and tapered per the steroid taper.

Patients who have started steroids up to 14 days prior to screening will also qualify as steroid naïve, however patient needs to be on 40 mg prednisone or 9 mg budesonide.

• Discontinue oral or rectal 5-Aminosalicylic acid (5-ASA) therapies, rectal steroids, ciprofloxacin or metronidazole at the screening visit.

Exclusion Criteria:

• CDAI > 450
• CD requiring hospitalization and intravenous (iv) corticosteroids, iv antibiotics or total parenteral nutrition (TPN).
• TPN or enteral nutrition of >1000 Calories/day (both TPN and elemental diets impact the CDAI).
• History of resection of more than 100 cm of small bowel, total proctocolectomy, or subtotal colectomy with ileorectal anastomosis
• Ileostomy or colostomy
• Severe fixed symptomatic stenosis of the small or large intestine
• Blood transfusion within 3 months before screening
• Treatment with 6-MP or AZA within the 6 months prior to screening
• Immunosuppressants or biologics 3 months before screening

• Treatment 2 weeks before screening:

  • Allopurinol;
  • Trimethoprim-sulfamethoxazole;
  • NSAIDs or aspirin >81mg/day;
  • Cholestyramine or other drugs interfering with enterohepatic circulation;
  • Furosemide and thiazide diuretics;
  • Fish-oil preparations.
• Discontinue use at screening: Oral or rectal 5-ASA, rectal steroids, metronidazole or quinolones
• Any prior treatment with natalizumab
• Presence of abnormal laboratory parameters:
• Carriage of hepatitis B surface antigen or positive hepatitis C antibody
• Lack of one acceptable form of contraception while receiving AZA
• Low TPMT activity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Azathioprine weight-based dose	Drug: Azathioprine weight-based dose; Other Names: Imuran
EXPERIMENTAL: Azathioprine individualised dose	Drug: Azathioprine individualised dose; Other Names: Imuran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects achieving clinical remission at week #16.	For the steroid-dependent subjects, clinical remission was defined as complete withdrawal of corticosteroids, and Crohn's Disease Activity Index (CDAI) score <150 in adults, or modified CDAI (mCDAI) score <150 in children. For the steroid-refractory and the steroid-naıve subjects, clinical remission was defined as CDAI score <150 (or mCDAI <150 in children), and a reduction of at least 70 points from the baseline score (CDAI or mCDAI), and complete withdrawal of corticosteroids.	16 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of subjects maintaining clinical remission at week #28	28 weeks
Proportion of subjects maintaining clinical remission at week #52	52 weeks

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Collaborators: Prometheus Laboratories
• Investigators: Principal Investigator: Stephen B Hanauer, MD, University of Chicago

Publications and helpful links

General Publications

• Dassopoulos T, Dubinsky MC, Bentsen JL, Martin CF, Galanko JA, Seidman EG, Sandler RS, Hanauer SB. Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease. Aliment Pharmacol Ther. 2014 Jan;39(2):163-75. doi: 10.1111/apt.12555. Epub 2013 Nov 17.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2005
• Primary Completion (ACTUAL): December 1, 2007
• Study Completion (ACTUAL): December 1, 2007

Study Registration Dates

• First Submitted: June 8, 2005
• First Submitted That Met QC Criteria: June 8, 2005
• First Posted (ESTIMATE): June 9, 2005

Study Record Updates

• Last Update Posted (ACTUAL): October 6, 2017
• Last Update Submitted That Met QC Criteria: October 4, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Inflammatory Bowel Disease, Crohn's disease, Crohn's Colitis
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Azathioprine
• Other Study ID Numbers: DK60083 (terminated); U01DK060083 (NIH)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No