Clinical trial NCT00113503: Imuran Dosing in Crohn's Disease Study
Official title: A Multi-site Trial of Azathioprine Dosing in Crohn's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Crohn's Disease
Keywords: Inflammatory Bowel Disease, Crohn's disease, Crohn's Colitis
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: Prometheus Laboratories
First posted: 2005-06-09
Enrollment: 50
Sex: ALL
Minimum age (years): 10
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion of subjects achieving clinical remission at week #16.
timeFrame: 16 weeks
Secondary outcomes:
measure: Proportion of subjects maintaining clinical remission at week #28
timeFrame: 28 weeks
measure: Proportion of subjects maintaining clinical remission at week #52
timeFrame: 52 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Atlanta
country: United States
facility: Atlanta Gastroenterology Associates, LLC
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Pediatric Gastroenterology
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Duluth
country: United States
facility: Duluth Clinic
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Great Neck
country: United States
facility: Long Island Clinical Research Assoc.
state: New York
city: New York
country: United States
facility: Mt. Sinai Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Chapel Hill
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
Study officials:
affiliation: University of Chicago
name: Stephen B Hanauer, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.