Imuran (Azathioprine) Dose-Ranging Study in Crohn's Disease
The purpose of this study is to identify an optimal weight based dose of azathioprine that is safe and effective in the treatment of subjects with active Crohn's disease requiring treatment with corticosteroids, and for maintaining remission in those subjects.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
|Official Title:||A Double-Blinded, Randomized, Parallel Arm, Dose Ranging Study of IMURAN in Subjects With Active Crohn's Disease Requiring Treatment With Prednisone: A Crohn's Disease Optimal Range Dose of IMURAN Study (ACORDIS)|
- To identify an optimal weight-based dose of azathioprine for the treatment of active Crohn's disease and for maintaining remission in those subjects.
- To characterize prospectively the predictive value of erythrocyte thioguanine nucleotide levels for response to azathioprine in who are wild type for the (thiopurine methyltransferase) TPMT gene
- To explore the relationship of 6-thioguanine (TGN) levels to TPMT enzyme activity
- To determine the effect of azathioprine dose upon time to relapse among subjects in remission induced by a course of prednisone
- To prospectively determine the rate of adverse events associated with a range of doses of azathioprine
- To preliminarily identify genetic polymorphisms associated with therapeutic response or toxicity to azathioprine.
|Study Start Date:||April 2005|
|Study Completion Date:||July 2007|
|Primary Completion Date:||July 2007 (Final data collection date for primary outcome measure)|
|Active Comparator: Azathioprine 0.5 mg/kg body weight||Drug: azathioprine|
|Active Comparator: Azathioprine 2.5 mg/kg body weight||Drug: azathioprine|
|Active Comparator: Azathioprine 3.5 mg/kg body weight||Drug: azathioprine|
DESCRIPTION: Medical therapy for Crohn's disease is of variable success in ameliorating the cardinal symptoms of the disease (diarrhea, abdominal pain), in treating extraintestinal manifestations (fatigue, anorexia, fever, weight loss, arthralgias, skin, eye, liver and kidney manifestations), and in preventing complications (stricture, fistula, abscess). Currently, therapy is most often implemented in a stepwise fashion, progressing through anti-inflammatory medications (sulfasalazine, mesalamine), antibiotics (metronidazole, ciprofloxacin), corticosteroids, immunomodulatory or immunosuppressive medications, including thioguanine compounds (6 mercaptopurine or its prodrug azathioprine), methotrexate, and finally, infliximab (anti-tumor necrosis factor). A common approach is the gradual addition of more potent medications to agents that are believed to be safer, but may also be less effective. Despite the current approach to medical therapy in Crohn's disease, a substantial number of patients—from 20 to 40%—require surgery within 3 years of diagnosis, excluding those requiring surgery at the time of diagnosis. Nearly 80% of patients require surgery by 20 years from the onset of disease.
Corticosteroids have long been a mainstay of therapy in Crohn's disease although side effects are frequently observed with both short term and long-term use. Potential side effects are well-described, and may include relatively minor problems such as insomnia and acne, as well as more serious adverse effects, including hypertension, narrow-angle glaucoma, depression, weight gain, adrenal suppression, Cushing's syndrome, diminished bone mineral density, and infections.
Azathioprine is often used to treat patients with steroid resistant or dependent Crohn's disease. Azathioprine is used as a steroid sparing agent, as treatment for active, inflammatory disease, for maintenance of remission, as therapy for perforating disease (fistulae), and for specific extraintestinal manifestations. To date, however, randomized, controlled clinical studies assessing a range of doses of azathioprine in Crohn's disease have not been conducted. The optimal weight-based dose is not known.
EXPECTED CONTRIBUTION: This study will identify an optimal weight based dose of azathioprine for treatment of patients with active Crohn's disease requiring treatment with corticosteroids.
STUDY HYPOTHESIS: An optimal weight-based dose of azathioprine will induce and maintain remission in subjects with steroid-dependent Crohn's disease.
COMPARISON: Three different doses of azathioprine will be compared in this study (0.5, 2.5, and 3.5mg/kg/day). Subjects will take the study medication for 9 months.
|United States, Massachusetts|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02114|
|Principal Investigator:||Bruce E Sands, M.D.,M.S.||Massachusetts General Hospital|