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.
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
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.
- Males and females ≥ 14 years old, including women of childbearing potential who are
not pregnant or nursing at the time of enrollment.
- Body weight between 40 and 100 kg (88-220 lbs), inclusive.
- Subjects diagnosed with Crohn's disease, based upon the criteria of Lennard-Jones,
for at least a 3-month period. The date of diagnosis will be the date of the first
diagnostic test that confirms the diagnosis of Crohn's disease. Subjects with a
diagnosis of less than 3 months may be considered after review of primary diagnostic
data by the study safety monitor.
- Need for treatment with oral prednisone, based upon the treating physician's clinical
judgment, for active Crohn's disease as indicated by a (Crohn's Disease Activity
Index) CDAI between 200 and 450, inclusive; OR Currently being treated with
prednisone for at least 4 weeks with a stable dose of 40mg/day or less for at least 2
weeks, or budesonide (Entocort EC) 9 mg/day for at least 4 weeks with a stable dose
for at least 4 weeks, and active Crohn's disease as indicated by a CDAI between 200
and 450, inclusive.
- Able to swallow tablets.
- Able to provide written informed consent (subjects ≥ 18 years old) or in the case of
a minor provide parental consent along with child assent (subjects 14-17 years old).
- If sexually active, willing to comply with effective contraception during the study;
or is abstinent.
- Diagnosis of indeterminate, microscopic, lymphocytic, collagenous, or ulcerative
- Previous or current therapy with 6-mercaptopurine, azathioprine, thioguanine,
methotrexate, cyclosporine, tacrolimus, thalidomide or mycophenolate mofetil.
- Previous or current treatment with infliximab.
- Treatment with narcotic pain medications. (Anti-diarrheal agents such as loperamide
and diphenoxylate are permitted, providing that the dose is not increased while on
- Subjects with short gut syndrome (defined as requiring oral or parenteral
supplemental or total nutrition in order to maintain stable body weight, or more than
100 cm of small bowel resected).
- Subjects with obstructive symptoms or demonstrated stenosis and prestenotic
dilatation on barium study.
- Subjects with active infection.
- Subjects with a stoma.
- Subjects with heterozygous or recessive homozygous genotype for TPMT.
- Poor access for peripheral venous phlebotomy.
- History of pancreatitis, except for self-limited episodes from a known cause, such as
- White blood cell count (WBC) <4.5 x 10^9/L, hemoglobin <8 gm/dL, Platelets (PLT)
<100,000/mm3 at screening (or within the previous 6 months, if known).
- History of abnormal liver function tests, including aspartate aminotransferase (AST)
or alanine aminotransferase (ALT) >1.5 times upper limit of normal, alkaline
phosphatase >2 times upper limit of normal, total bilirubin >2.5 mg/dL at screening
(or within the previous 6 months, if known).
- Subjects needing treatment with orally administered corticosteroids for the treatment
of other medical conditions. Inhaled or dermatologic preparations are acceptable.
- History of HIV infection (if known) or opportunistic infection.
- History of cancer, with the exception of basal cell carcinoma of the skin.
- Concurrent treatment, or need for treatment, with allopurinol.
- Women who are pregnant or nursing at the time of eligibility screening, or who intend
to be during the study period.
- Inability to comply with planned schedule of study visits.
- Participation in a clinical trial within the past 6 months.