A Trial of Rosiglitazone for Ulcerative Colitis

Ulcerative colitis is a disease characterized by inflammation (the changes that happen when
tissues in the body are injured) of all or a portion of the large intestine. There is
presently no medical cure for ulcerative colitis, although surgical removal of the colon
would cure the disease. Ulcerative colitis is generally treated with medications against
diarrhea and infection, medications which suppress the immune system (the body system that
protects a person against foreign substances) or with surgery.

It is thought that the chronic inflammation associated with ulcerative colitis may be related
to the release of certain chemicals produced by the body. Rosiglitazone has been shown to
inhibit the production of some of these chemicals. The active component of rosiglitazone has
also been shown to improve colitis in animal models of colitis. The purpose of this study is
to evaluate the benefit of the drug for ulcerative colitis by comparing it to placebo.

This is a randomized controlled trial of rosiglitazone versus placebo in patients who have
failed to respond to 5-ASA therapy. Participants will be randomized to receive either
rosiglitazone 4mg bid or placebo bid twice daily for a total of 12 weeks. Disease activity
will be measured using the Disease Activity Index (DAI) at visits 3 through 8. Additional
outcomes measured will include histological disease activity (visits 3 and 7) and quality of
life using the IBDQ (visits 3 through 8). The principle analyses will be an intent-to-treat
analysis to examine the efficacy of rosiglitazone at a dose of 4mg twice daily compared to
placebo to achieve a partial or complete response. Additionally, the change in NF-κB
activation prior to and following therapy with either placebo or rosiglitazone will be
examined using immunohistochemistry techniques.

INCLUSION CRITERIA: Participants must meet the following criteria for inclusion in the
trial:

- Must sign and date the informed consent form

- At least 18 years of age

- Documented diagnosis (endoscopic, surgical or x-ray) of ulcerative colitis (UC)

- Mild to moderate ulcerative colitis indicated by Disease Activity Index score of
greater than or equal to 4 and less than or equal to 10

- Unless the patient is intolerant of oral 5-ASA therapy, patient must be treated with a
minimum of 2 gm daily of an oral 5-ASA agent for a minimum of 4 weeks during the
current exacerbation of ulcerative colitis or immediately prior to study entry

- If treated with oral corticosteroids, dose must not exceed 20 mg per day of Prednisone
or equivalent

- If treated with corticosteroids, dose must be stable for 4 weeks prior to study entry
and remain on same dose throughout

- If treated with 6-mercaptopurine or azathioprine, must have been on medication for 4
months and a stable dose for 2 months prior to study entry

- If a female of childbearing age, the participant must have a negative serum pregnancy
test and have been using a medically approved form of contraceptive birth control for
3 months prior to enrollment. Participants, both male and female, must also be willing
to use medically approved contraceptive birth control (at least one barrier method)
throughout the study

- If treated with rectal therapy, dose must be stable for 2 weeks prior to study entry
and remain on same dose throughout

EXCLUSION CRITERIA: Participants will be ineligible for participation in the trial if they
meet any of the following criteria:

- Severe ulcerative colitis indicated by Disease Activity Index score of greater than 10

- Class III or IV congestive heart failure by NYHA classification system

- Allergy to thiazolidinediones

- Presence of any medical condition with an expected survival of less than 1 year

- Participants receiving therapy with cyclosporin, anti-TNF therapy, or methotrexate
within the last 2 months of screening

- Positive stool culture for enteric pathogens (salmonella, shigella, and
campylobacter), positive C.difficile toxin, or positive stool ova and parasite exam

- Positive proteinuria by urine dipstick

- History of chronic liver disease or baseline liver chemistries greater than the upper
limit of normal

- Diabetes mellitus requiring hypoglycemic agents

- Participation in study of experimental therapy within 2 months of first screening
visit

- Has any of the following laboratory abnormalities: WBC < 3,000 per uL, Neutrophil <
1,000 cell/cu.mm, Platelets <75,000 per uL, INR > 1.2

- Participant is female and is pregnant or currently breastfeeding