Inflammatory Bowel Disease, Ulcerative Colitis
Conditions
Keywords
Rosiglitazone, Ulcerative, Colitis
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled study evaluating rosiglitazone: 4 mg tablets or placebo tablets administered orally twice daily for 12 weeks. The purpose of the study is to evaluate the efficacy and safety of rosiglitazone in the treatment of mild to moderately active ulcerative colitis. Disease activity will be measured using a standard disease activity index. Calculation of the index requires patients to undergo flexible sigmoidoscopy at the start of the study and at week 12.
Detailed description
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.
Interventions
DRUGRosiglitazone
4mg orally twice daily for 12 weeks
DRUGPlacebo
pill that looks identical to rosiglitazone
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
GlaxoSmithKline
James Lewis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improvement of Signs and Symptoms of UC at 12 Weeks | 12 weeks | Mayo score decrease \>=2 points adjusted for age and smoking status. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Remission at 12 Weeks | 12 weeks | Mayo Score \<=2 at 12 weeks post intervention |
| Number of Participants With Endoscopic Remission at 12 Weeks | 12 weeks | — |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from 15 clinical centers between September 6, 2002 and January 11, 2006.
Participants by arm
| Arm | Count |
|---|---|
| Rosiglitazone rosiglitazone (Avandia): 4mg orally twice daily | 52 |
| Placebo Identical in appearance to study drug taken twice a day | 53 |
| Total | 105 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Lack of Efficacy | 4 | 11 |
| Overall Study | Other | 2 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 5 |
Baseline characteristics
| Characteristic | Rosiglitazone | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 42 years | 43 years | 46 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 48 Participants | 98 Participants | 50 Participants |
| Region of Enrollment United States | 52 participants | 105 participants | 53 participants |
| Sex: Female, Male Female | 22 Participants | 41 Participants | 19 Participants |
| Sex: Female, Male Male | 30 Participants | 64 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 36 / 52 | 30 / 53 |
| serious Total, serious adverse events | 1 / 52 | 5 / 53 |
Outcome results
Primary
Number of Participants With Improvement of Signs and Symptoms of UC at 12 Weeks
Mayo score decrease \>=2 points adjusted for age and smoking status.
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rosiglitazone | Number of Participants With Improvement of Signs and Symptoms of UC at 12 Weeks | 23 participants |
| Placebo | Number of Participants With Improvement of Signs and Symptoms of UC at 12 Weeks | 12 participants |
p-value: 0.00595% CI: [1.5, 10.5]Regression, Logistic
Secondary
Number of Participants With Clinical Remission at 12 Weeks
Mayo Score \<=2 at 12 weeks post intervention
Time frame: 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rosiglitazone | Number of Participants With Clinical Remission at 12 Weeks | 9 participants |
| Placebo | Number of Participants With Clinical Remission at 12 Weeks | 1 participants |
Secondary
Number of Participants With Endoscopic Remission at 12 Weeks
Time frame: 12 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rosiglitazone | Number of Participants With Endoscopic Remission at 12 Weeks | 4 Participants |
| Placebo | Number of Participants With Endoscopic Remission at 12 Weeks | 1 Participants |