WASHINGTON — Rosiglitazone shows some promise in reducing ulcerative colitis activity and may offer an alternative to conventional therapy for patients who fail to respond to the latter approach or can't tolerate it, said Dr. James D. Lewis at the annual Digestive Disease Week.
Rosiglitazone (Avandia) reduced disease activity significantly, compared with placebo in patients with mild to moderate ulcerative colitis activity.
In the study of 105 patients, 44% of those taking rosiglitazone achieved clinical remission—defined as at least a 2-point drop in the disease activity index at 12 weeks—compared with 23% of those on placebo.
Fifty-two patients were randomized to receive 4 mg rosiglitazone twice daily, and 53 received placebo. Most of the patients were male (79%), with an average age of 44 years.
“Rosiglitazone may represent a novel approach to the treatment of mild to moderately active ulcerative colitis and conceivably has a role in those patients who fail to respond to or are unable to tolerate 5-aminosalicylic acid therapy,” said Dr. Lewis, associate director of the University of Pennsylvania Health System's Inflammatory Bowel Disease Program in Philadelphia.
Dr. Lewis disclosed that he has received grants and research support from GlaxoSmithKline, maker of Avandia. The company also supplied rosiglitazone for this study.
Patients had to have been treated with at least 2 g/day of 5-aminosalicylic acid for at least 4 weeks prior to randomization, or they had to have documented intolerance to this therapy. Corticosteroids were allowed, as long as the patient was on a stable dose for at least 4 weeks or taking no more than 20 mg/day of prednisone or the equivalent.
Immunomodulators (azathioprine and 6-mercaptopurine) were also allowed if the patient had been treated with these for at least 4 months and was on a stable dose for at least 2 months. Rectal therapies were also allowed, as long as the dose had been stable for at least 2 weeks prior to randomization.
Patients were excluded if they had diabetes mellitus requiring treatment with a hypoglycemic agent or had New York Heart Association class III or IV heart failure. Patients were also excluded if they were taking cyclosporine, anti-tumor necrosis factor-α drugs, or methotrexate within 2 months of the study.
The researchers used a modified version of the Sutherland and Mayo disease activity indices to assess disease activity. This index (DAI) included four components: stool frequency, physician global assessment, rectal bleeding, and mucosal appearance. Each component could be scored 0–3. Patients were included if they had a score that was at least 4 but no more than 10.
Mucosal appearance could only be assessed at the time of sigmoidoscopy, so the researchers also used a modified disease activity index (mDAI) that excluded mucosal appearance and ranged from 0 to 9 points.
At baseline, patients had a complete DAI calculated and then were randomized. Follow-up occurred at weeks 4, 8, and 12. At weeks 4 and 8, an mDAI was calculated, and at week 12 (study end point) a complete DAI was calculated. During the course of the study, patients were not allowed to increase their usual medications, nor were corticosteroids tapered.
Clinical remission was defined as a final DAI score of no more than 2. Endoscopic remission required a final DAI score of less than 2 and a mucosal appearance score of 0. The researchers defined response as a reduction in DAI score of at least 3 points, as this definition has been used in other trials. Response at weeks 4 and 6 was defined as a reduction from baseline of at least 2 points on the mDAI.
With the more stringent definition of response, more patients on rosiglitazone (37%) responded than patients in the placebo group (13%). Likewise, more patients on rosiglitazone had clinical remission—17%, compared with 2% in the placebo group. In terms of endoscopic remission, 8% in the rosiglitazone group met the criteria, compared with 2% in the placebo group; this difference was not statistically significant.
In terms of adverse events, lower extremity edema was significantly more common among patients on rosiglitazone—17% vs. 2% for placebo. Patients were more likely to withdraw early because of worsening disease if they were in the placebo arm: 11 patients vs. 4 in the rosiglitazone arm.
In a post hoc analysis, the researchers excluded patients with lower extremity edema during the course of the study. They were concerned that such edema could have unmasked the treatment assignments for these patients because this is a common side effect of rosiglitazone. However, “the results are almost identical to those from our primary intention to treat analysis,” Dr. Lewis said.