A Double-Blind, Placebo Controlled, Multicentre Study of the Efficacy And Safety of 5-Aminosalicylic Acid Tablets in the Treatment of Ulcerative Colitis

Abstract

This double-blind, placebo controlled, multicentre, parallel trial assessed the efficacy of two oral doses of a new formulation of 5-aminosalicylic acid (5-ASA) targeted to release in the cecum which was given for six weeks to 136 patients with active ulcerative colitis. Seven centres participated (two Canadian, five American). Patients were randomly assigned to one of three treatment groups (4 g 5-ASA, 2 g 5-ASA or placebo). Medication was dispensed as 250 mg identically appearing tablets containing either 5-ASA or placebo to be taken four times a day. Subjects were assessed at baseline and after three and six weeks of treatment. Assessments included a disease activity index, physician's global assessment and flexible sigmoidoscopy. Compliance was assessed through pill count. A total of 136 patients participated ( 4 7 on 4 g 5-ASA, 45 on 2 g 5-ASA, and 44 on placebo). The three groups were similar in terms of age, weight, distribution of disease, extent of disease, and previous use of steroids or sulphasalazine. Ninety patients completed the six week study. Of the 46 dropouts, 38 (82.6%) left because of insufficient efficacy ( most on either place ho or 2 g 5-ASA), four (8.7%) had adverse reactions (all on 5-ASA), the remaining four (8.7%) left for reasons not related to their ulcerative colitis. The disease activity index represents a composite score ( maximum of 12) with categories for number of daily stools, presence of bleeding, abdominal pain and physician's assessment of disease activity. Patients who received 4 g 5-ASA daily demonstrated significant declines in disease activity index within three weeks of therapy and maintained improvement until the end of the stuuy. Although disease activity index declined for patients receiving 2 g 5-ASA daily, these changes did not reach statistical significance when compared to placebo-treated patients. On a five point scale (much improved, somewhat improved, unchanged, somewhat worse, much worse) the physician's global assessment mirrored the changes in disease activity index. Patients randomized to receive 4 g 5-ASA tablets were consistently noted as being either much or somewhat improved compared to placebo-treated patients. Side effects were few and minor and 52% (4 g 5-ASA), 42% (2 g 5-ASA) and 37% (placebo) of patients had no complaints. Headache was the most commonly cited adverse reaction for 6.9% (4 g 5-ASA) and 9.4% (2 g 5-ASA) of treated patients but 3.5% of placebo-treated patients also complained of headache. In conclusion in this randomized double-blind, placebo controlled study, patients with active ulcerative colitis randomized to 4 g 5-ASA per day noted improvement in disease activity as measured by disease activity index and physician's global assessment when compared to placebo-treated patients. ln contrast, patients who received 2 g 5-ASA daily did not demonstrate significant differences compared to the placebo group.

Direct comparison of two different mesalamine formulations for the induction of remission in patients with ulcerative colitis: A double-blind, randomized study

“…Schroeder et al13 demonstrated that a higher dose of the pH-dependent release formulation of 4.8 g/day showed greater efficacy than a dose of 1.6 g/day. In addition, when another formulation of pH-dependent release mesalamine (Rowasa) was administered to patients with active UC, UC-DAI after six weeks of treatment decreased from 8.5 to 4.8 at the 4 g/day dose, from 9.0 to 7.7 at the 2 g/day dose, and from 8.2 to 7.7 in the placebo group 14. In this report, we also showed that the pH-dependent release formulation at a higher dose significantly decreased UC-DAI (Table 2).…”

Meta-Analysis of the Placebo Response in Ulcerative Colitis

“…However, this difference was due to the studies performed exclusively in USA, and it disappeared after those studies were omitted from the analysis. [85] and Australia [86] and one carried out jointly in the USA and Canada [87]. Among the studies conducted exclusively in USA reporting data on improvement rate, the Mayo Clinic (Rochester, MN) participated in four [33,34,36,58], the University of Chicago participated in three [31,53,56], Mount Sinai School of Medicine (New York, NY) [56,57] and George Washington University (Washington D.C.) [54,55] participated in two RCTs each, and one RCT each was carried out partially or solely at the Massachusetts General Hospital Boston [33], University of Iowa [42] and Albert Einstein College of Medicine New York [59].…”

Voting with Their Feet (VWF) Endpoint: A Meta-Analysis of an Alternative Endpoint in Clinical Trials, Using 5-ASA Induction Studies in Ulcerative Colitis

“…1. ) Five studies 10,11,13,17,18 were excluded because they were either unavailable in full text format, used a low (Ͻ2 g/d) dose of 5-ASA, or they did not report the data required to perform the analysis. The Mesalamine Study Group trial 11 was excluded because the dosage of mesalamine used for the study was less than 2 g/day, in order to maximize the homogeneity of the studies in the metaanalyses.…”

“…Feurle et al 10 and Hetzel et al 13 used olsalazine and did not clearly differen-tiate between diarrhea caused by olsalazine versus lack of treatment effect. Sutherland et al 17 did not specify exactly how many patients left the study for lack of efficacy in each arm.…”

“…In fact, we had to drop 2 studies 11,17 from the meta-analysis due to the failure of these studies to report these data. In more recent studies, especially the ones using mesalamine MMX 7,14 the CONSORT guidelines were followed, and these data were consistently provided.…”