Randomised controlled trial of mesalazine in IBS

Abstract

Objective: Low-grade intestinal inflammation plays a role in the pathophysiology of IBS. In this trial, we aimed at evaluating the efficacy and safety of mesalazine in patients with IBS.

Design: We conducted a phase 3, multicentre, tertiary setting, randomised, double-blind, placebo-controlled trial in patients with Rome III confirmed IBS. Patients were randomly assigned to either mesalazine, 800 mg, or placebo, three times daily for 12 weeks, and were followed for additional 12 weeks. The primary efficacy endpoint was satisfactory relief of abdominal pain/discomfort for at least half of the weeks of the treatment period. The key secondary endpoint was satisfactory relief of overall IBS symptoms. Supportive analyses were also performed classifying as responders patients with a percentage of affirmative answers of at least 75% or >75% of time.

Results: A total of 185 patients with IBS were enrolled from 21 centres. For the primary endpoint, the responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group (p=0.870; 95% CI -12.8 to 15.1). In explorative analyses, with the 75% rule or >75% rule, the percentage of responders was greater in the mesalazine group with a difference over placebo of 11.6% (p=0.115; 95% CI -2.7% to 26.0%) and 5.9% (p=0.404; 95% CI -7.8% to 19.4%), respectively, although these differences were not significant. For the key secondary endpoint, overall symptoms improved in the mesalazine group and reached a significant difference of 15.1% versus placebo (p=0.032; 95% CI 1.5% to 28.7%) with the >75% rule.

Conclusions: Mesalazine treatment was not superior than placebo on the study primary endpoint. However, a subgroup of patients with IBS showed a sustained therapy response and benefits from a mesalazine therapy.

Trial registration number: ClincialTrials.gov number, NCT00626288.

Keywords: ABDOMINAL PAIN; CLINICAL TRIALS; GUT INFLAMMATION; INFLAMMATORY CELLS; IRRITABLE BOWEL SYNDROME.

Figure 1

Study design. There was a screening period of 2 weeks before randomisation (1:1), a 12-week placebo-controlled treatment period and a 12-week follow-up period. Study visits occurred every two weeks during treatment period and every four weeks during follow-up.

Figure 2

Flow chart of enrolment and randomisation of the study. A total of 185 patients with IBS were included in the study. Of these, five were not randomised and were excluded from all analyses. Of the 180 patients randomised, 88 were allocated to mesalazine and 92 to placebo. One patient randomised to placebo did not take at least one dose of the study treatment. Seven other patients were excluded from the intention-to-treat (ITT) population as they did not have any evaluation of the primary endpoint. Thus, 172 subjects were included in the ITT population. PP, per protocol.

Figure 3

Primary efficacy analysis (satisfactory relief of abdominal pain or discomfort). The logistic model for repeated measures did not reveal a statistically significant effect for treatment (p=0.324) nor interaction between treatment and time (p=0.897). The answers varied significantly with time (p<0.001). Using the same model to test the simple main effect, a borderline significant effect (p=0.060) resulted for week 8 (A). According to the prevalence approach, responder patients were 68.6% in the mesalazine group versus 67.4% in the placebo group, with a δ difference in favour of the mesalazine group of 1.2% (p=0.870; 95% CI −12.8% to 15.1%) (B). Explorative analyses. With the 75% rule, 43.0% of patients in the mesalazine group were responders versus 31.4% in the placebo group, with a δ difference of 11.6% (p=0.115; 95% CI −2.7% to 26.0%) (B). With the >75% rule, 32.6% of responder patients were identified in the mesalazine group versus 26.7% of patients in the placebo group, with a δ difference of 5.9% (p=0.404; 95% CI −7.8% to 19.4%) (B).

Figure 4

Secondary efficacy analysis (satisfactory relief of the overall IBS symptoms). The logistic model for repeated measures did not reveal statistically significant effect for treatment (p=0.155) nor interaction between treatment and time (p=0.640). The answers varied significantly with time (p=0.004). Using the same model to test the simple main effect, a borderline significant effect was detected at week 3 (p=0.060) and a statistical significance was detected at week 5 (p=0.038) (A). According to the prevalence approach, responder patients were 66.3% in the mesalazine group versus 61.6% in the placebo group, with a δ in favour of the mesalazine group of 4.7% (p=0.525; 95% CI −9.7% to 19.0%) (B). Explorative analyses. With the 75% rule, 46.5% of patients in the mesalazine group were responders versus 34.9% in the placebo group, with a δ difference of 11.6% (p=0.121; 95% CI −3.0% to 26.2%) (B). With the >75% rule, 38.4% of responder patients were identified in the mesalazine group versus 23.3% of patients in the placebo group, with a δ difference of 15.4% (p=0.032; 95% CI 1.5% to 28.7%) (B).