Shadreck M. Mareya

Rifaximin Therapy for Patients with Irritable Bowel Syndrome without Constipation

BACKGROUND Evidence suggests that gut flora may play an important role in the pathophysiology of the irritable bowel syndrome (IBS). We evaluated rifaximin, a minimally absorbed antibiotic, as treatment for IBS. METHODS In two identically designed, phase 3, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2), patients who had IBS without constipation were randomly assigned to either rifaximin at a dose of 550 mg or placebo, three times daily for 2 weeks, and were followed for an additional 10 weeks. The primary end point, the proportion of patients who had adequate relief of global IBS symptoms, and the key secondary end point, the proportion of patients who had adequate relief of IBS-related bloating, were assessed weekly. Adequate relief was defined as self-reported relief of symptoms for at least 2 of the first 4 weeks after treatment. Other secondary end points included the percentage of patients who had a response to treatment as assessed by daily self-ratings of global IBS symptoms and individual symptoms of bloating, abdominal pain, and stool consistency during the 4 weeks after treatment and during the entire 3 months of the study. RESULTS Significantly more patients in the rifaximin group than in the placebo group had adequate relief of global IBS symptoms during the first 4 weeks after treatment (40.8% vs. 31.2%, P=0.01, in TARGET 1; 40.6% vs. 32.2%, P=0.03, in TARGET 2; 40.7% vs. 31.7%, P<0.001, in the two studies combined). Similarly, more patients in the rifaximin group than in the placebo group had adequate relief of bloating (39.5% vs. 28.7%, P=0.005, in TARGET 1; 41.0% vs. 31.9%, P=0.02, in TARGET 2; 40.2% vs. 30.3%, P<0.001, in the two studies combined). In addition, significantly more patients in the rifaximin group had a response to treatment as assessed by daily ratings of IBS symptoms, bloating, abdominal pain, and stool consistency. The incidence of adverse events was similar in the two groups. CONCLUSIONS Among patients who had IBS without constipation, treatment with rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools. (Funded by Salix Pharmaceuticals; ClinicalTrials.gov numbers, NCT00731679 and NCT00724126.).

Safety and Efficacy of a New 3.3 g b.i.d. Tablet Formulation in Patients With Mild-to-Moderately-Active Ulcerative Colitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study

OBJECTIVES:To evaluate the safety and efficacy of a new twice-daily balsalazide disodium 1.1 g tablet dosing regimen (6.6 g/day, three tablets twice daily) for the treatment of mild-to-moderately-active ulcerative colitis (UC).METHODS:In a double-blind, multicenter study patients with symptoms of acute UC and a baseline Modified Mayo Disease Activity Index (MMDAI) score between 6 and 10, inclusive, with a subscale rating of ≥2 for both rectal bleeding and mucosal appearance were randomized to receive 3.3 g of balsalazide or placebo tablets twice daily for 8 weeks. The primary end point was the proportion of patients achieving clinical improvement (≥3 point improvement in MMDAI) and improvement in rectal bleeding (≥1 point improvement) at 8 weeks. Safety assessments were conducted from baseline through 2-weeks post-treatment.RESULTS:A total of 249 patients (166 balsalazide, 83 placebo) received at least 1 dose of study medication. The mean MMDAI score at baseline was 7.9; 62% of patients had a score ≥8.0 (moderate disease). A significantly larger proportion of patients achieved clinical improvement and improvement in rectal bleeding in the balsalazide group vs. the placebo group (55 vs. 40%, P=0.02). The most common adverse events reported were worsening of UC and headache; both were reported more often in the placebo group.CONCLUSIONS:Balsalazide disodium 1.1 g tablets administered as 3.3 g twice daily are effective, well tolerated and significantly better than placebo for improving signs and symptoms of mild-to-moderately-active UC. This new formulation with a reduced pill and dosing burden offers the potential to improve convenience and compliance in patients with active UC.

Sa1394 Durability and Predictability of Response to Lubiprostone in Patients With Opioid-Induced Constipation

Background: Lubiprostone is a ClC-2 chloride channel activator that is efficacious for treating opioid-induced constipation (OIC) in patients receiving opioids (other than methadone) for chronic, non-cancer pain. This exploratory analysis examined whether an early clinical response by week 3 predicted a durable response during the remaining 9 weeks in pivotal studies of patients with OIC who were treated with lubiprostone (24 mcg twice daily) or received placebo. Methods: Data were pooled from three 12-week, randomized, placebocontrolled, double-blind studies in patients ≥18 years old with OIC who were treated with opioids for chronic, non-cancer pain. Analyses were conducted with the intent-to-treat (ITT) population, excluding patients who received methadone. Response durability was analyzed among early responders, defined as patients who had a response in at least 2 of the first 3 weeks of the study. To be considered a weekly responder, a patient must have reported ≥3 spontaneous bowel movements (SBMs) and an increase in frequency of ≥1 SBM over baseline for a given week. An SBM was defined as any bowel movement that did not occur within 24 hours after the use of rescue medication. A generalized estimating equation (GEE) model was developed to estimate the overall treatment difference. Missing data were imputed using the last observation carried forward method. Results: Among early responders (lubiprostone, n=323; placebo, n=277), the initial (week 4) responder rates were 82.7% and 77.3% in patients treated with lubiprostone and placebo, respectively. Response rates throughout the treatment period were consistently and statistically significantly higher (P=0.049; GEEmodel) in patients treated with lubiprostone compared with those who received placebo. The early response at week 3 was significantly more durable (mean, 5.0 vs 4.0 weeks; P<0.001; 2sample t test) in patients treated with lubiprostone compared with those who received placebo. The percentage of continuous responders for all 3 months (ie, response in at least 3 weeks of every 4-week period) was significantly higher in patients treated with lubiprostone, compared with those who received placebo, both in the ITT population (39.1% vs 30.5%; P=0.004; Cochran-Mantel-Haenszel test, stratified by pooled study site) and in the perprotocol population (40.8% vs 29.5%; P=0.002). Monthly exposure to rescue medication was similar at baseline in either treatment group (mean, 1.7 days), but was significantly lower at months 1 (P=0.048) and 2 (P=0.031) in patients treated with lubiprostone compared with those who received placebo. Lubiprostone was well tolerated in these studies; the majority of adverse events were mild or moderate. Conclusions: Early responders treated with lubiprostone maintained significantly higher treatment response rates over time compared with patients who received placebo.