A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With Constipation

作者：Rao, Satish; Lembo, Anthony J.; Shiff, Steven J.; Lavins, Bernard J.; Currie, Mark G.; Jia, Xinwei D.; Shi, Kelvin; MacDougall, James E.; Shao, James Z.; Eng, Paul; Fox, Susan M.; Schneier, Harvey A.; Kurtz, Caroline B.; Johnston, Jeffrey M.^*

来源：American Journal of Gastroenterology, 2012, 107(11): 1714-1724.

DOI：10.1038/ajg.2012.255

• ABDOMINAL-PAIN
• PREVALENCE
• DISORDERS
• PATTERNS
• TRANSIT
• IMPACT

OBJECTIVES: Linaclotide is a minimally absorbed guanylate cyclase-C agonist. The objective of this trial was to determine the efficacy and safety of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C). @@@ METHODS: This phase 3, double-blind, parallel-group, placebo-controlled trial randomized IBS-C patients to placebo or 290 mu g oral linaclotide once daily in a 12-week treatment period, followed by a 4-week randomized withdrawal (RW) period. There were four primary end points, the Food and Drug Administration's (FDA's) primary end point for IBS-C (responder: improvement of >= 30% in average daily worst abdominal pain score and increase by >= 1 complete spontaneous bowel movement (CSBM) from baseline (same week) for at least 50% of weeks assessed) and three other primary end points, based on improvements in abdominal pain and CSBMs for 9/12 weeks. Adverse events (AEs) were monitored. @@@ RESULTS: The trial evaluated 800 patients (mean age=43.5 years, female=90.5%, white=76.9%). The FDA end point was met by 136/405 linaclotide-treated patients (33.6%), compared with 83/395 placebo-treated patients (21.0%) (P<0.0001) (number needed to treat: 8.0, 95% confidence interval: 5.4, 15.5). A greater percentage of linaclotide patients, compared with placebo patients, reported for at least 6/12 treatment period weeks, a reduction of >= 30% in abdominal pain (50.1 vs. 37.5%, P=0.0003) and an increase of >= 1 CSBM from baseline (48.6 vs. 29.6%, P<0.0001). A greater percentage of linaclotide patients vs. placebo patients were also responders for the other three primary end points (P<0.05). Significantly greater improvements were seen in linaclotide vs. placebo patients for all secondary end points (P<0.001). During the RW period, patients remaining on linaclotide showed sustained improvement; patients re-randomized from linaclotide to placebo showed return of symptoms, but without worsening of symptoms relative to baseline. Diarrhea, the most common AE, resulted in discontinuation of 5.7% of linaclotide and 0.3% of placebo patients. @@@ CONCLUSIONS: Linaclotide significantly improved abdominal pain and bowel symptoms associated with IBS-C for at least 12 weeks; there was no worsening of symptoms compared with baseline following cessation of linaclotide during the RW period.

• 出版日期2012-11