title: 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.
abstract: OBJECTIVE
  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 μ 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.
authors.affiliation: Section of Gastroenterology / Hepatology, Georgia Health Sciences University , Augusta , Georgia , USA.
authors.forename: Satish
authors.initials: S
authors.lastname: Rao
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Lembo
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Shiff
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Lavins
authors.forename: Mark G
authors.initials: MG
authors.lastname: Currie
authors.forename: Xinwei D
authors.initials: XD
authors.lastname: Jia
authors.forename: Kelvin
authors.initials: K
authors.lastname: Shi
authors.forename: James E
authors.initials: JE
authors.lastname: MacDougall
authors.forename: James Z
authors.initials: JZ
authors.lastname: Shao
authors.forename: Paul
authors.initials: P
authors.lastname: Eng
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fox
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Schneier
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Kurtz
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Johnston
mesh_terms: D015746:Abdominal Pain / Q000175:diagnosis; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D003248:Constipation / Q000188:drug therapy*; D004311:Double-Blind Method; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010919:Placebos; D016896:Treatment Outcome
chemical_list: D010455:Peptides; D010919:Placebos; C523483:linaclotide