title: Two randomized trials of linaclotide for chronic constipation.
abstract: BACKGROUND
  Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase C receptor. In two trials, we aimed to determine the efficacy and safety of linaclotide in patients with chronic constipation.
  
  
  METHODS
  We conducted two randomized, 12-week, multicenter, double-blind, parallel-group, placebo-controlled, dual-dose trials (Trials 303 and 01) involving 1276 patients with chronic constipation. Patients received either placebo or linaclotide, 145 μg or 290 μg, once daily for 12 weeks. The primary efficacy end point was three or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks. Adverse events were also monitored.
  
  
  RESULTS
  For Trials 303 and 01, respectively, the primary end point was reached by 21.2% and 16.0% of the patients who received 145 μg of linaclotide and by 19.4% and 21.3% of the patients who received 290 μg of linaclotide, as compared with 3.3% and 6.0% of those who received placebo (P<0.01 for all comparisons of linaclotide with placebo). Improvements in all secondary end points were significantly greater in both linaclotide groups than in the placebo groups. The incidence of adverse events was similar among all study groups, with the exception of diarrhea, which led to discontinuation of treatment in 4.2% of patients in both linaclotide groups.
  
  
  CONCLUSIONS
  In these two 12-week trials, linaclotide significantly reduced bowel and abdominal symptoms in patients with chronic constipation. Additional studies are needed to evaluate the potential long-term risks and benefits of linaclotide in chronic constipation. (Funded by Ironwood Pharmaceuticals and Forest Research Institute; ClinicalTrials.gov numbers, NCT00765882 and NCT00730015.).
authors.affiliation: Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, MA, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Lembo
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Schneier
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Shiff
authors.forename: Caroline B
authors.initials: CB
authors.lastname: Kurtz
authors.forename: James E
authors.initials: JE
authors.lastname: MacDougall
authors.forename: Xinwei D
authors.initials: XD
authors.lastname: Jia
authors.forename: James Z
authors.initials: JZ
authors.lastname: Shao
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Lavins
authors.forename: Mark G
authors.initials: MG
authors.lastname: Currie
authors.forename: Donald A
authors.initials: DA
authors.lastname: Fitch
authors.forename: Brenda I
authors.initials: BI
authors.lastname: Jeglinski
authors.forename: Paul
authors.initials: P
authors.lastname: Eng
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fox
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Johnston
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D003248:Constipation / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced; D004311:Double-Blind Method; D005260:Female; D006162:Guanylate Cyclase; D006801:Humans; D054368:Laxatives / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D050705:Receptors, Guanylate Cyclase-Coupled / Q000819:agonists; D028761:Withholding Treatment; D055815:Young Adult
chemical_list: D054368:Laxatives; D010455:Peptides; D006162:Guanylate Cyclase; D050705:Receptors, Guanylate Cyclase-Coupled; C523483:linaclotide