title: Comparison of adequate relief with symptom, global, and responder endpoints in linaclotide phase 3 trials in IBS-C.
abstract: BACKGROUND
  Optimal clinical trial endpoints for irritable bowel syndrome with constipation (IBS-C) are uncertain.
  
  
  OBJECTIVE
  The objective of this article is to compare adequate relief (AR) to abdominal/bowel symptoms, global endpoints, and FDA and EMA responder criteria; and to use AR as an anchor to assess clinically meaningful change (CMC) in IBS-C symptoms.
  
  
  METHODS
  Using pooled 12-week data from two phase 3 linaclotide clinical trials, daily abdominal/bowel symptoms and weekly global assessments were correlated with AR. Symptom CMC thresholds were estimated using AR as an anchor. Agreement between AR and FDA/EMA responder criteria was assessed.
  
  
  RESULTS
  Correlations of AR with percentage change in abdominal symptoms, bowel symptoms, and global endpoints ranged from 0.48-0.54, 0.32-0.39, and 0.61-0.71, respectively. Using AR as an anchor, CMC thresholds were 29% improvement in abdominal pain, 29% improvement in abdominal discomfort, and 0.7/week increase in CSBMs, similar to thresholds for IBS-C responder endpoints recommended by the FDA and EMA. There was considerable agreement of weekly responder rates between AR and the FDA and EMA endpoints (on average, 70%-76% and 71%-82% of weeks with agreement, respectively).
  
  
  CONCLUSIONS
  AR bridges IBS-C clinical trials, putting into perspective the disparate primary endpoints recommended by professional societies and regulatory authorities, and allowing researchers, practitioners, and regulators to compare trial results.
authors: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors: Michael
authors: M
authors: Camilleri
authors: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors: Anthony J
authors: AJ
authors: Lembo
authors: Ironwood Pharmaceuticals, Cambridge, MA, USA.
authors: Bernard J
authors: BJ
authors: Lavins
authors: Ironwood Pharmaceuticals, Cambridge, MA, USA.
authors: James E
authors: JE
authors: MacDougall
authors: Forest Research Institute, Jersey City, NJ, USA.
authors: Robyn T
authors: RT
authors: Carson
authors: RTI Health Solutions, Research Triangle Park, NC, USA.
authors: Valerie Sl
authors: VS
authors: Williams
authors: RTI Health Solutions, Research Triangle Park, NC, USA.
authors: Lauren M
authors: LM
authors: Nelson
authors: Forest Research Institute, Jersey City, NJ, USA.
authors: Steven J
authors: SJ
authors: Shiff
authors: Ironwood Pharmaceuticals, Cambridge, MA, USA.
authors: Mark G
authors: MG
authors: Currie
authors: Ironwood Pharmaceuticals, Cambridge, MA, USA.
authors: Caroline B
authors: CB
authors: Kurtz
authors: Ironwood Pharmaceuticals, Cambridge, MA, USA.
authors: Jeffrey M
authors: JM
authors: Johnston
keywords: GC-C; IBS-C; Linaclotide; adequate relief; clinically meaningful change; responder endpoints
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