title: Responders vs clinical response: a critical analysis of data from linaclotide phase 3 clinical trials in IBS-C.
abstract: BACKGROUND
  US Food and Drug Administration (FDA) set a rigorous standard for defining patient responders in irritable bowel syndrome-C (IBS-C; i.e., FDA's Responder Endpoint) for regulatory approval. However, this endpoint's utility for health-care practitioners to assess clinical response has not been determined. We analyzed pooled IBS-C linaclotide trial data to evaluate clinically significant responses in linaclotide-treated patients who did not meet the FDA responder definition.
  
  
  METHODS
  Percentages of FDA non-responders reporting improvement in abdominal pain, bowel function and/or global relief measures were determined using pooled data from two linaclotide Phase 3 IBS-C trials.
  
  
  RESULTS
  1602 IBS-C patients enrolled; 34% of linaclotide-treated and 17% of placebo-treated patients met the FDA Responder Endpoint (p < 0.0001). Among FDA non-responders at week 12, 63% of linaclotide-treated patients reported their abdominal pain was at least somewhat relieved, compared with 48% of placebo-treated patients. For stool frequency, 62% of linaclotide-treated patients reported that they were at least somewhat improved at week 12, compared with 46% of placebo-treated patients. For global IBS symptoms, 65% of linaclotide-treated patients reported at least some IBS-symptom relief, 43% reported adequate relief of IBS symptoms, and 57% reported being satisfied with linaclotide treatment, vs placebo rates of 48%, 34%, and 41% respectively.
  
  
  CONCLUSIONS
  Most linaclotide-treated IBS-C patients who were FDA non-responders reported some improvement in abdominal pain and stool frequency, and global relief/satisfaction. In addition to the FDA Responder Endpoint, differing response thresholds and symptom-specific change from baseline should be considered by clinicians for a complete understanding of clinical response to linaclotide and other IBS-C therapies.
authors.affiliation: Division of Gastroenterology & Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
authors.forename: B E
authors.initials: BE
authors.lastname: Lacy
authors.forename: A J
authors.initials: AJ
authors.lastname: Lembo
authors.forename: J E
authors.initials: JE
authors.lastname: Macdougall
authors.forename: S J
authors.initials: SJ
authors.lastname: Shiff
authors.forename: C B
authors.initials: CB
authors.lastname: Kurtz
authors.forename: M G
authors.initials: MG
authors.lastname: Currie
authors.forename: J M
authors.initials: JM
authors.lastname: Johnston
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D010455:Peptides; C523483:linaclotide
keywords: IBS-C; abdominal pain; clinical response; complete spontaneous bowel movement; guanylate cyclase type-C receptor