title: The neurokinin-2 receptor antagonist ibodutant improves overall symptoms, abdominal pain and stool pattern in female patients in a phase II study of diarrhoea-predominant IBS.
abstract: Tachykinins have been implicated in the pathophysiology of IBS with diarrhoea (IBS-D). Our aim was to study the efficacy and safety of ibodutant, a selective neurokinin-2 (NK2) receptor antagonist, in patients with IBS-D.
  
  
  
  This multinational double-blind, placebo-controlled study recruited 559 patients with IBS-D according to Rome III criteria. After a 2-week treatment-free run-in, patients were randomised to ibodutant 1 mg, 3 mg, 10 mg or placebo once daily for eight consecutive weeks. Responders were those with a combined response of satisfactory relief (weekly binary question yes/no) of overall IBS symptoms and abdominal pain/discomfort on ≥75% weeks (primary end point). Secondary end points included abdominal pain and stool pattern. Data were also analysed according to US Food and Drug Administration (FDA)-approved interim end points (improvement of pain and stool consistency). Safety was assessed by monitoring adverse events and laboratory tests. Prespecified statistical analysis involved the whole group as well as gender subgroups.
  
  
  
  Demographics and baseline characteristics were comparable for all treatment arms. In the overall population, responsiveness tended to increase with escalating ibodutant doses. In the prespecified analysis by gender, ibodutant 10 mg demonstrated significant superiority over placebo in females (p=0.003), while no significant effect occurred in males. This was confirmed for secondary end points and for the responder analysis according to FDA-approved end points. The tolerability and safety of ibodutant was excellent at all doses.
  
  
  
  Ibodutant showed dose-dependent efficacy response in IBS-D, reaching statistical significance at the 10 mg dose in female patients. The safety and tolerability profile of ibodutant was similar to placebo.
  
  
  
  NCT01303224.
authors.affiliation: Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Tack
authors.affiliation: Menarini Research & Business Service GmbH, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Schumacher
authors.affiliation: Menarini Ricerche S.p.A, Florence, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tonini
authors.affiliation: Menarini Ricerche S.p.A, Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Scartoni
authors.affiliation: Menarini Ricerche S.p.A, Florence, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Capriati
authors.affiliation: Menarini Ricerche S.p.A, Florence, Italy.
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
mesh_terms: D015746:Abdominal Pain / Q000209:etiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D003967:Diarrhea / Q000209:etiology; D004151:Dipeptides / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D012737:Sex Factors; D063189:Symptom Assessment; D013876:Thiophenes / Q000009:adverse effects / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D004151:Dipeptides; D005765:Gastrointestinal Agents; D018041:Receptors, Neurokinin-2; D013876:Thiophenes; C556791:ibodutant
keywords: CLINICAL TRIALS; IRRITABLE BOWEL SYNDROME; MOTILITY DISORDERS; NEUROGASTROENTEROLOGY; VISCERAL SENSITIVITY