title: Relamorelin Relieves Constipation and Accelerates Colonic Transit in a Phase 2, Placebo-Controlled, Randomized Trial.
abstract: OBJECTIVE
  Ghrelin receptors are located in the colon. Relamorelin is a pentapeptide selective agonist of ghrelin receptor 1a with gastric effects, but its effects in the colon are not known. We aimed to evaluate the effects of relamorelin on bowel movements (BMs) and gastrointestinal and colonic transit (CT) in patients with chronic constipation.
  
  
  METHODS
  We performed a study of 48 female patients with chronic constipation who fulfilled the Rome III criteria and had 4 or fewer spontaneous BMs (SBMs)/wk. In a randomized (1:1), double-blind, parallel-group, placebo-controlled trial, the effects of relamorelin (100 μg/d, given subcutaneously) were tested during 14 days after a 14-day baseline, single-blind phase in which patients were given placebo at 2 Mayo Clinic sites. The participants' mean age was 40.6 ± 1.5 y, with a mean body mass index of 25.7 ± 0.6 kg/m(2), with 1.7 ± 0.1 SBM/wk, and a mean stool consistency of 1.2 ± 0.1 on the Bristol scale during this baseline period. The effect of treatment on transit was measured in 24 participants with colonic transit of less than 2.4 (geometric center at 24 h) during the baseline period. Gastric emptying, small-bowel transit, and CT were measured during the last 2 days that patients received relamorelin or placebo. Bowel function was determined from daily diaries kept by patients from days 1 through 28. Study end points were time to first BM, SBMs/wk, complete SBMs/wk, stool form, and ease of stool passage. Effects of relamorelin were assessed by analysis of covariance.
  
  
  RESULTS
  Compared with placebo, relamorelin accelerated gastric emptying half-time (P = .027), small-bowel transit (P = .051), and CT at 32 hours (P = .040) and 48 hours (P = .017). Relamorelin increased the number of SBMs (P < .001) and accelerated the time to first BM after the first dose was given (P = .004) compared with placebo, but did not affect stool form. Adverse events associated with relamorelin included increased appetite, fatigue, and headache.
  
  
  CONCLUSIONS
  Relamorelin acts in the colon to significantly reduce symptoms of constipation and accelerate CT in patients with chronic constipation, compared with placebo. ClinicalTrial.Gov registration number: NCT01781104.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Andres
authors.initials: A
authors.lastname: Acosta
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota. Electronic address: camilleri.michael@mayo.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gururaj
authors.initials: G
authors.lastname: Kolar
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Johanna
authors.initials: J
authors.lastname: Iturrino
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Szarka
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Amy
authors.initials: A
authors.lastname: Boldingh
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael
authors.initials: M
authors.lastname: Ryks
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Deborah
authors.initials: D
authors.lastname: Rhoten
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
authors.affiliation: Rhythm Pharmaceuticals, Boston, Massachusetts.
authors.forename: Sharon C
authors.initials: SC
authors.lastname: Spence
authors.affiliation: Rhythm Pharmaceuticals, Boston, Massachusetts.
authors.forename: Keith
authors.initials: K
authors.lastname: Gottesdiener
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Jacksonville, Florida.
authors.forename: Ernest P
authors.initials: EP
authors.lastname: Bouras
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Jacksonville, Florida.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Vazquez-Roque
mesh_terms: D000328:Adult; D003106:Colon / Q000187:drug effects*; D003248:Constipation / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage*; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D007279:Injections, Subcutaneous; D009842:Oligopeptides / Q000008:administration & dosage*; D010919:Placebos / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D005765:Gastrointestinal Agents; D009842:Oligopeptides; D010919:Placebos; C000593860:relamorelin
keywords: Bowel Function; Gastric Emptying; Ghrelin Receptor; SBTT