title: Libertas: a phase II placebo-controlled study of NRL001 in patients with faecal incontinence showed an unexpected and sustained placebo response.
abstract: OBJECTIVE
  Faecal incontinence (FI) is distressing, significantly reduces quality of life (QoL) and has few pharmacological treatments. The α1-adrenoceptor agonist NRL001 (1R,2S-methoxamine hydrochloride) improves anal sphincter tone. NRL001 efficacy was evaluated by changes in Wexner scores at week 4 vs. baseline in NRL001-treated patients compared with placebo. Impact of NRL001 on QoL and safety were also assessed.
  
  
  METHODS
  Four hundred sixty-six patients received NRL001 (5, 7.5 or 10 mg) or placebo as suppository, once daily over 8 weeks. Wexner score, Vaizey score and QoL were analysed at baseline, week 4 and week 8. FI episodes and adverse events were recorded in diaries.
  
  
  RESULTS
  At week 4, mean reductions in Wexner scores were -3.0, -2.6, -2.6 and -2.4 for NRL001 5, 7.5, 10 mg and placebo, respectively. All reduced further by week 8. As placebo responses also improved, there was no significant treatment effect at week 4 (p = 0.6867) or week 8 (p = 0.5005). FI episode frequency improved for all patients, but not significantly compared with placebo (week 4: p = 0.2619, week 8: p = 0.5278). All patients' QoL improved, but not significantly for all parameters (p > 0.05) except depression/self-perception at week 4 (p = 0.0102) and week 8 (p = 0.0069), compared with placebo. Most adverse events were mild and judged probably or possibly related to NRL001.
  
  
  CONCLUSIONS
  All groups demonstrated improvement in efficacy and QoL compared with baseline. NRL001 was well-tolerated without serious safety concerns. Despite the improvement in all groups, there was no statistically significant treatment effect, underlining the importance of relating results to a placebo arm.
authors.affiliation: CHU Pontchaillou, Rennes, France.
authors.forename: L
authors.initials: L
authors.lastname: Siproudhis
authors.affiliation: Institution of Surgical Sciences, Akademiska Sjukhuset, Uppsala University, 75185, Uppsala, Sweden.
authors.forename: W
authors.initials: W
authors.lastname: Graf
authors.affiliation: University College Hospital, 235 Euston Road, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Emmanuel
authors.affiliation: Norgine Ltd, Norgine House, Widewater Place, Moorhall Road, Uxbridge, UB9 6NS, UK. dwalker@norgine.com.
authors.forename: D
authors.initials: D
authors.lastname: Walker
authors.affiliation: Norgine Ltd, Norgine House, Widewater Place, Moorhall Road, Uxbridge, UB9 6NS, UK.
authors.forename: R Ng Kwet
authors.initials: RN
authors.lastname: Shing
authors.affiliation: Norgine Ltd, Norgine House, Widewater Place, Moorhall Road, Uxbridge, UB9 6NS, UK.
authors.forename: C
authors.initials: C
authors.lastname: Pediconi
authors.affiliation: Norgine Ltd, Norgine House, Widewater Place, Moorhall Road, Uxbridge, UB9 6NS, UK.
authors.forename: J
authors.initials: J
authors.lastname: Pilot
authors.affiliation: Cleveland Clinic Florida, Weston, FL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wexner
authors.affiliation: Division of Surgery, University Hospital Nottingham, Nottingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Scholefield
mesh_terms: D003710:Demography; D005242:Fecal Incontinence / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008729:Methoxamine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D017060:Patient Satisfaction; D010919:Placebos; D011788:Quality of Life; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
chemical_list: D010919:Placebos; D008729:Methoxamine
keywords: Alpha-1 receptor agonist; Episode frequency; Faecal incontinence; NRL001; Quality of life