title: P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.
abstract: BACKGROUND
  Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough.
  
  
  METHODS
  We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730.
  
  
  RESULTS
  Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219.
  
  
  CONCLUSIONS
  P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives.
  
  
  BACKGROUND
  Afferent Pharmaceuticals.
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; University Hospital of South Manchester, Education and Research Centre, University Hospital of South Manchester, Manchester, UK.
authors.forename: Rayid
authors.initials: R
authors.lastname: Abdulqawi
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; University Hospital of South Manchester, Education and Research Centre, University Hospital of South Manchester, Manchester, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Dockry
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; University Hospital of South Manchester, Education and Research Centre, University Hospital of South Manchester, Manchester, UK.
authors.forename: Kimberley
authors.initials: K
authors.lastname: Holt
authors.affiliation: ParamStat Ltd, Ash, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Layton
authors.affiliation: Afferent Pharmaceuticals, San Mateo, CA, USA.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: McCarthy
authors.affiliation: Afferent Pharmaceuticals, San Mateo, CA, USA.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Ford
authors.affiliation: Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; University Hospital of South Manchester, Education and Research Centre, University Hospital of South Manchester, Manchester, UK. Electronic address: jacky.smith@manchester.ac.uk.
authors.forename: Jaclyn A
authors.initials: JA
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D000996:Antitussive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D002940:Circadian Rhythm; D003371:Cough / Q000188:drug therapy*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058920:Purinergic P2X Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use; D012720:Severity of Illness Index; D013449:Sulfonamides; D016896:Treatment Outcome; D055815:Young Adult; D000096926:Benzenesulfonamides
chemical_list: D000996:Antitussive Agents; D058920:Purinergic P2X Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; C000597312:Gefapixant; D000096926:Benzenesulfonamides