title: Glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of hypersalivation induced by clozapine (GOTHIC1): study protocol for a randomised controlled feasibility study.
abstract: Clozapine is the only medication licensed for the treatment of resistant schizophrenia in the UK. Although efficacious, a common and unpopular side effect of clozapine treatment is clozapine-induced hypersalivation (CIH), which can contribute to non-adherence. The standard treatment for CIH in the UK is hyoscine hydrobromide but this may aggravate cognitive deficits in patients with schizophrenia while glycopyrrolate may be an effective alternative with a more tolerable side effect profile. There is currently no convincing evidence for hyoscine, or any other medication, as an effective treatment for CIH.
  
  
  
  This is a multicentre randomised, double-blind, placebo-controlled feasibility study of glycopyrronium bromide (glycopyrrolate) and hyoscine hydrobromide (hyoscine) in patients with clozapine-induced hypersalivation. We aim to recruit 42 patients who have been prescribed clozapine and are experiencing hypersalivation, and randomise them to one of three study arms (either hyoscine, glycopyrrolate or placebo). The primary outcome measures will be the participant recruitment and attrition rates, and the secondary outcome will be the metrics of the daytime hypersalivation measure. After a 1-week washout period (discontinuing CIH medication, if any), there will be a 4-week treatment period where participants will be titrated up to the maximum tolerated dose of hyoscine, glycopyrrolate or placebo. Measurements of daytime salivation, nocturnal salivation, cognition and side effects will be taken during home visits in week 2 and week 5. Information on salivation and side effects will also be taken through telephone calls in week 3 and week 4. To gather information on the experience of study participants, exit interviews will also be requested with all participants who drop out of the study and a sample of participants who complete the study.
  
  
  
  There is currently no convincing evidence for hyoscine, or any other medication, as an effective treatment for CIH. There is promising evidence that glycopyrrolate may be more successful in the treatment of CIH causing fewer cognitive side effects. We propose to conduct a randomised placebo-controlled feasibility study of glycopyrrolate and hyoscine in the treatment of clozapine-induced hypersalivation to inform the design of a future efficacy trial.
  
  
  
  Clinicaltrials.gov NCT02613494 , 23 November 2015.
authors.affiliation: Ashworth Research Centre, Mersey Care NHS Foundation Trust, Liverpool, UK.|Institute of Mind, Brain and Behaviour, University of Manchester, Manchester, UK.
authors.forename: Inti
authors.initials: I
authors.lastname: Qurashi
authors.affiliation: Ashworth Research Centre, Mersey Care NHS Foundation Trust, Liverpool, UK. simon.chu@merseycare.nhs.uk.|School of Psychology, University of Central Lancashire, Preston, UK. simon.chu@merseycare.nhs.uk.
authors.forename: Simon
authors.identifier: 0000-0001-8921-4942
authors.initials: S
authors.lastname: Chu
authors.affiliation: Institute of Mind, Brain and Behaviour, University of Manchester, Manchester, UK.
authors.forename: Nusrat
authors.initials: N
authors.lastname: Husain
authors.affiliation: Institute of Mind, Brain and Behaviour, University of Manchester, Manchester, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Drake
authors.affiliation: Institute of Mind, Brain and Behaviour, University of Manchester, Manchester, UK.
authors.forename: Imran
authors.initials: I
authors.lastname: Chaudhry
authors.affiliation: Institute of Mind, Brain and Behaviour, University of Manchester, Manchester, UK.
authors.forename: J F W
authors.initials: JF
authors.lastname: Deakin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000009:adverse effects*; D002985:Clinical Protocols; D003024:Clozapine / Q000009:adverse effects*; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D006024:Glycopyrrolate / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D012107:Research Design; D012472:Salivation / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy*; D012601:Scopolamine / Q000009:adverse effects / Q000627:therapeutic use*; D012798:Sialorrhea / Q000139:chemically induced / Q000175:diagnosis / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D018727:Muscarinic Antagonists; D012601:Scopolamine; D003024:Clozapine; D006024:Glycopyrrolate
keywords: Adult; Clozapine; Feasibility; Glycopyrrolate; Hyoscine; Randomised trial; Sialorrhea