Title: A feasibility trial of glycopyrrolate in comparison to hyoscine hydrobromide and placebo in the treatment of clozapine-induced hypersalivation.
Funder: Department of Health and Social Care

Abstract: The research question Can a multi-centre randomised double-blind placebo-controlled efficacy trial of glycopyrrolate compared to hyoscine hydrobromide for the treatment of clozapine-induced hypersalivation be conducted in the NHS? Background One of the most debilitating side-effects of clozapine is hypersalivation occurring in 30-80% of patients. Clozapine-induced hypersalivation (CIH) is a profoundly socially stigmatizing side effect that contributes to medical complications and non-adherence. There are no licensed treatments for CIH and a Cochrane review of treatments for CIH noted there was insufficient evidence to inform clinical practice. A recent small non-UK trial showed promising evidence for oral glycopyrrolate in the treatment of CIH with minimal effect on cognitive functioning compared to treatment as usual. However the hypersalivation measure used in the trial has not previously been used in the UK, routine measures for side effects to assess tolerability were not used and community patients were not recruited. Aims As a step towards a future four site, randomised, double-blind, placebo-controlled trial of glycopyrrolate and hyoscine in the treatment of CIH we aim to: 1. Assess the feasibility of recruiting community and in-patients from different centres because the future efficacy trial will require recruitment from different types of unit. In particular to: a. demonstrate that the trial design is acceptable to participants including randomisation and use of telephone interviews. b. demonstrate that the interventions are acceptable to participants and indicate likely attrition rates and tolerability. 2. Ascertain the standard deviation of the daytime hypersalivation measure to estimate the required sample size for a future RCT. Research Plan This feasibility study will involve participants in a 5-week (1 week wash-out and 4 weeks active treatment) double-blind, randomised, placebo-controlled trial of oral hyoscine hydrobromide and oral glycopyrrolate. Participants will be capacitous, consenting, in-patients and community patients with CIH. We plan to recruit 42 patients in 12 months across three mental health trusts in the North-West. A clinical trials unit (Manchester Academic Health Sciences Centre - Trials Coordination Unit) will randomise patients to each of three study arms; glycopyrrolate, hyoscine and placebo. Measures of salivation and side-effects will be completed weekly by telephone and tests of cognitive functioning will be completed at the start and end of the study medication period in person by a Research Assistant. With a service user researcher we plan to conduct exit interviews with all participants who drop out of the study and a sample of participants who complete the study to gather data on participants experiences of the trial. At the end of the study, we will have data on recruitment and attrition rates, tolerability of the medication and generated essential metrics for the daytime salivation measures to be used in the future full RCT. We will also explore the feasibility of collecting information on hypersalivation and side-effects using weekly telephone calls assessing whether telephone consultations are acceptable to trial participants. Likely benefits of the proposed research to patients and NHS This research proposal is important in terms of improving patient health, well-being (by reducing the side-effect burden and consequences of CIH), and satisfaction with treatment. CIH leads to many secondary problems both medical (e.g. skin infections, aspiration pneumonia) and social (stigma and social withdrawal). Reducing relapse rates reduces risk of harm to the patient and others. Establishing a treatment for CIH that is clinically effective, tolerable and less likely to aggravate cognitive deficits in schizophrenia would benefit patients. For the NHS the importance lies in reducing non-adherence with clozapine treatment. For example, one study found that over 10% of patients discontinued clozapine treatment because of its side effects and the economic and health implications of relapse in schizophrenia are considerable.

Lay abstract: For some people with schizophrenia the only medicine that alleviates their symptoms is an antipsychotic medication called clozapine but unfortunately it also causes many people to produce far too much saliva (hypersalivation). A survey of people taking clozapine within Mersey Care NHS Trust found hypersalivation to be the most unacceptable side effect of clozapine; it is an embarrassing- and socially stigmatizing side-effect causing social withdrawal and disturbed sleep. Hyoscine hydrobromide is usually prescribed to treat hypersalivation but there is no convincing information about how effective it is. Hyoscine also causes side-effect that cause problems (e.g. confusion, poor concentration) which may contribute to a poorer long-term outcome for patients with schizophrenia. There have been encouraging results from small studies investigating a medication called glycopyrrolate for the treatment of hypersalivation. Although the evidence indicates it may be effective, its use may be limited by side effects and patients have not been asked which medication they would prefer if different treatments were similarly effective. In the longer term we want to conduct a large clinical trial to examine several important issues; which (if any) of the two medicines, hyoscine hydrobromide and glycopyrrolate, is most effective in treating hypersalivation? Which medication causes the least thinking side effects? Which medication do patients prefer? We propose to conduct a preliminary (feasibility) study to answer some important questions to inform the design of a larger future trial. These are: 1. Will our proposed study design be acceptable to potential participants? a) Are in-patient and community patients willing to join such a study? b) Are the medications tolerated by participants,if they drop out what are the reasons and what can we change? 2. Are the hypersalivation assesments suitable for use in a UK population and how many participants will we need in a future large randomised controlled trial?

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;ORAL AND GASTROINTESTINAL