Title: GOTHIC2: A multi-centre randomised placebo-controlled trial of glycopyrrolate and hyoscine hydrobromide for the treatment of clozapine-induced hypersalivation.
Funder: Medical Research Council

Abstract: Why this study is needed: Clozapine is a medication used to treat schizophrenia when other medications have not helped and there are no alternatives. When patients begin taking clozapine they, in almost all cases, will be taking it for the rest of their lives. Clozapine can cause serious side effects and one of the most distressing is excessive drooling, called clozapine-induced hypersalivation (CIH). CIH can cause serious physical health problems, such as pneumonia and mouth ulcers and psychological problems such as reduced self-esteem. Without treatment CIH can lead patients to stop clozapine which almost always results in worsening schizophrenia symptoms and increases the risk of suicide and long admission to a psychiatric hospital. At the moment there is no proven treatment for CIH. The medication that is usually prescribed for CIH is called hyoscine, but the evidence that hyoscine can reduce CIH is very weak. Also, hyoscine can cause unpleasant side effects such as bowel problems (constipation) and thinking problems (causing problems with attention and concentration). Some studies suggest that a different medication, called glycopyrrolate, might be helpful for CIH and may cause fewer thinking problems because it does not enter the brain like hyoscine does. However, it may still cause other side effects like constipation. It is important to know which medications may improve CIH and what side effects are caused by them so patients can make an informed choice based on their mental illness symptoms and experience of side-effects._x000D_ Aims: To conduct a clinical trial to find out if either of hyoscine or glycopyrrolate can improve CIH by comparing patients taking these medications with patients taking a dummy treatment (placebo). If they both reduce CIH, we will compare the two medications to see which one causes fewer thinking and other side effects and assess patient preference. _x000D_ Methods: We will recruit 252 patients with CIH from oupatients and inpatients from eight NHS mental health trusts. There are two stages to the study; in the first 12-week stage, patients will be randomly put into one of three groups to receive either hyoscine, glycopyrrolate or placebo. Neither the patient nor the researchers will know which group anyone has been assigned to. In this stage we will regularly measure drooling, thinking, constipation and all possible side effects in order to see what effect the medication has. We will also measure how much clozapine is in the participants’ blood to see if that affects symptoms of schizophrenia and side effects. At the end of this stage the person will be given the option of staying on the medication they have been taking or leaving the trial. If they opt to continue they will be told which medication they have been receiving and in the second phase of the trial, which will last a further 12 weeks, he/she will be followed up every four weeks to measure drooling, constipation and side effects in the same way as before. This phase of the study is designed to obtain longer term information on safety and participant preference about the study medication. This will be the first time this method has been used in a study of CIH and will be the longest funded trial of CIH medication that has been conducted. This trial will provide the first reliable evidence about whether medication for CIH is helpful and will help patients with CIH to decide what medication is better for them based on individual symptom characteristics.

Lay abstract: Research Question: Are either hyoscine or glycopyrrolate medication more efficacious than placebo in the treatment of clozapine induced hypersalivation (CIH) and which is associated with fewer cognitive and other side-effects._x000D_ Background: Clozapine is the only effective antipsychotic for schizophrenia that has not responded to other medication. Clozapine has a high burden of side-effects including hypersalivation (excessive drooling) experienced by up to 85%. There are no licensed drug treatments for CIH and left untreated many patients stop clozapine leading to relapse and hospitalisation. The usual treatment for CIH is hyoscine however the evidence base for efficacy is weak and because it crosses the blood brain barrier (BBB) it can cause additional problems including worsening hallucinations and impaired cognition (e.g. verbal memory, attention and concentration) that are closely linked to poor long-term outcomes in schizophrenia. Hyoscine also has peripheral nervous system actions that increase the risk of constipation (already high with clozapine) and of life-threatening paralytic ileus. Recently an alternative treatment, glycopyrronium bromide (glycopyrrolate), has been used to treat CIH. Early evidence suggests that glycopyrrolate may be effective in treating CIH whilst being better tolerated in comparison to hyoscine mainly because reduced penetration of the BBB minimises central nervous system anticholinergic adverse effects. It offers the hope of targeting the important problem of CIH without aggravating cognitive impairment or hallucinations. However, glycopyrrolate may also cause or worsen peripheral nervous anticholinergic side-effects. _x000D_ Research Aim: To assess the efficacy of hyoscine and glycopyrrolate for CIH; their side effects, tolerability and safety profile to inform a risk/benefit analysis._x000D_ Study methods: A multi-centre double-blind, randomised, placebo-controlled trial of oral hyoscine or oral glycopyrrolate of patients with CIH and the trial will comprise a 12 week placebo RCT period followed by a 12 week open label phase. The trial uses a gateway approach in that the first hypothesis tests both active arms against placebo for reduction in hypersalivation. The secondary objectives are only evaluated if both actives are superior to placebo. During the RCT period efficacy, safety and tolerability data will be collected by research assistants (RA) during three visits: baseline (prior to randomisation), week 6 and week 12 with intervening telephone assessments for community patients. The primary outcome is change in Drooling Rating Scale (DRS). During the open label phase unblinded participants who wish to remain on the study intervention will be followed up with additional data points (efficacy, side-effects, adverse events) at weeks 16, 20 and 24 with telephone/case note reviews. We aim to recruit 252 participants (84 per arm) and the trial is powered to detect the minimum clinically important difference of one point on the DRS. _x000D_ Timelines: 48 month study duration with 33 month recruitment period._x000D_ The anticipated impact is providing, for the first time, high quality evidence for effective and tolerable treatment(s) for CIH, reducing clozapine discontinuation that in almost all cases leads to hospitalisation and increased NHS costs and providing clinicians with information to make patient-centred treatment decisions based on pre-existing symptom profiles.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL