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

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. 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. 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. 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. Timelines: 48 month study duration with 33 month recruitment period. 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.