The effect of glycopyrroniumbromide oral solution for nocturnal drooling due to the use of clozapine.

Recruting countries: The Netherlands.



Background of the study:

Hypersalivation or sialorrhea is one of the most frequently occuring side effects of clozapine use with an incidence ranging from 30 to 90%. In most cases it occurs at the start of clozapine treatment, mostly at night and persists during further treatment.

Several symptomatic (farmacologic) therapies exists that reduce sialorrhea by reducing saliva excretion. There is no drug therapy registered for clozapine induced sialorrhea and most of the medications that are used often have central side effects.

Glycopyrroniumbromide is a quaternairy ammonium compound and an effective and potent anticholinergic agent with poor penetration across the blood-brain-barrier, causing less central side effects than other anticholinergics. In a number of relatively small studies oral glycopyrroniumbromide was found to be effective in reducing sialorrhea in children with cerebral palsy, patients suffering from Parkinson’s disease and schizophrenic patients using clozapine.
The effect on nocturnal sialorrhea in patients using clozapine compared to placebo has not been studied yet.



Study design:

Double blind, randomized, cross-over trial with an extended open label phase. The length of the study will be 6 weeks in total. The first phase (week 1 up to and including week 4) of the study will be a randomised, double blind, placebo controlled and cross-over design, where an equal amount of glycopyrroniumbromide oral solution 0,2 mg/ml (1 mg = 5 ml) and placebo oral solution are compared. The second phase (week 5 and 6) is an extended open-label phase, with patients receiving a double dose of glycopyrroniumbromide oral solution 0,2 mg/ml (2 mg = 10 ml) if they well tolerated the oral solution in the first phase of the study. In week 1 there will be baseline-measurements. In week 2 and week 4 the patients will take during 6 days oral
glycopyrroniumbromide 1 mg or placebo before the night. In week 3 and week 5 no studymedication is taken (wash-out period). In a weekly consult in week 2 up to and including week 6 the patient scores the severity and possible improvement of the sialorrhea. Also the occurence of side effects will be questioned. In week 6 the patients who well tolerated the glycopyrroniumbromide oral solution in the first phase of the study receive a double dose glycopyrroniumbromide oral solution 2 mg during 6 days before the night. At the end of week 4 or 6 a concluding visit will take place.

Hypersalivation or sialorrhea is one of the most frequently occuring side effects of clozapine use with an incidence ranging from 30 to 90%. In most cases it occurs at the start of clozapine treatment, mostly at night and persists during further treatment.

Several symptomatic (farmacologic) therapies exists that reduce sialorrhea by reducing saliva excretion. There is no drug therapy registered for clozapine induced sialorrhea and most of the medications that are used often have central side effects.

Glycopyrroniumbromide is a quaternairy ammonium compound and an effective and potent anticholinergic agent with poor penetration across the blood-brain-barrier, causing less central side effects than other anticholinergics. In a number of relatively small studies oral glycopyrroniumbromide was found to be effective in reducing sialorrhea in children with cerebral palsy, patients suffering from Parkinson’s disease and schizophrenic patients using clozapine.
The effect on nocturnal sialorrhea in patients using clozapine compared to placebo has not been studied yet.

Main objective: To determine the effect, defined as the percentage of patients that show a clinical relevant improvement on the severity of complaints of nocturnal sialorrhea, of oral glycopyrroniumbromide in comparison with placebo in psychiatric patients treated with clozapine.

1. % PGI-I score 1 or 2, timepoints: 2 weeks, 4 weeks, 6 weeks;

2. Mean PGI-I, timepoints: 2 weeks, 4 weeks, 6 weeks;

3. Mean PGI-S, timepoints: every week (6 weeks in total);

4. Mean NHRS, timepoints: every week (6 weeks in total);

5. Mean MSQ, timepoints: every week (6 weeks in total);

6. Occurence of side effects, timepoints: week 1, week 2, week 4, week 6;

7. Satisfaction with oral glycopyrroniumbromide, timepoints: week 2, week 4, week 6.

Alternating treatment with 1 mg glycopyrroniumbromide oral solution or placebo oral solution for 1 week interrupted by 1 week wash-out.

Patients who have no problems enduring the treatment with 1 mg glycopyrroniumbromide will be treated with 2 mg
glycopyrroniumbromide oral solution in the extended open label phase.



Intervention medicine: Glycopyrroniumbromide oral solution 0,2 mg/ml (ATC-code: A03AB02).

Dose during double-blind phase: 1 mg (5 ml).

Dose during open-label phase (if applicable): 2 mg (1 ml).



Control intervention: Placebo oral solution, 5 ml during double-blind phase.



Other interventions: Short questionnaires.