The effect of glycopyrroniumbromide on nocturnal clozapine induced sialorrhea in psychiatric patients: a randomized, cross-over, double blind, placebo controlled trial with an extended open label phase (QUITSPIT 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.

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.

Secondary objectives:
1) to determine patient's satisfaction with oral glycopyrroniumbromide compared
to placebo regarding nocturnal sialorrhea
2) to determine the effect of oral glycopyrroniumbromide compared to placebo on
patient's opinion to clozapine
3) to determine the effect of oral glycopyrroniumbromide compared to placebo on
the occurence of side effects
4) previously mentioned primary and secundary objectives in a subset of
patients receiving a double dose of oral glycopyrroniumbromide in an open label
extension compared to single dose oral glycopyrroniumbromide treatment in the
randomized, double-blind phase

Double blind, randomized, cross-over trial with an extended open label phase.
The length of the study will be, from randomisation visit, 3 or 5 weeks in
total. To this comes a period of screening and baseline measurements before
(period 1), it takes about 7 days, with a range of up to 28 days. The first
phase (period/week 2 up to and including period/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 (period/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 period/week 2 and period/week 4 the patients will take during 6 days oral
glycopyrroniumbromide 1 mg or placebo before the night. In period/week 3 and
period/week 5 no studymedication is taken (wash-out period). In a weekly
consult in period/week 2 up to and including period/week 6 the patient scores
the severity and possible improvement of the sialorrhea. Also the occurence of
side effects will be questioned.
In period/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 period/week 4 or 6 a concluding visit will take place.

Alternating treatment with 1 mg oral glycopyrroniumbromide or placebo for 1
week interrupted by 1 week wash-out. Patients that have no problems enduring
the 1 mg glycopyrroniumbromide will be treated with 2 mg glycopyrroniumbromide
in the extended open label phase.

The risk will be mainly possible side effects of anticholinergic origin. In
clinical studies with oral glycopyrroniumbromide the following side effects are
most reported: dry mouth, miction problems, nausea, obstipation, flushing,
nasal congestion and inner unrest. Furthermore, there is a small risk (< 2%) of
cardial effects with oral usage, like tachycardia and palpitations.

The strain of the study includes five or seven visits at the researcher. In
four to six of these visits (depending on the participation in the extended
phase) five short questions will be asked, a set of side effects questioned and
the occurence of obstipation will be asked.
Physical exam: two times blood pressure and body weight measurements, also four
or six times (depends on the participation in the extended phase) measurement
of pulse frequency.