The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12618000051246
Ethics application status
Approved
Date submitted
8/12/2017
Date registered
16/01/2018
Date last updated
9/11/2018
Date data sharing statement initially provided
9/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
The effect of atropine sulfate 1% administered under the tongue on excessive saliva secretion and drooling caused by clozapine in patients with schizophrenia.
Scientific title
The effect of sublingual atropine sulfate on the rate of saliva secretion in patients with schizophrenia who are found to have Clozapine-Induced Hypersalivation and/or Drooling
Secondary ID [1] 293562 0
Protocol No: CH62/6/2016-195
Universal Trial Number (UTN)
U1111-1206-3646
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Clozapine-Induced Hypersalivation

305793 0
Clozapine-Induced Drooling 305794 0
Schizophrenia 305916 0
Condition category
Condition code
Mental Health 305011 305011 0 0
Schizophrenia
Oral and Gastrointestinal 305012 305012 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The clinical trial aims to test the effect of sublingual atropine sulfate on clozapine induced hypersalivation and drooling. The effect will be compared to that of a placebo.
One dose composed of 2 drops of atropine sulfate 1% solution will be administered to participants at least one hour after dinner. This dose will be administered once only over one night by the nurse looking after the patient on the ward in the presence of the trial coordinator.
Prior to administering the study medication to the participant, the nurse will administer two drops of the study medication in the plastic container to feel the pressure needed to squeeze the MINIM bottle.
Intervention code [1] 299806 0
Treatment: Drugs
Comparator / control treatment
Chloramphenicol 0.5% solution will be the placebo. It will be administered once only at least one hour after dinner over one night only.
Control group
Placebo

Outcomes
Primary outcome [1] 304177 0
Mean change in saliva flow rate in each patient.
Timepoint [1] 304177 0
Saliva secreted over 5 minutes will be collected at least one hour after dinner immediately prior to the administration of the study medication and again two hours after the administration of the study medication.
Secondary outcome [1] 341140 0
The effect of the study medication on sleep, A questionnaire designed by the researchers will be used to assess Baseline Sleep-Time Sialorrhea Final Sleep-Time Sialorrhea.
Timepoint [1] 341140 0
Baseline Sleep-Time Sialorrhea will be completed by the study coordinator during the two hours waiting time after the administration of the study medication. The answers will be those provided by the participants in response to the questions in the questionnaire. It will assess sleep on the last night prior to the study night. The Final Sleep-Time Sialorrhea will be completed by the study coordinator, physician or nurse looking after the patient on the morning following the study night.
Secondary outcome [2] 341141 0
The effect of study medication on drooling severity. The "5-minutes Drooling Quotient Test" and the drooling severity part of the "Drooling Severity and Frequency Scale" will be used to assess the drooling severity
Timepoint [2] 341141 0
Drooling will be assessed by the study coordinator every 15 seconds over 5 minutes and a score for drooling severity will be assigned at the end of the 5 minutes.
The observations will be carried out immediately before the administration of the study medication and 2 hours after the administration of the study medication.

Eligibility
Key inclusion criteria
1. Non pregnant and non-breast feeding adults 18 or more year old,
2. Treated with clozapine.
3. Hypersalivation or drooling started after starting clozapine, and the treating psychiatry physician believes it is most likely due to clozapine therapy.
Hypersalivation or drooling is identified through either: Screening patients treated with clozapine for clozapine-induced hypersalivation or drooling as per the screening protocol. Or Examining patient for clozapine-induced hypersalivation or drooling after it is reported by the patient, healthcare team, or carers
4. Consents ,willingly, to participate in the study
5. The treating psychiatry physician chooses to enrol the patient in the study
Note: all patients treated with clozapine must have schizophrenia
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnant, breast feeding, or < 18 year old
2. Allergy to atropine or chloramphenicol.
3. Has any of the following disease:
Anaemia, diarrhoea (suggestive of pseudomembranous colitis), neutropaenia (suggestive of bone marrow suppression), Narrow-Angle Glaucoma, Myasthenia Gravis, Prostatic Hypertrophy, bladder obstruction, Glucose-6-Phosphate Dehydrogenase (G-6-PD) Deficiency, GI obstructive disease such as ileus, or other medical illness that may be seriously adversely affected by atropine or quinine.
4. Treated with an anticoagulants or antiarrhythmics.
5. Have been given or started on any medication known to have an anticholinergic effect after the detection of hypersalivation or drooling

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involves contacting the clinical trials pharmacist in each pharmacy department where the randomization list is kept.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomization using a randomization table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We are planning a study of a continuous response variable from independent control and experimental subjects with 1 control per experimental subject. In a previous study the response within each subject group was normally distributed with standard deviation 0.3. If the true difference in the experimental and control means is 0.19, We will need to study 80 participants (40 in each arm) to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with probability (power) 0.8. The Type I error probability associated with this test of this null hypothesis is 0.05.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 9513 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 9514 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 18258 0
2050 - Camperdown
Recruitment postcode(s) [2] 18259 0
2139 - Concord

Funding & Sponsors
Funding source category [1] 298175 0
University
Name [1] 298175 0
The University of Sydney
Address [1] 298175 0
The University of Sydney
Darlington NSW 2006
Australia
Country [1] 298175 0
Australia
Funding source category [2] 298176 0
Government body
Name [2] 298176 0
Sydney Local Health District
Address [2] 298176 0
Royal Prince Alfred Hospital
Level 11 King George V Building
Missenden Rd
Camperdown NSW 2050
Australia
Country [2] 298176 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
The University of Sydney
Darlington NSW 2006
Australia
Country
Australia
Secondary sponsor category [1] 297274 0
None
Name [1] 297274 0
Address [1] 297274 0
Country [1] 297274 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299191 0
Sydney Local Health District (SLHD) Human Research Ethics Committee – CRGH
Ethics committee address [1] 299191 0
Concord Repatriation General Hospital (CRGH)
Building 20, Hospital Road
Concord NSW 2139
Australia
Ethics committee country [1] 299191 0
Australia
Date submitted for ethics approval [1] 299191 0
29/09/2016
Approval date [1] 299191 0
22/05/2017
Ethics approval number [1] 299191 0
HREC/16/CRGH/265

Summary
Brief summary
Clozapine is one of the most effective medications used for the treatment of schizophrenia. Up to 80% of patients treated with clozapine may complain of an increased secretion of saliva in the mouth (known as hypersalivation) as a result of being treated with clozapine. Hypersalivation may result in an overspill of saliva outside the mouth (known as drooling).

Excessive production of saliva may disrupt sleep and speech, and cause aspiration pneumonia. Drooling is not pleasant and may damage the skin around your mouth.

Atropine sulfate is one of the medications used most often in inpatient units in New South Wales-Australia to treat hypersalivation or drooling that is caused by clozapine. However, studies testing the effect of atropine are lacking.

The aim from this study is to test the effect of atropine sulfate when administered under the tongue for the treatment of hypersalivation and/or drooling that is caused by clozapine.
One sub-study to this study involves testing the chemical content of saliva by researchers in the ANZAC Research Institute at Concord Hospital.

This research is designed by the mental health pharmacist Omar Mubaslat and overseen and supervised by consultant psychiatrist Professor Tim Lambert.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79598 0
Prof Tim Lambert
Address 79598 0
Concord Repatriation and General Hospital
Sydney Medical School, Concord
Hospital Road, Concord | NSW 2139 AUSTRALIA

Country 79598 0
Australia
Phone 79598 0
61 2 9767 7161
Fax 79598 0
Email 79598 0
Tim.Lambert@Sydney.edu.au
Contact person for public queries
Name 79599 0
Mr Omar Mubaslat
Address 79599 0
Royal Prince Alfred Hospital
Department of Pharmacy
Missenden Rd
Camperdown 2050 NSW AUSTRALIA
Country 79599 0
Australia
Phone 79599 0
61 2 9515 8145
Fax 79599 0
Email 79599 0
omar.mubaslat@health.nsw.gov.au
Contact person for scientific queries
Name 79600 0
Mr Omar Mubaslat
Address 79600 0
Royal Prince Alfred Hospital
Department of Pharmacy
Missenden Rd
Camperdown 2050 NSW AUSTRALIA
Country 79600 0
Australia
Phone 79600 0
61 2 95158145
Fax 79600 0
Email 79600 0
omar.mubaslat@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The percentage reduction in saliva secretion with atropine
When will data be available (start and end dates)?
The data will be available at the end of the study and break of randomization code. No end date
Available to whom?
All physicians and clinicians who have access to the participant's medical records
Available for what types of analyses?
To guide future treatment of the condition of interest
By what mechanism will data be made available?
Entry into electronic medical records under "Progress Notes"
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable