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Trial registered on ANZCTR


Registration number
ACTRN12617001067369
Ethics application status
Approved
Date submitted
16/07/2017
Date registered
21/07/2017
Date last updated
21/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Single patient multiple cross-over trials to determine the efficacy of pilocarpine 5 mg orally dissolving tablets in patients suffering from dry mouth.
Scientific title
Single patient multiple cross-over trials to determine the efficacy of pilocarpine 5 mg orally dissolving tablets in relieving xerostomia

Secondary ID [1] 292311 0
Nil Known
Universal Trial Number (UTN)
U1111-1198-5399
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Xerostomia 303863 0
Condition category
Condition code
Oral and Gastrointestinal 303222 303222 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
Single patient trials (n-of-1 or SPTs) of 5 mg pilocarpine orally dissolving tablets (ODTs) vs placebo ODTs, one tablet orally, 3 times per day for 18 days consisting of 3 cycles. Each cycle contains two periods: 3 days treatment, 3 days placebo. The first day of each period is considered to be the washout and data collected will not be included in analysis. The order of treatment and placebo will be randomly allocated for each cycle. Treatment allocation will be blinded to the participant and the Primary Investigator.

Participants will take one dose of trial medication 60 minutes prior to breakfast, lunch and dinner, each day for the 18 day trial. They will collect saliva samples in pre-labelled tubes 60 minutes after taking the breakfast and dinner doses, just before eating. Participants will complete a daily diary recording symptom scores using validated measures for dry mouth and related symptoms, the presence of any side effects and their estimate of which drug they believe they are taking at the time. The principal investigator will call every participant every 3 days to check their compliance with the medication and completing the daily diary and if there are any adverse effects or serious adverse effects.
Intervention code [1] 298495 0
Treatment: Drugs
Comparator / control treatment
The control treatment will be be matching placebo orally dissolving tablets, one tablet to be taken three times daily. All orally dissolving tablets are made from: Medi-RDT base, a sucrose-free, finely granulated powder that is compatible with a wide range of active ingredients, Bitterness Reducing Agent (NF01) Natural (Powder), flavour (Powder) and stevia powder (stevioside) as sweetener. All components are pharmaceutical grade.
Control group
Placebo

Outcomes
Primary outcome [1] 302598 0
Mean change from baseline in each of the three questions of the Subjective Rating of Symptoms questionnaire across the 3 cycles of the trial. This questionnaire is completed by the participant three times a day after each dose taken. Improvement of 2 or more on the 0-10 numerical rating scale (NRS )compared to baseline is classified as a response,
Timepoint [1] 302598 0
Baseline and three times daily for 18 days after intervention commencement.
Secondary outcome [1] 336470 0
Mean change from baseline in weight of saliva across the 3 cycles of the trial. Saliva will be collected by the participants twice daily (60 minutes after the morning dose and 60 minutes after the evening dose) and mailed to the Principal Investigator at the end of the trial for weighing.
Timepoint [1] 336470 0
Baseline and twice daily for 18 days after the intervention commencement.
Secondary outcome [2] 336471 0
Mean change from baseline in the Summated Xerostomia Inventory Dutch-version (SXI-D) scores, a 5-item validated shortened summated rating scale that represents the severity of dysphagia, measured daily across the 3 cycles of the trial. The significance of the difference between treatment and placebo will be tested at P<0.05
Timepoint [2] 336471 0
Baseline and once daily for 18 days after the intervention commencement.
Secondary outcome [3] 336472 0
Mean change from baseline in the Xerostomia-related Quality of Life Scale (XeQOLS) score, a 15-item validated questionnaire, across the 3 cycles of the trial.. The XeQOLS is completed at the end of each period. The significance of the difference between treatment and placebo will be tested at P<0.05
Timepoint [3] 336472 0
Baseline and every 3 days for 18 days after the intervention commencement.
Secondary outcome [4] 336473 0
Mean change from baseline in the scores for the Visual Analogue Scale (VAS) of the EQ-5D, a 5 item questionnaire which assesses the overall health performance, across the 3 cycles of the trial. The EQ-5D is completed at the end of each period. The significance of the difference between treatment and placebo in VAS will be tested at P<0.05. The scores for the 5 domains, which have a 3-point scale, will be used descriptively
Timepoint [4] 336473 0
Baseline and every 3 days for 18 days after the intervention commencement.
Secondary outcome [5] 336474 0
Mean change from baseline in the global score for the Oral Health Impact Profile (OHIP), a 14 item questionnaire that has been validated in a population with xerostomia, across the 3 cycles of the trial. The OHIP is completed at the end of each period. The significance of the difference between treatment and placebo will be tested at P<0.05
Timepoint [5] 336474 0
Baseline and every 3 days for 18 days after the intervention commencement.
Secondary outcome [6] 336475 0
Comparison of the number of people reporting that they experienced each of the adverse events listed in the symptom checklist included in the daily diary, which are assessed daily, will be made between treatment and placebo. The significance of the difference in number of people experiencing each adverse event between treatment and placebo will be tested at P<0.05. AEs assessed are: Increased sweating, urinary frequency, rhinitis, flushing, nausea/vomiting, dizziness, chills, asthenia, dyspepsia, headache and diarrhoea.
Timepoint [6] 336475 0
Baseline and daily for 18 days after the intervention commencement.
Secondary outcome [7] 336476 0
Number of uses of other saliva treatments, self-reported daily in the study diary; Differences between treatment and placebo will be assessed descriptively. Consideration of use is important because it may affect their rating of the Subjective Rating of Symptoms questionnaire.
Timepoint [7] 336476 0
Baseline and daily for 18 days after the intervention commencement.
Secondary outcome [8] 336477 0
Participant’s guessing of the intervention taken over the past three days, either the drug or the placebo to ensure proper masking of the bitter taste of pilocarpine and hence adequate blinding.
Timepoint [8] 336477 0
every 3 days for 18 days after the intervention commencement.

Eligibility
Key inclusion criteria
•Males and females aged 18 years or older.
•To ensure that xerostomia is significant enough to warrant treatment with pilocarpine, participants must self-report xerostomia of any etiology as a score of 3 or more on a numerical rating scale (NRS) from 0 – 10 (where 0 = no dry mouth and 10 = worst possible dry mouth) .
•As pilocarpine action requires some residual salivary function, participants must self-report evidence of saliva production in the mouth upon chewing a piece of gum .
•Participants are able and willing to give appropriate informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
•Ocular problems contraindicating the use of parasympathetic agents (e.g. irido-cyclitis, increased intra-ocular pressure);
•Other comorbidity where there is a risk of worsening co-existing medical problems during the trial period and/or active treatment is contemplated. For example, severe or uncontrolled asthma or pulmonary disease, uncontrolled hypotension or hypertension, hyperthyroidism, uncontrolled seizures or cardiac arrythmias, (especially bradycardias) and Parkinson's disease. If these diseases are well controlled, they do not constitute exclusion criteria.
•An active oral infection i.e. candidiasis, herpetic infections, mucositis, mouth ulcers;
•Suspected or confirmed pregnancy;
•Intervention (e.g. radiotherapy, chemotherapy, surgery that might alter dry mouth symptoms during the 2 weeks prior to the study period or plans to undergo such therapy during the study period;
•Plans to change any medication with the potential to cause dry mouth within the trial period;
•Plans to use any other prescribed medication which is known to increase saliva production and relieve dry mouth during the trial period. Patients already on pilocarpine are eligible, but must stop taking it 1 week before trial commencement;
•A poor understanding of written or spoken English that would preclude completion of all trial requirements

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 concealment will be done via central randomization by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation will be done by simple randomization using a randomization table created by computer software (computerized sequence generation).
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
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Power calculations were based on the primary outcome variable, the NRS score, and a pooled baseline score across groups had mean 3.250 (standard deviation 2.975) from a cross-over study of 70 patients comparing artificial saliva and pilocarpine in the management of xerostomia in patients with advanced cancer. An article on testing the xerostomia inventory was used to estimate patients intra class correlation, ICC. Simulations in Stata programmed to model the repeated measures design, attrition rates and variances revealed that 70 patients are required to detect a 2 cm change in NRS. With this, we would expect 44% to complete all 3 cycles, 6% complete 2 cycles, 10% complete 1 cycle, and 28% will fail to complete any cycles, ie, (31x3)+(4x2)+(7x1)=106 cycles delivered by 42 people. With 20% attrition, the required number of participants is 51.

Both individual and population treatment differences will be estimated via fitting Bayesian hierachial model with noninformative priors. Where necessary, the appropriateness of the assumed likelihood distributions will be assessed for violations and data transformations undertaken. Markov chain Monte Carlo methods will be used to sample from the posterior distribution of the parameters, and conventional burn-in periods, model convergence, stability diagnostics and goodness-of-fit checks will be employed. The software package WinBUGS will be used for the Bayesian analysis.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Participant recruitment difficulties
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)
QLD
Recruitment postcode(s) [1] 16544 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 296852 0
University
Name [1] 296852 0
School of Pharmacy, University of Queensland
Address [1] 296852 0
20 Cornwall St, Woolloongabba, QLD 4102
Country [1] 296852 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
St. Lucia, QLD, 4072
Country
Australia
Secondary sponsor category [1] 296005 0
None
Name [1] 296005 0
None
Address [1] 296005 0
None
Country [1] 296005 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298081 0
University of Queensland Human Research Ethics Committee
Ethics committee address [1] 298081 0
University of Queensland
St. Lucia
QLD 4072
Ethics committee country [1] 298081 0
Australia
Date submitted for ethics approval [1] 298081 0
31/08/2017
Approval date [1] 298081 0
02/11/2017
Ethics approval number [1] 298081 0

Summary
Brief summary
Xerostomia or dry mouth is a major problem that many people experience, especially those who have received radiotherapy for the treatment of head and neck cancer and it accompanies other diseases such as Sjögren syndrome. Saliva plays many vital roles in our daily life and people with reduced saliva production can experience a variety of health problems.

Pilocarpine is a medication that stimulates the nerves supplying the salivary glands. This stimulates the production of your own saliva. The effect lasts for about three hours, and so it is usually taken three times daily. Pilocarpine is usually taken before a meal to produce more saliva in time for eating.

Pilocarpine is only available as eye drops to treat glaucoma in Australia, but tablets are available for treating dry mouth in many countries around the world. This trial investigates pilocarpine orally dissolving tablets (ODTs), which are little tablets that dissolve rapidly in the mouth and can be compounded in pharmacies.

This trial will provide information about whether pilocarpine ODTs are effective in treating dry mouth, and this information will help to improve management of dry mouth in Australia.

A series of single patient (N-of-1) trials of 5 mg pilocarpine ODTs (intervention) vs placebo ODTs (control) will be run, in people suffering with xerostomia, with a population estimate of the benefit following the combination of multiple SPTs. Participants will complete 18 days of treatment, consisting of 3 cycles. Each cycle contains two periods: 3 days treatment, 3 days placebo. The first day of each period is considered to be the washout and data collected will not be included in analysis. The order of treatment and placebo will be randomly allocated for each cycle. Treatment allocation will be blinded to the participant and the Primary Investigator.
Trial website
https://pharmacy.uq.edu.au/project/dry-mouth-research-group
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75930 0
A/Prof Kathryn Steadman
Address 75930 0
School of Pharmacy,
The University of Queensland,
20 Cornwall St,
Woolloongabba,
QLD 4102
Country 75930 0
Australia
Phone 75930 0
+61733461886
Fax 75930 0
Email 75930 0
k.steadman@uq.edu.au
Contact person for public queries
Name 75931 0
A/Prof Kathryn Steadman
Address 75931 0
School of Pharmacy,
The University of Queensland,
20 Cornwall St,
Woolloongabba,
QLD 4102
Country 75931 0
Australia
Phone 75931 0
+61 7 3346 1886
Fax 75931 0
Email 75931 0
k.steadman@uq.edu.au
Contact person for scientific queries
Name 75932 0
Prof Geoff Mitchell
Address 75932 0
Faculty of Medicine
The University of Queensland.
St Lucia,
QLD 4072
Country 75932 0
Australia
Phone 75932 0
+61 7 3365 5380
Fax 75932 0
Email 75932 0
g.mitchell@uq.edu.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary