Local Application of Pilocarpine for Relieving Dry Mouth Complaints: A Randomized Controlled Pilot Trial
Phase: EARLY_PHASE1
Conditions: Patients of Advanced Age (≥ 70 Years) With a Clinical Diagnosis of Chronic Dry Mouth
Sponsor: Maastricht University Medical Center

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Local Application of Pilocarpine for Relieving 
Dry Mouth Complaints: 
A randomized controlled pilot trial 
 
S. C. Seferina1, F.J.H. Magdelijns1, S.M.J. van Kuijk2, D.J.A. Janssen3, R.M.J.M. van Geel4, B.P.A. 
Spaetgens1, M.H.J. van den Beuken-van Everdingen3 
 
1 Department of Internal Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands 
2 Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Centre 
(MUMC+), Maastricht, The Netherlands 
3 Centre of Expertise in Palliative Care MUMC+ (EPZM), Maastricht University Medical Centre (MUMC+), Maastricht, The 
Netherlands  
4 Department of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre (MUMC+), Maastricht, The 
Netherlands 
 
 
 
 
 
Version no: 8 
 
 
 
 

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Can locally administered pilocarpine drops  relieve dry mouth (xerostomia) in the elderly at cost of 
minimal side-effects? 
Protocol ID 
 
Short title 
Local Application of Pilocarpine for Relieving Dry Mouth 
Complaints: “Proof-of-Concept” 
EudraCT number  
2018-004352-38  
Version 
1 
Date 
 
Coordinating investigator/project 
leader 
 
MHJ van den Beuken-van Everdingen MD, PhD 
Professor Palliative Medicine 
University Hospital Maastricht (MUMC+) 
PO Box 5800 
6202AZ Maastricht 
The Netherlands 
0031(0)43 3877392 
m.vanden.beuken@mumc.nl 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
 
M.H.J. van den Beuken-van Everdingen MD, PhD1 
F.J.H. Magdelijns MD, PhD2 
 
Project team 
D. J.A. Janssen, MD PhD1 
S.C. Seferina, MD PhD2 
R.M.J.M. van Geel3 
S.M.J. van Kuijk, PhD4 
B.P.A. Spaetgens2 
 
1Centre of expertise for Palliative Care, Maastricht UMC+ 
2University Hospital Maastricht, department of internal 
medicine 
3 University Hospital Maastricht, Department of clinical 

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Pharmacy & Toxicology  
4 University Hospital Maastricht, KEMTA 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
azM 
 
 
Subsidising party 
CZ Fonds 
Independent expert (s) 
Drs. M. Martens 
Laboratory sites  
N.A.  
Pharmacy  
Maastricht UMC+ 
Department of clinical Pharmacy & Toxicology Clinical Trial 
Unit 
P. Debyelaan 25; 6229 HX Maastricht  
The Netherlands 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
J.F.B.M. Fiolet 
 
 
[Coordinating Investigator/Project 
leader/Principal Investigator]: 
M.H.J. van den Beuken-van Everdingen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .................................................................................................. 10 
2. 
OBJECTIVES .................................................................................................................................... 11 
3. 
STUDY DESIGN ............................................................................................................................... 11 
4. 
STUDY POPULATION ...................................................................................................................... 12 
4.1 Population (base) ........................................................................................................................ 12 
4.2 Inclusion criteria .......................................................................................................................... 12 
4.3 Exclusion criteria ......................................................................................................................... 12 
4.4 Sample size calculation ................................................................................................................ 13 
5. 
TREATMENT OF SUBJECTS ............................................................................................................. 13 
5.1 Investigational product/treatment ............................................................................................. 13 
5.2 Use of co-intervention (if applicable) .......................................................................................... 13 
5.3 Escape medication (if applicable) ................................................................................................ 13 
6. 
INVESTIGATIONAL PRODUCT......................................................................................................... 13 
6.1 
Name and description of investigational product(s) ............................................................. 13 
6.2 
Summary of findings from non-clinical studies ..................................................................... 13 
6.3 
Summary of findings from clinical studies ............................................................................ 13 
6.4 
Summary of known and potential risks and benefits ............................................................ 14 
6.5 
Description and justification of route of administration and dosage ................................... 15 
6.6 Dosages, dosage modifications and method of administration .................................................. 15 
6.7 Preparation and labeling of Investigational Medicinal Product .................................................. 15 
6.8 Drug accountability ..................................................................................................................... 15 
7. 
NON-investigational products ....................................................................................................... 16 
8. 
METHODS ...................................................................................................................................... 16 
8.1 
Study parameters/endpoints ................................................................................................ 16 
8.1.1 
Main study parameter/endpoint................................................................................... 16 
8.1.2 Secondary study parameters/endpoints .............................................................................. 16 
8.1.3 Other study parameters (if applicable) ................................................................................ 16 
8.2 Randomisation, blinding and treatment allocation .................................................................... 16 
8.3 Study procedures ........................................................................................................................ 16 
8.4 Withdrawal of individual subjects ............................................................................................... 19 
8.4.1 
Specific criteria for withdrawal ..................................................................................... 19 
8.5 
Replacement of individual subjects after withdrawal ........................................................... 19 

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8.6 
Follow-up of subjects withdrawn from treatment ................................................................ 19 
8.7 
Premature termination of the study ..................................................................................... 19 
9. 
SAFETY REPORTING ....................................................................................................................... 21 
9.1 
Section 10 WMO event .................................................... Fout! Bladwijzer niet gedefinieerd. 
9.2 
AEs, SAEs and SUSARs ........................................................................................................... 21 
9.2.1 
Adverse events (AEs) ..................................................................................................... 21 
9.2.2 
Serious adverse events (SAEs) ....................................................................................... 21 
9.3 
Annual safety report .............................................................................................................. 23 
9.4 
Follow-up of adverse events ................................................................................................. 23 
9.5 
Data Safety Monitoring Board (DSMB) ................................................................................. 23 
Not applicable. .................................................................................................................................. 23 
10. 
STATISTICAL ANALYSIS ............................................................................................................... 23 
Primary and secondary study parameter(s) ...................................................................................... 23 
Other study parameters .................................................................................................................... 24 
Interim analysis ................................................................................................................................. 24 
11. 
ETHICAL CONSIDERATIONS ....................................................................................................... 24 
11.1 Regulation statement ................................................................................................................ 24 
11.2 Recruitment and consent .......................................................................................................... 24 
11.3 Objection by minors or incapacitated subjects ......................................................................... 25 
11.4 Benefits and risks assessment, group relatedness .................................................................... 25 
Compensation for injury .................................................................................................................... 25 
11.5 Incentives .................................................................................................................................. 25 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ................................................ 25 
12.1 Handling and storage of data and documents .......................................................................... 25 
12.2 Monitoring and Quality Assurance ............................................................................................ 26 
12.3 Amendments ............................................................................................................................. 26 
12.4 Annual progress report ............................................................................................................. 26 
 Not applicable ................................................................................................................................... 26 
12.5 End of study report .................................................................................................................... 26 
12.6 Public disclosure and publication policy ................................................................................... 27 
13. REFERENCES 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
ABR form, General Assessment and Registration form, is the application form that is 
required for submission to the accredited Ethics Committee (In Dutch, ABR = 
Algemene Beoordeling en Registratie) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CAT 
COPD Assessment Test 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale 
Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
COPD 
Chronic Obstructive Pulmonary Disease 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT 
FNA 
European drug regulatory affairs Clinical Trials  
Formularium Nederlandse Apothekers 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  
METC  
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
NRS 
Numeric Rating Scale 
(S)AE 
(Serious) Adverse Event  
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst) 
Sponsor 
The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 

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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SUMMARY 
Rationale:  
Xerostomia, the subjective feeling of dry mouth, is a frequent symptom in the elderly. Xerostomia 
leads to functional alterations and has disabling social consequences and reduces quality of life. 
Objectives  
The objective of this study is to deliver the “proof-of-concept” that locally administered pilocarpine 
drops are effective in a population of elderly with xerostomia at expense of a minimum of side 
effects. 
Study design:  
Open-label randomised controlled pilot study 
Study population:  
Patients of advanced age (≥ 70 years) with a clinical diagnosis of chronic dry mouth (NRS score of ≥ 5) 
visiting the outpatient clinic of MUMC+. 
Intervention:  
Local administration of  pilocarpine (eye)drops orally in  a low dose or a high dose for 14 days. 
Main study parameters/endpoints:  
Change in xerostomia score   
Change in oral health-related quality of life  
Secondary study parameters/endpoints  
- Adverse effects 
- Other symptoms 
- Global perceived effect 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  
The extent of the burden associated with participation in this study is considered to be low. Total 
follow up will last a total of 3 weeks. In these 3 weeks the patient will visit the hospital twice and will 
be contacted through phone calls twice. Local oral administration of pilocarpine is reported to have 
none or only minor side effects. During the two hospital visits whole resting saliva will be collected, 
and blood pressure will be measured. The burden of both these procedures is considered low. The 
patient will also be asked to complete a total of four questionnaires in these 3 weeks. These 
questionnaires consists of 45 questions, which will take 20 minutes, the level of burden is low.  
  

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1. INTRODUCTION AND RATIONALE 
 
Introduction 
Xerostomia is the subjective feeling of dry mouth, a symptom associated with alterations in the 
quality and quantity of saliva. Xerostomia leads to functional alterations such as halitosis, burning 
sensations, altered taste perception, pain, and difficulties of chewing, swallowing, speaking and 
sleeping.[1, 2] Also, xerostomia has disabling social consequences[3] and reduces quality of life.[2, 4-
8] 
Xerostomia has been associated with radiation therapy, the use of medications, various chronic 
diseases and/or poor health.[2] Reported prevalence rates among patients with cancer, Chronic 
Obstructive Pulmonary Disease (COPD) or heart failure are about 50%.[9-11] The prevalence among 
community-dwelling elderly ranges from 17% to 40%.[2] In a cohort of vulnerable elderly the 
prevalence of xerostomia was estimated at 100%, with low, moderate, and high xerostomia 
according to the xerostomia index at a rate of 49.3%, 30.3%, and 20.4%, respectively.[8] 
In the elderly, xerostomia is mostly caused by side effects of chronic drug treatment in combination 
with a 30%-40% decrease of acinar cells of salivary glands between the ages of 34 and 75 years.[1] 
Withdrawal or substitution of xerostomia-inducing drugs is the most effective treatment. However, 
this does not always outweighs the drug´s benefits, e.g. with treatment of depression or pain. 
Therefore other treatment possibilities to effectively reduce xerostomia and improve quality of life 
should be considered.  
Current symptomatic treatment options include local treatment with artificial saliva/mouthwashes or 
systemic or local administration of pilocarpine. The former has mainly been researched in advanced 
cancer patients[12, 13] and was not better than chewing gum.[14] The latter are the current 
mainstay treatment of patients in the palliative phase of their illness.[12] Pilocarpine is a 
parasympathomimetic drug that increases saliva production by activating muscarinic receptors.[12] 
Pilocarpine tablets (systemic treatment) are more effective than placebo in radiation-induced 
xerostomia,[15-18] Sjögrens disease, [19] tramadol induced oral dryness[20] and improved salivation 
in patients taking xerogenic medications.[21] However, systemic administration of pilocarpine has 
frequent side-effects such as sweating (20 -50%), flushing, rhinitis (12%), headaches (12%), increased 
frequency of urination (11-34%), flu-like symptoms (8%), asthenia (7%)[21-23] and, mainly in elderly 
patients, dizziness (17%) leading to dropout rates between 6% and 15% in clinical studies.[16] Local 
oral administration of pilocarpine (drops, lozenges and mouthwashes) are reported to have none [24, 
25] or minor local side effects (irritation of mouth and tongue).[26] In addition, a 5 mg pilocarpine 
lozenge produced better clinical results than a 5 mg pilocarpine tablet in 33 head-and-neck cancer 

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patients.[27], Furthermore, pilocarpine eye drops 2% relieved xerostomia immediately in 19 patients 
with opioid-induced complaints of dry mouth.[25] However, inconclusive results have been reported 
about the effectiveness of these local formulations in other studies.[24, 28]. 
Literature is scarce on the effectiveness of pilocarpine in elderly patients with xerostomia. 
Pilocarpine mouthwash relieved dry mouth in 19 elderly patients[26], whereas a systematic review 
evaluating the effectiveness of systemic pilocarpine in 242 elderly patients with xerostomia due to 
medication or unknown causes  showed inconclusive results.[1] As our population is ageing and poly-
pharmacy is common among elderly, more patients will be poly-medicated in the future. Hence, 
xerostomia will be a major problem and thus more research on this topic is necessary.  
 
This study intents to deliver the “proof-of-concept” that locally administered pilocarpine drops are 
effective in reducing xerostomia complaints in a population of elderly (aged ≥ 70 years) with 
xerostomia at the expense of a minimum of side effects. 
 
2. OBJECTIVES 
 
Objective 
This study intents to deliver the “proof-of-concept” that locally administered pilocarpine drops in two 
doses are effective in a population of elderly (aged ≥ 70 years) with xerostomia at the expense of 
limited adverse events. To this end, the study aims to quantify the effect size of pilocarpine in two 
different dosages. In case we observe clinically meaningful changes in xerostomia through measured 
NRS, a sufficiently-powered RCT will be prepared to compare pilocarpine to placebo. 
 
3. STUDY DESIGN 
 
DESIGN: 
Open-label randomised controlled pilot study 
PARTICIPANTS 
The study will be performed at the outpatient clinic internal medicine/elderly care of the Maastricht 
University Medical Centre+.  
INTERVENTION: 
The intervention concerns the treatment of xerostomia in 2 treatment groups: 
1. low dose pilocarpine = 3 x 2.0 mg = 3 x 2 drops of pilocarpine 20.0 mg/ml (2%) per day 
2. high dose pilocarpine = 3 x 5.0 mg = 3 x 5 drops of pilocarpine 20.0 mg/ml (2%) per day 

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The study lasts 21 days of which the first 14 days with medication and the last 7 days without 
medication to measure a possible “switch-on” effect. 
 
MEASUREMENTS 
Xerostomia 
 
Numeric Rating Scale (NRS) 
Geriatric Oral Health Assessment Index (GOHAI-
NL) 
Concurrent symptoms 
Utrecht symptom Diary (USD) 
Generic Health-Related Quality of Life (HRQoL) 
EuroQoL 5D (EQ5D) 
Global Perceived Effect (GPE)  
 
GPE 7-point scale 
Side effects 
 
4-point Likert scale 
(flu-like symptoms, sweating, headache, 
urinary frequency, diarrhoea, nausea, 
vomiting, palpitations, dizziness, rhinitis, 
other) 
 
Whole resting saliva                                                   
Total amount of unstimulated saliva measured in   
5minutes  
 
 
 
 
 
Patient characteristics that are collected at inclusion include gender, age, primary diagnosis, co-
morbidity, medication and relevant history.  
 
4. STUDY POPULATION 
 
4.1 Population (base)  
The study will be performed at the outpatient clinic internal medicine/elderly care of the Maastricht 
University Medical Centre+ (MUMC+). Potentially eligible patients will be identified on the outpatient 
clinic and will be invited to participate when meeting the inclusion criteria. 
 
4.2 Inclusion criteria 
• 
≥ 70 years of age 
• 
Clinical diagnosis of chronic dry mouth defined  as a Numeric Rating Scale (NRS) score ≥ 5 
(scale 0 – 10, with 0 = no dry mouth and 10= worst possible dry mouth) on severity of 
xerostomia for more than 3 months. 
4.3 Exclusion criteria 
• 
Existence of cognitive impairment and/or diagnosis of dementia appraised by treating 
physician  
• 
Inability to fill out the questionnaires due to other reasons 
• 
Prior radiation therapy of the head-and-neck region 

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• 
Known m. Sjögren disease 
• 
Contra-indications for parasympathicomimetics (uncontrolled asthma, acute heart failure, 
active peptic ulceration, known hypersensitivity to pilocarpine, and when miosis is 
undesirable, e.g., in acute iritis and in narrow-angle (angle closure) glaucoma. 
 
 
4.4 Sample size calculation 
 
For this study we will take a pragmatic approach, as too little is known of the mean and variance of 
xerostomia complaints, quantified using the NRS, and the effect size of pilocarpine. This study will 
provide input for the sample size calculation for a future study. It would be feasible to include at least 
24 patients in a period of 6 months, or 12 per group, as suggested as a rule of thumb for pilot studies 
to obtain sufficient precision about the mean and variance .[29] 
 
5. TREATMENT OF SUBJECTS 
 
5.1 Investigational product/treatment 
Patients will receive regular clinical care and pilocarpine drops in unit dose vials (Pilocarpine 
Minims (nitraat), eye drops, Bausch & Lomb), 2%, two or five drops administered three times a 
day (6 or 15mg/24h). Patients will receive the study drug for 14 days.  
5.2 Use of co-intervention (if applicable) 
Not applicable 
5.3 Escape medication (if applicable) 
Not applicable 
 
6. INVESTIGATIONAL PRODUCT  
 
6.1 Name and description of investigational product(s) 
Investigational product: 
Pilocarpine Minims (nitraat), eye drops, Bausch & Lomb, 20 mg/ml (2%), 0.5 ml 
(Oculoguttae pilocarpine sine conservans) 
6.2 Summary of findings from non-clinical studies 
We refer to the Summary of Product Characteristics (SmPC) 
6.3 Summary of findings from clinical studies 
Pilocarpine tablets are registered for dry mouth in Sjögrens disease and post radiation therapy.  

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Pilocarpine drops are registered for treatment of open-angle glaucoma and narrow-angle glaucoma 
and to antagonize  mydriasis. 
Pilocarpine tablets (systemic treatment) has proven to be effective in radiation-induced 
xerostomia,[15-18] Sjögrens disease, [19] tramadol induced oral dryness[20] and in patients taking 
xerogenic medications.[21] However, systemic administration of pilocarpine has frequent side-
effects.   
Off-label local oral administration of pilocarpine (drops, lozenges and mouthwashes) are reported to 
have none [24, 25] or minor local side effects (irritation of mouth and tongue).[26] In addition, a 5 
mg pilocarpine lozenge produced better clinical results than a 5 mg pilocarpine tablet in 33 head-
and-neck cancer patients.[27], Furthermore, pilocarpine eye drops 2% relieved xerostomia 
immediately in 19 patients with opioid-induced complaints of dry mouth.[25] However, inconclusive 
results have been reported about the effectiveness of these local formulations in other studies.[24, 
28]. 
 
Dosing: 
Post-radiation studies reveal an optimum oral dose of 5 mg 3 dd/day.  Higher doses result in higher  
saliva flow but at the expense of more inacceptable adverse effects. Effect and side effects increase 
with increasing dosages.[15, 16] A trial with 2,5 mg 3dd/day showed an increase in salivary flow but 
not a subjective improvement.[18] Possibly this low dose is insufficient in damaged salivary glands. 
In this pilot study we will compare two doses (5 mg 3 dd/day and 2mg 3dd/day) in intact glands. 
 
6.4 Summary of known and potential risks and benefits 
Pilocarpine is a cholinergic parasympathomimetic agent exerting a broad spectrum of pharmacologic 
effects with predominant muscarinic action.[30] 
- 
 In systemic use pilocarpine, in appropriate dosage, can increase secretion by the exocrine 
glands. The sweat, salivary, lacrimal, gastric, pancreatic, and intestinal glands and the 
mucous cells of the respiratory tract may be stimulated. Dose-related smooth muscle 
stimulation of the intestinal tract may cause increased tone, increased motility, spasm, and 
tenesmus. Bronchial smooth muscle tone may increase. The tone and motility of urinary 
tract, gallbladder, and biliary duct smooth muscle may be enhanced. Pilocarpine may have 
paradoxical effects on the cardiovascular system. The expected effect of a muscarinic agonist 
is vasodepression, but administration of pilocarpine may produce hypertension after a brief 
episode of hypotension. Bradycardia and tachycardia have both been reported with use of 
pilocarpine. 

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- 
In use as eye drops: systemic reactions rarely occur when treating chronic simple glaucoma 
at normal doses. However, in the treatment of acute closed-angle glaucoma the possibility of 
systemic reactions must be considered because of the higher doses given. Caution is 
particularly advised in patients with acute heart failure, bronchial asthma, peptic ulceration, 
hypertension, urinary tract obstruction, Parkinson's disease and corneal abrasions.[31] 
 
Contraindications: 
Pilocarpine HCl Tablets are contraindicated in patients with uncontrolled asthma, known 
hypersensitivity to pilocarpine, and when miosis is undesirable, e.g., in acute iritis and in narrow-
angle (angle closure) glaucoma. 
Pilocarpine eye drops are contraindicated in conditions where pupillary constriction is undesirable 
e.g. acute iritis, anterior uveitis and some forms of secondary glaucoma. 
Pilocarpine eye drops are also contraindicated in case of hypersensitivity to the active substance or 
to any of the excipients thereof.  
  
6.5 Description and justification of route of administration and dosage 
Polypharmacy is common among elderly patients;  patients may even object against more “pills”. In a 
crossover study in advanced cancer patients, pilocarpine tablets was found to be more effective than 
artificial saliva, however 50% of patients preferred the saliva. The commonest reason for preferring 
the artificial saliva was the fact that it was a spray, rather than a tablet.[32] 
Patients don’t experience local application as “pills”, which makes pilocarpine drops better 
acceptable. Moreover, local oral administration of pilocarpine (drops, lozenges and mouthwashes) 
are reported to have none [24, 25] or minor local side effects.[26] 
 
6.6 Dosages, dosage modifications and method of administration 
The two doses pilocarpine nitrate  ( 3 x 2.0 mg = 3 x 2 drops or 3 x 5.0 mg = 3 x 5 drops) will be stable 
over the first 14 days of the study. Day 15 through day 21 patients will not receive medication. Drops 
will be administered left and right outside the molars and behind the front teeth under. 
 
6.7 Preparation and labeling of Investigational Medicinal Product 
The pilocarpine nitrate drops are commercially available  (Bausch & Lomb), registered for treatment 
of open-angle glaucoma and narrow-angle glaucoma and to antagonize  mydriasis. 
 
 
6.8 Drug accountability 
Drug accountability will be done at the Pharmacy. 

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7. NON-investigational products 
NA 
8. METHODS 
 
8.1 Study parameters/endpoints 
8.1.1 Main study parameter/endpoint 
- change in xerostomia score  (NRS) 
- change in oral health-related quality of life (GOHAI-NL) 
 
8.1.2 Secondary study parameters/endpoints  
- Adverse effects 
- Other symptoms 
- Global perceived effect 
 
8.1.3 Other study parameters (if applicable) 
 
  
- whole resting salivary flow 
8.2 Randomisation, blinding and treatment allocation 
Randomisation will be performed by a sealed envelope system.  
In this participating clinicians are given treatment allocations randomly drawn from one of 24 
sealed opaque envelopes that include 12 allocations to the low dose, and 12 to the high dose 
group to ensure perfect balance. Once a patient has consented to enter the study an envelope is 
opened and the patient is then offered the allocated treatment regimen. 
8.3 Study procedures 
The study will be performed at the outpatient clinic internal medicine/elderly care of the Maastricht 
University Medical Centre+. Potentially eligible patients will be identified on the outpatient clinic by 
answering the question if they have suffered from a dry mount in the last three months. If the 
answer to this question is yes they will be invited to participate when meeting the inclusion criteria. 
Each patient that participates in this study will receive a restaurant coupon and their travel expenses 
will be covered.  
Randomisation will occur through a sealed envelope system. Once a patient has consented to the 
trial, a sealed opaque envelope is opened and the patient will receive the allocated treatment 
regime. This sealed opaque envelope will also contain a two digit number wherein the patient will be 
identified from this point forward in the database. The sealed opaque envelopes with all its content 
will be arranged by the researcher before start of the study. 

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Measures will be performed on day 0, 7, 14 and 21. Questionnaires on day 0, 7, 14 and 21, whole 
resting salivary flow on day 0 and 14, blood pressure will be measured on day 0 before and 1 hour 
after pilocarpine administration and on day 14.  
 
 
Day 0 
Day 7 
Day 14 Day 21 
Hospital visit 
X 
 
X 
 
Patient characteristics 
X 
 
 
 
Xerostomia NRS / GOHAI-NL 
X 
X 
X 
X 
USD 
X 
X 
X 
X 
EQ5D 
X 
X 
X 
X 
GPE 
X 
X 
X 
X 
Side effects 
X 
X 
X 
X 
RR 
X 
 
X 
 
Whole resting saliva 
X 
 
X 
 
After inclusion the patient will visit the outpatient clinic twice on day 0 and day 14. On the first visit 
(day 0) after inclusion a questionnaire consisting of 45 questions, will be filled in, this will take 20 
minutes. Also patient characteristics, including use of medication, will be accessed. Blood pressure 
and whole resting saliva will be measured.  The blood pressure will be measured in sitting position 
using the Dinamap technology V100 care scape from general electric. The whole resting saliva will be 
measured by the doctor/research nurse. The patient will have to sit straight in a chair and will be 
asked to swallow the saliva that is currently in their mouth, in the next five minutes the patient will 
be asked to accumulate all the saliva that is spontaneously  produced in their mouth. This whole 
resting saliva will be collected in a previously weighted cup and the result of each patient will be 
compared. The cups and the whole resting saliva will be measured with the SARTORIUS AC210p 
scale.  
On day 14 all of these procedures but one (assessment of patient characteristic ) will be repeated.  
On day 7 and day 21 the patient will receive a phone call wherein the questionnaires will be taken by 
the doctor/research nurse. At the end of the study patients will be offered to continue the 
pilocarpine drops as off-label use. The reimbursement status for this indication is uncertain. 
 
 
 
 
 

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Table 1: Description of study procedures 
 
Procedure 
Parameter 
Description 
Measurements 
Whole resting saliva 
Amount of saliva 
collected in 5 
minutes 
This procedure will be done 
twice during the study 
Blood pressure 
mmHg 
The sitting blood pressure will 
be measured using the 
Dinamap technology V100 care 
scape from general electric. 
Questionnaires 
 
0-10 Numeric Rating Scale (NRS) 
Xerostomia 
The NRS is used to quantify the 
level of severity of xerostomia 
using a 0-10 cm NRS ranging from 
0 = no dry mouth to 10 = worst 
possible dry mouth.[28] 
 
Geriatric Oral Health Assessment 
Index (GOHAI-NL) 
 
Xerostomia 
Oral health-related quality of 
life (OHRQoL) of adults, in 
particular older people is 
measured 4 times during this 
study by the doctor/research 
nurse .  It comprises of 12 
items that measure 
three dimensions of OHRQoL: 
physical function items, 
psychosocial function and 
pain/discomfort. [33] 
Utrecht symptom Diary (USD) 
concurrent 
symptoms  
 
The USD asks patients to self-
asses eleven symptoms and 
their wellbeing on a daily basis, 
by using a numerical rating 
scale ranging from 0 to 10. 
Patients can also indicate 
which symptom is a priority for 
them.[34, 35] 
EuroQoL 5D (EQ5D) 
generic Health-
Related Quality 
of Life (HRQoL) 
Health-related quality of life is 
measured 4 times during this 
study by the doctor/research 
nurse, using five dimensions: 
mobility, self-care, usual 
activities, pain/discomfort and 
anxiety/depression.[36] 

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8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 
8.4.1 Specific criteria for withdrawal  
 
 
Unacceptable adverse effects. 
 
 
8.5 Replacement of individual subjects after withdrawal 
Individual subjects will not be replaced after withdrawal. 
 
8.6 Follow-up of subjects withdrawn from treatment 
Patients will receive usual care after withdrawal 
 
8.7  Premature termination of the study 
Criteria for termination of the study prematurely: Since none or only minor side effects are 
expected, there is no specific criteria for premature termination of the study that can be stated 
beforehand. In the case of premature termination of the clinical trial, the investigator will inform 
Global Perceived Effect (GPE 7-point 
scale) 
Global Perceived 
Effect (GPE) 
 
The GPE scale asks the patient 
to rate, on a numerical scale, 
how much their condition has 
improved or deteriorated since 
some predefined time 
point.[37]  
4-point Likert scale 
Side effects 
 
Patients are asked if they 
experienced  flu-like 
symptoms, sweating, 
headache, urinary frequency, 
diarrhoea, nausea, vomiting, 
palpitations, dizziness, rhinitis, 
or other symptoms, while on 
the treatment. 
 
 
 
 
 
 
 
 
 
 
 

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the reviewing accredited METC and the sponsor. Reasons for termination will be stated in writing. 
All participants will be informed. Participants will receive usual care. 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there is 
sufficient ground that continuation of the study will jeopardise subject health or safety.  The sponsor 
will notify the accredited METC without undue delay of a temporary halt including the reason for 
such an action. The study will be suspended pending a further positive decision by the accredited 
METC. The investigator will take care that all subjects are kept informed. 
 
 
9.2 AEs, SAEs and SUSARs 
9.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the investigational product. All adverse events 
reported spontaneously by the subject or observed by the investigator or his staff will be 
recorded. 
 
9.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that at any dose:  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; 
- 
Any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered a serious adverse experience when, based 
upon appropriate medical judgement, the event may jeopardize the subject or may 
require an intervention to prevent one of the outcomes listed above. 
- 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events.  
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to complete the 

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initial preliminary report. All other SAEs will be reported within a period of maximum 15 
days after the sponsor has first knowledge of the serious adverse events. 
 
 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
 
Adverse reactions are all untoward and unintended responses to an investigational product related 
to any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of the 
administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity of the 
adverse reaction are not in agreement with the product information as recorded in: 
- 
Summary of Product Characteristics (SPC) for an authorised medicinal product; 
- 
Investigator’s Brochure for an unauthorised medicinal product. 
 
The sponsor will report expedited the following SUSARs through the web portal ToetsingOnline  to 
the METC 
− SUSARs that have arisen in the clinical trial that was assessed by the METC; 
− SUSARs that have arisen in other clinical trials of the same sponsor and with the same 
medicinal product, and that could have consequences for the safety of the subjects 
involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once every 
half year to the METC. This line-listing provides an overview of all SUSARs from the study medicine, 
accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or ToetsingOnline is 
sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other Member States, 
according to the requirements of the Member States.  
 

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The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the 
adverse reactions. For fatal or life threatening cases the term will be maximal 7 days for a preliminary 
report with another 8 days for completion of the report.  
 
 
9.3 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout 
the clinical trial, a safety report to the accredited METC, competent authority, and competent 
authorities of the concerned Member States. 
This safety report consists of: 
− a list of all suspected (unexpected or expected) serious adverse reactions, along with an 
aggregated summary table of all reported serious adverse reactions, ordered by organ 
system, per study; 
− a report concerning the safety of the subjects, consisting of a complete safety analysis 
and an evaluation of the balance between the efficacy and the harmfulness of the 
medicine under investigation. 
 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol  
 
9.5 Data Safety Monitoring Board (DSMB) 
Not applicable. 
 
10. STATISTICAL ANALYSIS 
 
Primary and secondary study parameter(s) 
Baseline characteristics will be described in detail per group in order to assess any imbalance. In case 
of missing data, we will use stochastic regression imputation to produce a synthetic part of the data 
to allow for an intention to treat analysis. 
Per group, the post-treatment xerostomia score will be described as mean and standard deviation, or 
median and interquartile range in case of severe skewness. Additionally, we will compute a change-
from-baseline score for both groups, which will be described in a similar matter. All secondary 

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outcome measures will be described in full using either mean and standard deviation or median and 
interquartile range for continuous measures, and count and proportion for categorical measures. 
For exploratory purposes, we will use the independent-samples t-test to test for differences in 
xerostomia complaint scores (NRS) between the two groups. However, as this is a pilot study, the 
emphasis will lie on clinical interpretation of the effect sizes of both groups separately. Preliminary 
analyses on secondary outcome measures will be performed using the independent samples t-test 
and Fisher’s Exact test, depending on the measurement level of each variable. 
 
Other study parameters 
Not applicable. 
 
Interim analysis  
No interim analysis will be performed. 
 
11. ETHICAL CONSIDERATIONS 
 
11.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, Brazil, October 2013) and in accordance with the Medical Research 
Involving Human Subjects Act (WMO) and other guidelines, regulations and Acts. 
 
11.2 Recruitment and consent 
Patients who fulfill the inclusion criteria, will be informed about the study by their treating 
physician or physician assistant during a regular outpatient clinic visit. The treating physician or 
physician assistant will hand out the patient information leave and introduce the patient to the 
researcher.  
The patient will have a minimum of 7 days period to decide if he or she wants to participate in 
the study. If a patient decides to participate , the researcher will plan a new appointment for the 
patient where additional questions can be answered and the informed consent can be signed. 
This day will be considerd day 0, and the start of the study for this patient.  
Inclusion will take place on Tuesdays and Wednesdays in the outpatient clinic of internal 
medicine. On these days there are the largest amount of patients at the outpatient clinic. A total 
of 6 patients per doctor is expected to be seen. This means that on a Tuesday about 18 patients 
will be seen and on a Wednesday 12 patients.  
 

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11.3 Objection by minors or incapacitated subjects  
Not applicable. 
 
11.4 Benefits and risks assessment, group relatedness 
The risk to and burden for the subject will be in proportion to the potential value of the 
research because we expect possible less complaints of dry mouth at cost of minimal 
side effects of the drugs. Main burden of the patients will be 1 or 2 extra outpatient 
visits and time investment for filling in questionnaires.11.5 Compensation for injury   
The sponsor/investigator has a liability insurance which is in accordance with article 7, of the 
WMO.  
The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects 
through injury or death caused by the study. The insurance applies to the damage that becomes 
apparent during the study or within 4 years after the end of the study. 
 
1. € 650.000,-- (i.e. six hundred and fifty thousand Euro) for death or injury for each subject 
who participates in the Research; 
2. € 5.000.000,-- (i.e. five million Euro) for death or injury for all subjects who participate in 
the Research;  
3. € 7.500.000,-- (i.e. seven million five hundred thousand Euro) for the total damage 
incurred by the organisation for all damage disclosed by scientific research for the 
Sponsor as ‘verrichter’ in the meaning of said Act in each year of insurance coverage. 
 
The insurance applies to the damage that becomes apparent during the study or within 4 years 
after the end of the study. 
11.6 Incentives  
Patient will receive a restaurant coupon of €7.50 and their travel expenses will be covered.  
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
12.1 Handling and storage of data and documents 
Data will be handled confidentially and encoded. Only authorized personnel (researchers and 
monitor) will have access to these confidential files. Also the National Supervisory Authority can 
have access to these files. A subject identification code list will be used to trace data to an 
individual subject. The code (01, 02 etc.) will not be based on the patient initials and birth-date. 
The key to the code will be safeguarded by the investigator.  General Data Protection Regulation 

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(GDPR) en de Uitvoeringswet AVG (UAVG; in het Engels: the Dutch Act on Implementation of the 
General Data Protection Regulation. Data will be saved for 15 years.  
12.2 Monitoring and Quality Assurance  
Monitoring will be performed by the Clinical Trial Center Maastricht. Monitoring will follow the 
international ICH-GCP guidelines. Monitoring will consist of: site initiation visit; interim monitoring 
visits; and close out visit.  
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. 
A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or 
to the protocol or any other supporting documentation, that is likely to affect to a significant 
degree: 
- the safety or physical or mental integrity of the subjects of the trial; 
- the scientific value of the trial; 
- the conduct or management of the trial; or 
- the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
Non-substantial amendments will be notified to the accredited METC. 
12.4 Annual progress report 
 The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, 
serious adverse events/ serious adverse reactions, other problems, and amendments.  
 
12.5 End of study report 
The sponsor will notify the accredited METC and the competent authority of the end of the study 
within a period of 90 days. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action. 
 
In case the study is ended prematurely, the sponsor will notify the accredited METC and the 
competent authority within 15 days, including the reasons for the premature termination. 
 

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 Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC and the Competent Authority.  
 
 
12.6 Public disclosure and publication policy 
The investigator will be responsible for the quality of the study performance, and he/she has the 
right to publish the results of this study in the appropriate well-accepted scientific journals. All 
publications will be confirming the basic principles of the CCMO publication policy 
(www.ccmo.nl). The study will be registered in the trial register (www.trialregister.nl)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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