'The Experience Sampling Method (ESM): a Real-time Patient-Reported Outcome Measure for Symptom Assessment in Patients With Overactive Bladder Syndrome.'
Conditions: Overactive Bladder, Overactive Bladder Syndrome
Sponsor: Maastricht University Medical Center

 
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RESEARCH PROTOCOL 
(November 2019) 
 
‘The Experience Sampling Method (ESM):  
a real-time Patient-Reported Outcome Measure for symptom 
assessment in patients with overactive bladder syndrome.’  
 
 

 
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PROTOCOL TITLE ‘The Experience Sampling Method (ESM):  a real-time Patient-Reported 
Outcome Measure for symptom assessment in patients with overactive bladder syndrome.’’ 
 
Short title 
ESM in OAB patients 
Version 
5.0 
Date 
08.10.2019 
Coordinating investigator/project 
leader 
 
A G M Herrewegh, MD 
Department of Urology  
Maastricht University Medical Centre + 
P.O. Box 5800, 6202 AZ Maastricht, The Netherlands 
E: alexandra.herrewegh@mumc.nl 
T: +31 (0)43 387 72 62 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
D M J Vrijens, MD, PhD 
Department of Urology  
Maastricht University Medical Centre + 
P.O. Box 5800, 6202 AZ Maastricht, The Netherlands 
E: desiree.vrijens@mumc.nl 
T: +31 (0)43 387 72 62 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Academisch Ziekenhuis Maastricht 
 
 
Subsidising party 
Academisch Ziekenhuis Maastricht 
Independent expert (s) 
S.O. Breukink, MD, PhD 
Department of Surgery  
Maastricht University Medical Centre + 
Maastricht, The Netherlands 
 
Project team 
Prof. G. van Koeveringe, MD, PhD  
Department of Urology  
Maastricht University Medical Centre + 
Maastricht, The Netherlands 
 
L. Vork, MD 
Division of Gastroenterology-Hepatology,  

 
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Department of Internal Medicine  
Maastricht University Medical Centre + 
Maastricht, The Netherlands 
 
J. Kruimel, MD, PhD 
Division of Gastroenterology-Hepatology,  
Department of Internal Medicine  
Maastricht University Medical Centre + 
Maastricht, The Netherlands 
 
 
C. Leue, MD, PhD 
Department of Psychiatry and Psychology,  
Maastricht University Medical Centre+ 
Maastricht, The Netherlands 
 
W. Spaans, MD, PhD 
Department of Gynaecology/Obstetrics 
Maastricht University Medical Centre + 
Maastricht, The Netherlands 
 
 M. Kuenen, MD 
Department of Urology 
Zuyderland Heerlen/Sittard 
Heerlen, Sittard, The Netherlands 
 
Prof. S. De Wachter, MD, PhD 
Department of Urology 
University Hospital Antwerp 
Antwerp, Belgium 
Laboratory sites  
Maastricht University Medical Centre,  
room SURO 4.15  
P. Debyelaan 25 
6229 HX Maastricht, The Netherlands 
 
 

 
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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
Prof. Dr. G. van Koeveringe 
 
 
 
[Coordinating Investigator/Project 
leader/Principal Investigator]: 
Dr. D. Vrijens 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................11 
2. 
OBJECTIVES ................................................................................................................13 
3. 
STUDY DESIGN ...........................................................................................................16 
4. 
STUDY POPULATION ..................................................................................................18 
4.1 
Population ..............................................................................................................18 
4.2 
Inclusion criteria .....................................................................................................18 
4.2.1 
Inclusion criteria OAB patients ........................................................................18 
4.2.2 
Inclusion criteria healthy volunteers .................................................................18 
4.3 
Exclusion criteria ....................................................................................................18 
4.3.1 
Exclusion criteria .............................................................................................18 
4.3.2 
Exclusion criteria healthy volunteers ...............................................................18 
4.4 
Sample size calculation ..........................................................................................19 
5. 
METHODS ....................................................................................................................20 
5.1 
Study parameters/endpoints ...................................................................................20 
5.1.1 
Part I Comparison of the ESM vs. SR-BDs ......................................................20 
Main study parameter/endpoint .....................................................................................20 
Secondary study parameters/endpoints (if applicable) ..................................................20 
5.1.2 
Part II Validation ..............................................................................................20 
Main study parameter/endpoint .....................................................................................20 
Secondary study parameters/endpoints (if applicable) ..................................................20 
5.1.4 
Other study parameters (if applicable) .............................................................21 
5.2 
Study procedures ...................................................................................................22 
5.2.1 
PROM development ........................................................................................23 
5.2.2 
Tool development ............................................................................................23 
5.2.3 
Retrospective symptom assessment – conventional questionnaires ...............24 
5.3 
Withdrawal of individual subjects ............................................................................25 
5.4 
Replacement of individual subjects after withdrawal ...............................................26 
5.5 
Follow-up of subjects withdrawn from treatment .....................................................26 
5.6 
Premature termination of the study .........................................................................26 
6. 
SAFETY REPORTING ..................................................................................................27 
All safety reporting will be handled in accordance with METC protocol .............................27 
6.1 
Temporary halt for reasons of subject safety ..........................................................27 
6.2 
AEs, SAEs and SUSARs ........................................................................................27 
6.2.1 
Adverse events (AEs) ......................................................................................27 
6.2.2 
Serious adverse events (SAEs) .......................................................................27 
6.3 
Follow-up of adverse events ...................................................................................28 
7. 
STATISTICAL ANALYSIS .............................................................................................29 
7.1 
Primary study parameter ........................................................................................30 
7.2 
Other study parameters ..........................................................................................32 
8. 
ETHICAL CONSIDERATIONS ......................................................................................33 
8.1 
Regulation statement .............................................................................................33 

 
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8.2 
Recruitment and consent........................................................................................33 
8.2.1 
OAB patients ...................................................................................................33 
8.2.2. 
Healthy volunteers ..........................................................................................34 
8.3 
Benefits and risks assessment, group relatedness .................................................34 
8.4 
Compensation for injury .........................................................................................35 
8.5 
Incentives ...............................................................................................................35 
9. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .............................36 
9.1 
Handling and storage of data and documents ........................................................36 
9.2 
Monitoring and Quality Assurance ..........................................................................37 
9.3 
Amendments ..........................................................................................................37 
9.4 
Annual progress report ...........................................................................................37 
9.5 
End of study report .................................................................................................37 
9.6 
Public disclosure and publication policy ..................................................................37 
10. 
REFERENCES ..........................................................................................................39 

 
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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
3IQ 
ABR 
3 Incontinence Questions  
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 
CCMO 
Central Committee on Research Involving Human Subjects; in 
Dutch: Centrale Commissie Mensgebonden Onderzoek 
DSMB 
ePRO 
ESM 
Data Safety Monitoring Board 
electronic Patient-reported Outcome Measure 
Experience Sampling Method 
EU 
European Union 
EudraCT 
European drug regulatory affairs Clinical Trials  
GCP 
HADS 
HRQL 
Good Clinical Practice 
Hospital Anxiety and Depression Scale  
Health-related Quality of Life 
IB 
IBS 
Investigator’s Brochure 
Irritable Bowel Syndrome 
IC 
ICC 
ICI-RS 
ICIQ-FLUTS 
 
ICIQ-MLUTS 
 
ICS 
Informed Consent 
Intraclass Correlation Coefficient 
International Consultation on Incontinence-Research Society 
International Consultation on Incontinence Modular Questionnaire 
for female lower urinary tract symptoms 
International Consultation on Incontinence Modular Questionnaire 
for male lower urinary tract symptoms 
International Continence Society 
IIEF-5   
IMP 
International Index of Erectile Function 5 
Investigational Medicinal Product  
IMPD 
IPSS 
LUTS 
Investigational Medicinal Product Dossier  
International Prostate Symptom Score 
Lower Urinary Tract Symptoms 
METC  
 
MUMC+ 
NRS 
NVOG 
OAB 
OAB-q 
PRO(M) 
Medical research ethics committee (MREC); in Dutch: medisch 
ethische toetsing commissie (METC) 
Maastricht University Medical Centre + 
Numeric Rating Scale 
Nederlandse Vereniging Obstetrie & Gynaecologie 
Overactive bladder syndrome 
Overactive Bladder Questionnaire 
Patient-Reported Outcome (Measure) 
(S)AE 
SF-36 
(Serious) Adverse Event  
Short Form Health Survey 36 (questionnaires) 
Sponsor 
 
The sponsor is the party that commissions the organisation or 
performance of the research, for example a pharmaceutical 

 
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SR-BD 
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. 
Sensation-related bladder diary 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
VPSS 
Wbp 
 
WMO 
Visual Prostate Symptom Score 
Personal Data Protection Act (in Dutch: Wet Bescherming 
Persoonsgevens)  
Medical Research Involving Human Subjects Act (in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen) 
 
 
 
 

 
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SUMMARY 
 
Rationale: The overactive bladder syndrome is diagnosed clinically by using the ICS criteria 
of ≥8 micturitions and at least 1 urgency episode per 24 hours. To determine whether 
patients fit the criteria, micturition diaries (‘sensation-related bladder diaries’) and other 
symptom questionnaires with considerable limitations are used. This makes it difficult to get a 
good impression of the fluctuation of complaints during the day / week. These limitations are 
overcome using the Experience Sampling Method (ESM). This is an electronic questioning 
method which is characterized by repeated and random, momentary assessments in the 
subject’s current environment and state. This study follows other successful ESM studies 
done within the Gastroenterology and Psychiatry Department.1-4 The aim of this study is to 
evaluate if the ESM is more accurate in the assessment of urological complaints in OAB 
compared to the current assessment with the use of the sensations-related bladder diaries 
(SR-BDs) and retrospective questionnaires. Furthermore the aim is to assess the reliability 
and validity of this OAB-specific electronic patient-reported outcome measure (ePRO), based 
on the Experience Sampling Method-principle, for symptom assessment and assessment of 
triggers for symptoms in OAB. 
Objective: To evaluate the accuracy of the ESM to assess urological complaints in OAB 
compared to SR-BDs and retrospective questionnaires. To assess content validity, reliability 
and the accuracy to validate the developed ePRO in OAB patients.  
Study design: The ESM study is a multi-centre, prospective, cross-sectional study.  
Study population: 66 OAB patients will be recruited at the outpatient Pelvic Care Centre at 
Maastricht UMC+, the outpatient clinic Urology at Zuyderland Heerlen/Sittard and the 
outpatient clinic Urology at University Hospital Antwerp. 66 healthy volunteers will be 
recruited as well.  
Methods: In a period of 7 days, participants will fill out an electronic ESM assessment at 10 
random moments during the day. Moreover, they will fill out a sensation-related bladder diary 
(SR-BD) during the last three consecutive days of filling out the ESM and several symptom 
questionnaires at the end of the study period. 
Main study endpoints: The main study outcome comprehends the psychometric properties 
of the PROM for symptom assessment of OAB symptoms. Secondary outcomes are  
increase in ESM score for OAB symptoms and environmental and psychosocial factors (e.g. 
as measured by the PROM) from one time point (t-1) to the next (t). 
Burden, risks and benefits: The burden that is associated with participation in this study 
comprises completing the PROM questionnaire several times a day, which interrupts daily 
life due to its random character. Furthermore, the burden is limited to completing a SR-BD 
and other symptom questionnaires. Most importantly, participating does not bring along 

 
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important health related risks. However, awareness could trigger symptoms and therefore be 
considered as a burden. Nevertheless, for the patients it could be beneficial too to know what 
triggers complaints, to cope better with their disease.

 
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INTRODUCTION AND RATIONALE 
 
The overactive bladder syndrome (OAB) is defined by the International Continence Society 
(ICS) as a symptom complex of urgency, usually with frequency and nocturia (awakening at 
night to void), with (OAB wet) or without (OAB dry) urinary urgency incontinence. Urgency is 
the complaint of a sudden compelling desire to pass urine, which is difficult to defer5. OAB is 
clinically diagnosed using the ICS criteria of ≥8 micturitions and at least 1 urgency episode 
per 24 hours.  
It is estimated that approximately 16-17% of the adult population of the Western world is 
affected by OAB 6,7. The incidence of OAB, both wet and dry increases by age 8-10, and 
because of the worldwide ageing of the population, the number of adults affected by urinary 
urgency incontinence (UUI) would increase 11. The health care costs of OAB are high 12, and 
work productivity can be significantly impacted as well 13. In addition, OAB can be associated 
with comorbidity and increased mortality14,15. Furthermore, OAB with and without 
incontinence has been associated with significantly lower quality of life scores compared to 
matched controls without voiding complaints8. It is of particular interest that OAB does not 
only affect the patients, but also has an impact on family members 10. 
There is a strong association between OAB and psychiatric comorbidities such as 
depression, anxiety and stress 15-19. This association is most likely bidirectional.16,18,19  
The current methods of diagnosis rely on voiding diaries (the sensation-related bladder diary) 
and retrospective questionnaires.  
Retrospective, self-reported outcomes have important limitations. Firstly, there is a high risk 
for recall bias, in which retrospective information consists of a reconstruction of a few specific 
moments rather than a reliable reflection of symptoms over a predefined period of time20-22. 
Furthermore, it is well described that memory retrieval is influenced by the individual’s 
environment and mental state at the time of recall, known as ecological bias.20,21 In 
conclusion, patient experiences about symptoms in the past can be significantly distorted 
when retrospectively reported. Furthermore, lack of patient compliance is an important 
disturbing factor in recalled assessments. Studies that employed paper diaries in a 
population of patients with chronic somatic pain to measure symptoms resulted in very low 
patient compliance: only 11% actual compliance, but up to 80% fake compliance was 
determined, the latter presumably resulting from filling in diaries after the proscribed time 
window.23 
The Experience Sampling Method (ESM), also referred to as Ecological Momentary 
Assessment (EMA), may overcome these limitations. ESM is an electronic questioning 
method characterized by random, repeated assessments in the subject’s current state and 
environment, for several consecutive days. A digital device sends out an auditory beep at 

 
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random moments during the day, to which subjects have to respond by completing several 
assessments at the device. The assessments are identical between the moments 20,21,24. 
Hereby, ESM offers the opportunity to reduce the risk for recall bias and to capture symptom 
variability over time with taking into account contextual, social and psychological factors, 
which might have an impact on symptom reporting.  
ESM has already been used in different patient populations with different disorders, such as; 
irritable bowel syndrome (IBS) 1, depression 25,26, Parkinson’s Disease 27 and mental illness 
in a broad sense.28 
ESM has proven to be a viable and novel approach to assess symptoms, affective states and 
contextual factors at the level of the individual subject27. It provides precise, prospective 
information that may contribute to clinical practice26 with several distinct advantages over 
traditionally used (retrospective) assessment of mental health related phenomena28. OAB 
shows fluctuating symptom patterns in which urological complaints might be influenced by 
daily life factors as well as psychological and psychiatric comorbidities. To our knowledge, 
there are no previous studies on the use of ESM in a urological patient population. In order to 
study the performance of ESM in a population as such there is a need for developing a 
patient-reported outcome measure suitable for real-time symptom assessment of urological 
symptoms, using the ESM principle. Patient-reported outcome measures (PROMs) are 
assessment methods completed by patients, and are meant to capture one or several 
aspects of a disease course or health status29.  Focus group research in OAB patients was 
done for item selection and to evaluate the quality of the PROMs according to the ESM 
principle. The outcomes of the focus groups have been discussed in an expert meeting and a 
final questionnaire has been constructed, specifically for the ESM in the urological patient 
population. Now, this OAB-specific ESM tool should be tested to see if there is a difference 
between symptom scores on ESM and the currently used retrospective reports and SR-BDs. 
Furthermore content validity, reliability and the accuracy will be tested to validate the 
developed ePRO in OAB patients. Additionally, specific triggers for the onset of OAB 
complaints will be objectified, with use of the OAB specific ESM tool. It will be objectified if 
there is a direct link between OAB and psychiatric disorders as depression, anxiety and 
stress too. 
 
Summarizing, electronic, repeated symptom assessments during daily activities should 
assure ecological validity and eliminate recall bias, lead to higher compliance rates, and 
capture symptom variability during the day. For these reasons it is expected that the 
Experience Sampling Method (ESM) may prove to be a more objective tool for evaluation 
and quantification of urgency and other urological complaints that will overcome the 
limitations of currently used retrospective symptom assessment methods in OAB. 

 
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1. OBJECTIVES 
 
This project will be subdivided into three sections: 
 
Part I. Comparison of the ESM vs. SR-BDs and other retrospective questionnaires in the 
assessment of urological complaints in OAB such as urgency.  
Part II. Validation of new patient-reported outcome measure, based on the Experience 
Sampling Method, which will be used in the assessment of urological symptoms in patients 
with overactive bladder syndrome. 
 
Part I – Comparison of assessment methods 
Primary aim: To compare the ESM to SR-BDs and other retrospective questionnaires in the 
assessment of urological complaints in OAB.   
 
Objectives: 
1. To compare the ESM to SR-BDs and other retrospective questionnaires in the 
assessment of urological complaints in OAB. 
Hypothesis: The ESM is more accurate in the assessment of urological complaints in 
OAB compared to the current use of SR-BDs and other retrospective questionnaires (like 
the OAB-q). We hypothesize to find good correlations between ESM scores (i.e. the 
newly developed ePRO) and ‘concurrent’ instruments (i.e. conventional retrospective 
questionnaires), since we purport to measure the same constructs with both methods. 
However, ESM measures real-time symptoms whereas our conventional questionnaires 
measure retrospectively. Therefore, we do not expect to find perfect correlation 
coefficients, i.e. >0.8. Correlation coefficients between 0.4 and 0.8 are considered 
appropriate. Correlation coefficients lower than 0.4 reflect very weak or no correlation 
between the methods, which probably means that we are measuring some other 
construct with our new ePRO than is measured with the conventional method (current 
‘gold standard’). On the contrary, correlation coefficients higher than 0.8 reflect very 
strong correlations, meaning that we are more or less measuring exactly the same 
construct. In this case, there is no rational for replacing the conventional methods by the 
new (more intensive) method. For each correlation coefficient its significance will be 
checked as well. 
Furthermore it is expected that the mean urgency scores from the ESM will be 
significantly lower when compared to the urgency scores from the SR-BDs and 
retrospective questionnaires.  

 
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Additionally it is expected that in the SR-BDs the daily peak of urgency scores is reported 
rather than the average level of urgency over the day.  
 
Part II - Validation 
Primary aim: To validate and test the reliability of electronic patient-reported outcome 
(ePRO) for the evaluation of the complex symptoms and their potential triggers in OAB 
patients in day-to-day life with the use of the Experience Sampling Method.  
 
Objectives:  
1. To assess content validity of the developed ePRO. 
 
Hypothesis: We consider content validity of the ePRO adequate since items 
were carefully selected based on evidence from qualitative studies. Furthermore, item 
relevance was judged by a multidisciplinary panel of experts in the fields of urology, 
gastro-enterology, psychiatry and gynaecology as well as by OAB patients.  
 
2. To assess concurrent validity of the developed ePRO.  
Hypothesis: We hypothesize to find good correlations between ESM scores 
(i.e. the newly developed ePRO) and ‘concurrent’ instruments (i.e. 
conventional retrospective questionnaires), since we purport to measure the 
same constructs with both methods. However, ESM measures real-time 
symptoms whereas our conventional questionnaires measure retrospectively. 
Therefore, we do not expect to find perfect correlation coefficients, i.e. >0.8. 
Correlation coefficients between 0.4 and 0.8 are considered appropriate. 
Correlation coefficients lower than 0.4 reflect very weak or no correlation 
between the methods, which probably means that we are measuring some 
other construct with our new ePRO than is measured with the conventional 
method (current ‘gold standard’). On the contrary, correlation coefficients 
higher than 0.8 reflect very strong correlations, meaning that we are more or 
less measuring exactly the same construct. In this case, there is no rational for 
replacing the conventional methods by the new (more intensive) method. For 
each correlation coefficient its significance will be checked as well. 
3. To assess internal consistency of the developed ePRO. 
Hypothesis: We hypothesize that internal consistency of the ePRO will be moderate 
to good, since items were based on theoretical constructs as described in literature. 
Therefore, we expect to find correlation coefficients (Cronbach’s α) of >0.6. 
 
4. To assess test-retest reliability of the developed ePRO. 

 
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Hypothesis: Since OAB symptoms might fluctuate within the study period, we do not 
expect to find perfect test-retest reliability (i.e. test-retest reliability coefficients close 
to 1.00). However, it is hypothesized that symptoms will show certain subject-specific 
patterns, so consistency between the first half-week and the second-half week is 
expected. Therefore, we hypothesize to find test-retest reliability coefficients around 
0.70-0.80. 
 
5. To assess how well the developed ePRO differentiates between OAB and healthy 
subjects, by determining the accuracy of the discriminatory model using a confusion 
matrix. 
Hypothesis: We hypothesize that the accuracy of the ePRO to differentiate between 
OAB and healthy subjects will be comparable with ICS criteria, i.e. moderately to 
good. There are no studies that examined the sensitivity or specificity of these criteria.  
However, since OAB-like symptoms often occur in healthy subjects we expect that 
the ePRO might classify some healthy subjects as OAB (i.e. false positives) resulting 
in moderate sensitivity and high specificity.  
 
 
 
 

 
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2. STUDY DESIGN 
 
Focus group research in OAB patients was previously done for item selection and to 
evaluate the quality of the PROMs according to the ESM principle (METC 16-4-189). The 
outcomes of the focus groups have been discussed in an expert meeting and a final 
questionnaire has been constructed, specifically for the ESM in the urological patient 
population. Now, this OAB-specific ESM tool should be tested to see if there is a difference 
between symptom scores on ESM and the currently used retrospective reports and SR-BDs. 
The ESM study is a multi-centre, prospective, cross-sectional study in Maastricht UMC+, 
Zuyderland Heerlen/Sittard and University Hospital Antwerp. 
OAB patients will be recruited at the outpatient Pelvic Care Centre at Maastricht UMC+, the 
outpatient clinic Urology at Zuyderland Heerlen/Sittard and the outpatient clinic Urology at 
University Hospital Antwerp. Eligible patients are patients that are referred to the urologist by 
their general physician, other medical specialists or other hospitals with a differential 
diagnosis of OAB or urinary urgency incontinence.  Presently, all new patients that are seen 
in the outpatient clinic Urology in the MUMC+, the outpatient clinic Urology at Zuyderland 
Heerlen/Sittard and the outpatient clinic Urology at University Hospital Antwerp are triaged by 
the staff members of the urology department following the standard of care on the basis of 
the guidelines for urinary incontinence. 36,37 Patients that are referred with a differential 
diagnosis of OAB or urinary urgency incontinence receive SR-BDs and a HADS 
questionnaire by post, together with the information about the date of the outpatient clinic 
appointment in an information package sent by the outpatient nurse. They are asked to fill 
these out and take these with them for their first urologist appointment.  
Since the patients already need to fill out these SR-BDs (and HADS) for their first regular 
urologist visit, patients will receive a recruitment letter within the information package   to 
inform them about the study (see ‘E3. Wervingstekst_ESM_Urologie_Versie 2.0 
(27.10.2017)’). They will also receive written information (see ‘E1. Proefpersoon 
informatie_ESM studie Versie 2.0(18.10.2017)’) about the purpose of the ESM study in this 
information package. During the study, patients have to fill out a lot of questionnaires and 
repeated assessment of the ESM app. By contacting them prior to the first urology visit, there 
is no any additional burden of filling out an extra SR-BD (and HADS) for study purposes 
solely. Patients are asked to contact the coordinating investigator by email or telephone in 
case of interest in participation. If this is the case, the first visit will be scheduled with one 
week respite at the medical centre to sign the informed consent form (by the participant as 
well as the researcher) and to instruct the participant about the study procedures. No study 
procedures will be performed until the informed consent form is signed. After signing the 
informed consent form they will receive the login codes of the ESM app and the additional 

 
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(retrospective) questionnaires.  This way of inclusion ensures that patients are not entrusted 
with filling out an extra SR-BD for study purposes solely, since they already need to fill these 
out following the standard of care for their regular scheduled visit.  
 
Healthy volunteers will be recruited by advertisements on bulletin boards at Maastricht 
University Medical Centre, other public bulletin board in Maastricht and on the website 
‘www.digiprik.nl’ (see ‘E3. Advertentie gezonde controles_ESM_Versie 2.0 (18.10.2017)’). 
Persons that are interested in participating after reading an advertisement are asked to 
contact the coordinating investigator via email and will then receive the written patient 
information letter and informed consent form  E1. Proefpersoon informatie_ESM 
studie_Vrijwilligers Versie 2.0(18.10.2017) and E2. IC_ESM_Versie 2.0 (18.10.2017)). One 
week after receiving this information, a telephone call will follow to answer any additional 
questions and to verify whether or not the subject is still interested in participating. If this is 
the case, the first visit will be scheduled at the medical centre to sign the informed consent 
form (by the participant as well as the researcher), receive the ESM login codes and 
additional retrospective questionnaires, and to instruct the participant about the study 
procedures. No study procedures will be performed until the informed consent form is signed. 
 
Study participation will comprise two appointments with the coordinating researcher. During 
the first visit written informed consent will be obtained and instructions about the study 
procedures (i.e. ESM and retrospective questionnaires) will be given. Hereafter, the 
participant will complete ESM and the SR-BD during the following week. At the end of the 
study, the single-time symptom questionnaires will be completed. At the end of this week 
another appointment (‘last visit’) follows during which a debriefing session concerning ESM 
will take place. In the case of included new patients, this appointment directly takes place 
after the patient is seen by the urologist for their regular outpatient visit. At that moment, all 
data are collected and study participation is completed. A timeline of the study period is given 
in figure 1. 
 

 
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3. STUDY POPULATION 
3.1 Population  
Thirty-three male and thirty-three female OAB patients will be recruited at the outpatient 
Pelvic Care Centre in Maastricht UMC+ the outpatient clinic Urology at Zuyderland 
Heerlen/Sittard and the outpatient clinic Urology at University Hospital Antwerp. Patients will 
be diagnosed with OAB by their urologist using the ICS criteria for OAB5.  
Furthermore, thirty-five male and thirty-five female healthy volunteers will be included in 
order to exploratively evaluate the ability of ESM to discriminate between OAB patients and 
healthy controls, in terms of triggers for the occurrence and/or persistence of urological 
symptoms. This control group will be sex- and age-matched to the group of OAB patients.  
 
3.2 Inclusion criteria  
3.2.1 
Inclusion criteria OAB patients 
Patients between 18-70 years with either subjectively experienced OAB for which they have 
sought medical help or have been diagnosed with OAB by a medical physician.  Participants 
need to be able to understand written Dutch and speak the Dutch language, since the ESM 
app will be conducted in Dutch. They also have to understand how to practice the ESM tool.  
3.2.2 
Inclusion criteria healthy volunteers 
 Age between 18 and 70 years; 
 Male and female 
 Ability to understand and speak Dutch; 
 Ability to understand how to utilize the ESM tool. 
 
3.3 Exclusion criteria 
3.3.1 
Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from 
participation in this study: 
 
Patients with a clear anatomical or other urological cause for OAB (e.g. bladder 
cancer, benign prostate hyperplasia (BPH), prostate cancer, urolithiasis, chronic or 
acute urinary tract infections (UTI), neurological disease).  
 
Patient with severe stress incontinence  
 
Pregnancy  
3.3.2 
Exclusion criteria healthy volunteers 
 Current or past diagnosis of lower urinary tract symptoms; 

 
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 No more than one urinary tract infection in half a year.  
 Start-up of regularly used medication from one month before inclusion until the end 
of study participation. 
 
3.4 Sample size calculation 
The outcome of the ESM is multidimensional; it gives information about the (urological) 
complaints but also the context in which the complaints arise. An inter-individual analysis can 
be made with the use of ESM, and because of this extensive data can be collected per 
patient. 
An appropriate sample size can therefore not be made.  
In previous literature the sample size differs from N=5 27, N= 10 38, N = 19 39, N= 26 1 to  
N=40 40.  In the study of Cabrita et. al. random slopes could not be included in the multilevel 
regression analysis  because of the sample size being too small to validly estimate all 
associated parameters, but an individual analysis with linear regression models with random 
intercept has been made.38 Other studies using ESM in a population between 19 to 40 
patients have shown that clinically relevant differences could be detected using an alpha of 
0.05.1,39-41 However, epidemiologic literature suggest that as a rule-of-thumb, a sample of at 
least N = 50 is required to evaluate construct validity42,43 and to recognize a factor pattern.44 
Therefore, we need to include at least 50 participants.  
Empirical studies using ESM  showed that about 5% to 23.2% of the patients did not comply 
(defined as completing the ESM questionnaire in less than 50% of the beeps).1,27,38-41 Taking 
into account a conservative non-valid ESM data rate of 23%, a sample size of 66 patients is 
needed to obtain 50 ESM questionnaires that can be used for the analysis. 

 
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4. METHODS 
4.1 Study parameters/endpoints 
Divided in three parts in accordance with the study objectives.  
4.1.1 
Part I 
Comparison of the ESM vs. SR-BDs  
Main study parameter/endpoint 
 Urgency scores as measured by two self-report measures: 
 
The ESM tool (i.e. momentary measurement) 
 
The sensation-related bladder diary (i.e. retrospective measurement 
with a recall period of several minutes) 
Secondary study parameters/endpoints (if applicable) 
 Symptom scores (other than urgency) as measured using the ESM tool: 
 
Micturition habits, i.e. number of micturitions each day and the force of 
the urinary stream using the Visual Prostate Symptom Score (VPSS) 
 Symptom scores (other than urgency) as measured using the single-time 
retrospective questionnaires: 
 
Urological symptoms:  
 
Female participants: OABq, ICIQ-FLUTS, 3IQ 
 
Male participants: OABq, ICIQ-MLUTS, 3 IQ, IPSS, IIEF-5   
4.1.2 
Part II Validation 
Main study parameter/endpoint 
 Urgency scores as measured by two self-report measures: 
 
The ESM tool (i.e. momentary measurement) 
 
The sensation-related bladder diary (i.e. retrospective measurement 
with a recall period of several minutes) 
Secondary study parameters/endpoints (if applicable) 
 Symptom scores (other than urgency) as measured using the ESM tool: 
 
Micturition habits, i.e. number of micturitions each day and the force of 
the urinary stream using the Visual Prostate Symptom Score (VPSS) 
(see Figure 2). 
 
Gastrointestinal symptoms 
 
Psychological symptoms 
 
Gynaecological symptoms 
 
Extra-intestinal somatic symptoms 

 
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 
Data on context and environment at each time an ESM questionnaire 
is completed  
 Symptom scores (other than urgency) as measured using the sensation-
related bladder diary: 
 
Micturition habits, i.e. number of micturitions each day  
 Symptom scores (other than urgency) as measured using the single-time 
retrospective questionnaires: 
 
Urological symptoms:  
 
Female participants: OABq, ICIQ-FLUTS, 3IQ 
 
Male participants: OABq, ICIQ-MLUTS, 3 IQ, IPSS, IIEF-5   
 
Psychological symptoms: HADS 
 
Gynaecological symptoms : Questionnaire Werkgroep Bekkenbodem 
NVOG 
 
Extra-intestinal symptoms and Quality of Life scores: SF-36 
 
Figure 2. The Visual Prostate Symptom Score. 
4.1.3 
Other study parameters (if applicable) 
Baseline parameters include: sex, age, body weight, type of disorder, socio-economic status, 
comorbidities and medication use. 

 
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4.2 Study procedures 
Participants will accomplish the Experience Sampling Method for seven consecutive 
days during their regular daily life. Previous ESM validation studies validated for the 
use of the ESM for seven days too.43   
During the last three consecutive days of the ESM, patients will also keep a SR-BD 
following the standard of care. A 7-day voiding diary is a reliable and valid method 
for documenting the change in symptoms of overactive bladder in men and women 
with predominantly urge incontinence. However, 3-day voiding diaries are as 
accurate as the 7-day diary, but patient burden is reduced. Therefore, a 3-day 
sensation-related bladder diary is used in the standard of care of the department of 
Urology of MUMC+, Zuyderland Heerlen/Sittard and University Hospital Antwerp.46,47 
Furthermore, during the first four days of the study, ESM outcomes are not 
influenced by outcomes reported with the sensation-related bladder diaries. This is 
in alignment with previous studies.4,43 
On the last day of the study period, participants will fill out the several retrospective 
symptom questionnaires. 
To accomplish the ESM, they need to carry their own smartphone or (in case they 
do not have one) another digital device, which will be lent to them for this period. On 
the smartphone or digital device an application, specifically developed for this 
project, will be downloaded. This application will run the PROM as follows. 
The concerning device will send out an auditory signal 10 times a day at random 
moments between 07:00 am and 22:00 pm. During 10 minutes following the signal 
participants can complete a questionnaire, i.e. the developed PROM, on the device 
(see F1. ‘ESM_Vragenlijst_Versie 1.0 (11.08.2017)’). After these 10 minutes the 
questionnaire will not be available until the next beep and is considered missing 
data. Therefore, subjects are instructed to complete as many questionnaires as 
possible each day, as soon as possible following each beep, but to pass over 
questionnaires when completing is impossible. For example, subjects should not fill 
out questions when driving a car. The questions will be identical between the 
different moments during the day.  
Additionally, participants will be instructed to complete a different ESM questionnaire 
in the morning when they wake up (see F1. ‘ESM_Ochtend Vragenlijst_Versie 1.0 
(11.08.2017)’). A timeline portraying which questionnaire has to be filled out at what 
time during the study period is reported in figure 2. 
 

 
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4.2.1 
PROM development 
 
 
The process of question selection for the development of an OAB specific 
ESM tool is a crucial step since content, construct and criterion validity are 
dependent on these questions. The questions that will be used were 
derived from previously published ESM studies and currently used OAB 
symptom questionnaires and further selection took place based on patients 
input during focus group interviews. Following, the items were evaluated by 
a multidisciplinary expert group consisting of highly esteemed and 
experienced investigators in the fields of urology, gastroenterology, 
psychiatry and gynaecology. Herewith, the number of items was further 
reduced in order to minimize the burden associated with completing the 
questionnaire at regular intervals. 
This stepwise approach was performed according to guidelines for 
symptom assessment tool development.  
4.2.2 
Tool development 
To apply ESM as a symptom assessment method in this study, an 
application suitable for smartphones has been developed. This application 
runs the previously selected set of items, as described in section 5.2.1.1. 
‘PROM development’.  
The application can be downloaded freely on the personal smartphone of 
each participating subject. Once the application is downloaded and 
activated, it will work both online and offline to ensure that no assessments 
will be missed when not connected to the Internet. In online situations the 
answers will be directly and automatically sent to the general database; 
when offline the answers will be temporary stored at the smartphone and 
will be sent to the database as soon as an Internet connection is available. 
Encryption of data to assure on patient’s privacy is described in detail in 
section 9.1 ‘Handling and storage of data and documents’. 
Questions in the application will be designed in a hierarchical order, i.e. if 
the patient has no symptoms at that particular moment, there is no rationale 
for assessing triggers and therefore these questions will be automatically 
set to a default of “no” or “none”. Further, if patients find an auditory signal 

 
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disturbing during their daily activities, they will be able to choose a vibration 
signal instead. 
 
4.2.3 
Retrospective symptom assessment – conventional questionnaires 
Apart from ESM, participants will be instructed to complete a SR-BD during 
last 3 consecutive days of filling out the ESM (see ‘F2. ESM_sensation-
related bladder diary_Versie 1.0 (11.08.2017)’). The SR-BD has to be filled 
out after each micturition. This is a voiding diary where people fill out at 
what time they had to void, how high the voided volume was and how high 
the urgency and perception of bladder fullness was what they experienced. 
Furthermore they have to fill out if and how much urine loss they had.    
Furthermore, participants will be instructed to complete additional (single-
time) retrospective questionnaires, at the end of the test period of 7 days: 
 
Baseline questionnaire for demographic characteristics (see F1. 
‘ESM_Algemene Vragenlijst_Versie 1.0 (11.08.2017)’). 
 
Sensation-related bladder diaries (see ‘F2. ESM_sensation-related 
bladder diary_Versie 1.0 (11.08.2017)’). Besides urinary frequency 
and voided volume, these diaries also include the degree of urge 
and the perception of bladder fullness during each void. It has been 
recommended that evaluation of bladder sensations during daily 
activities is the most representative. 48-50 Sensation-related bladder 
diaries (SR-BDs) are a non-invasive tool that is used to evaluate 
these bladder sensations in daily life.  
 
Overactive 
Bladder 
Questionnaire 
(OAB-q) 
(see 
F1. 
‘ESM_OABq_Versie1.0 (2016.10.17)’). 33-item questionnaire on 
LUTS and Health-related quality of life (HRQL) items.51  
 
3 Incontinence Questionnaire (3IQ) (see ‘F1. ESM_3IQ_Versie 1.0 
(11.08.2017)’)52 
 
Female participants only : 
o International 
Consultation 
on 
Incontinence 
Modular 
Questionnaire 
– 
Female 
LUTS 
(see 
F1. 
‘ESM_ICIQFLUTS_Versie 
1.0 
(11.08.2017)’).13-item 
questionnaire on lower urinary tract symptoms 53,54.   
o Vragenlijst Werkgroep Bekkenbodem NVOG (see ‘F1. 
ESM_VragenlijstNVOG_Versie 1.0 (11.08.2017)’). 47-short 
item questionnaire on pelvic symptoms. 

 
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 
Male participants only: 
o International 
Consultation 
on 
Incontinence 
Modular 
Questionnaire 
– 
Male 
LUTS 
(see 
‘F1. 
ESM_ICIQMLUTS_Versie 
1.0 
(11.08.2017)’).13-item 
questionnaire on lower urinary tract symptoms 53,54.   
o International 
Prostate 
Symptom 
Score 
(see 
‘F1. 
ESM_IPSS_Versie 1.0 (11.08.2017)’). 7 item questionnaire 
on LUTS and 1 item questionnaire on Quality of Life55.   
o International Index of Erectile Functions 5 (IIEF-5) (see ‘F1.  
ESM_IIEF5_Versie 1.0 (11.08.2017). 5-item questionnaire to 
screen for erectile dysfunction. 56 
 
Hospital Anxiety and Depression Scale (HADS) ((see ‘F1. 
ESM_HADS_Versie 1.0 (11.08.2017)’).57 
 
Short Form-36 (SF-36) (see F1. ESM_SF36_Versie 1.0 
(11.08.2017)’). Self-survey after general quality of life (not disease-
specific)58 
Figure 2: Questionnaire timeline. 
 
4.3 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. 

 
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4.4 Replacement of individual subjects after withdrawal 
We do not expect many dropouts, because the study is not very burdensome in a 
physical way and so, is not very difficult to complete. However, accomplishing ESM 
for 7 days is quite time-consuming and might intervene with daily activities, so 
possibly, not all subjects will be perfectly compliant to the method (i.e. completing 
the PROM at 10 random moments during 7 consecutive days). In case a subject 
decides to end participation before the 7-day participation period is completed, this 
subject will be considered a drop-out. Data can still be used in the comparison of 
assessment methods (part I), to determine the test-retest reliability and to assess 
the accuracy of the discriminatory model using a confusion matrix. 
4.5 Follow-up of subjects withdrawn from treatment 
Since there is no intervention involved in the study, there is no need for follow up of 
withdrawn participants. 
4.6  Premature termination of the study 
There are no expected reasons for premature termination of the study.  
 
 

 
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5. SAFETY REPORTING 
All safety reporting will be handled in accordance with METC protocol  
5.1 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. 
5.2 AEs, SAEs and SUSARs 
5.2.1 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 / 
the experimental intervention]. All adverse events reported spontaneously by the 
subject or observed by the investigator or his staff will be recorded. 
 
5.2.2 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. 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the 
accredited METC that approved the protocol, within 15 days after the sponsor has 
first knowledge of the serious adverse events. 
 

 
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SAEs that result in death or are life threatening should be reported expedited. The 
expedited reporting will occur not later than 7 days after the responsible investigator 
has first knowledge of the adverse event. This is for a preliminary report with another 
8 days for completion of the report.  
 
5.3 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  
 

 
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6. STATISTICAL ANALYSIS 
 
 
Part I – Comparison of the ESM to SR-BDs and other retrospective questionnaires 
In case of incomplete ESM data, we will not use imputation techniques as these techniques 
have similar assumptions on the mechanisms of missing data as the statistical model 
described in the remaining text. 
Experience Sampling Methods produce complex multilevel data structures, and analysis 
techniques need to take the variation between subjects and repeated measures within 
subjects into account. Associations between urological symptom scores of the SR-BD and 
corresponding ESM scores will be tested using linear mixed-effects models, with a random 
intercept to account for clustering of measurements within patients, and an autoregressive 
(AR1) covariate structure to account for correlations of measurements over time. Currently 
the SR-BD can be seen as the standard method and will therefore be used as dependent 
variable in the analysis. For each participant, ESM day-mean scores of individual symptoms 
will be used as predictor, to test whether average symptom scores of the day reﬂect the day-
mean SR-BD scores. 
To quantify the difference of scores between the two methods, ESM data will be subtracted 
from corresponding day-mean SR-BD scores, resulting in a delta score, which will be 
statistically tested using the same multilevel analysis, adjusting for repeated measures. In 
like manner, the differences between the mean SR-BD scores and ESM maximum scores of 
the day will be tested. 
To investigate if certain patient characteristics lead to a different retrospective perception of 
urgency, possible predictors of a larger delta-score (i.e. the differences in urgency reporting 
between ESM day-mean scores and the day-mean SR-BD scores) will be tested: i.e. gender, 
age, presence of comorbid panic disorder and psychological symptoms (HADS).  
 
 
 

 
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Part II Validation 
The COSMIN guidelines are used to validate the Experience Sampling Method as a health-
related ePRO. In this COSMIN (COnsensus-based Standards for selection of health 
Measurement INstruments) checklist manual, the methodology to examine responsiveness, 
i.e. “the instruments ability to detect change over time in the construct to be measured” gives 
the following instructions.59-61 Studies evaluating the measurement properties of an 
instrument should be of high methodological quality to guarantee appropriate conclusions 
about the measurement properties of the instrument. Therefore, the COSMIN initiative 
developed a taxonomy of measurement properties relevant for evaluating health instruments, 
with three domains: reliability, validity and responsiveness. Each domain contains one or 
more measurement property:59 
6.1 Primary study parameter 
Data used for analysis will comprise patient-reported scores from ESM, paper SR-
BDs and single-time paper symptom questionnaires. The PROM will be 
psychometrically evaluated with regard to validity and reliability. These parameters 
will characterize the ESM measure and allow insight into the potential role of this 
method in clinical practice. Validity and reliability will be assessed according to 
following components 29,62,63:  
 
Content validity reflects the extent to which the instrument as a whole 
measures all the relevant aspects that are indicative to the specific condition 
and population. This can be determined by taking into account evidence from 
qualitative studies, performing cognitive interviews to evaluate patients’ 
understanding with the instrument and by taking into account experts’ 
opinions 62,63. In this study, content validity is assured by basing ESM items 
on theoretical constructs from the literature as well as by performing patient 
focus groups and expert meetings. 
 
Concurrent validity reflects the correlation between a new test and an 
existing test that purport to measure the same construct. ESM scores will be 
correlated with scores of so-called ‘concurrent’ instruments. In the present 
study, ESM measures will be compared to scores obtained from SR-BDs 
and symptom questionnaires. Since ESM data have a hierarchical structure, 
with repeated measurements (level 1) nested within subjects (level 2), these 
analyses will be performed using linear mixed-effects models, including a 
random intercept and an autoregressive (AR1) covariate structure. 62,63. 
 To quantify the difference of scores between the two methods (ESM and SR-
BD), a delta score is calculated. Using the same multilevel analysis, thus 
adjusting for clustering within patients and for correlations between repeated 

 
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measures, we will test whether this delta score is different from 0. In like 
manner, the differences between SR-BD scores and ESM maximum scores 
of the day will be tested. 
 
Internal consistency is a reliability measure to analyse correlations between 
single items of an instrument/scale that are supposed to measure similar 
symptoms or domains. The homogeneity of a scale (e.g. internal 
consistency) is analysed by Cronbach’s α-statistic. A coefficient of at least 
0.6 is generally considered as acceptable, values above 0.8 are considered 
as good to very good 29,64-66. As subjects are usually not able to respond after 
every beep (for example because of driving a car), completion of ≥6 of the 10 
beep-questionnaires per day will be considered as being compliant. Not 
completed beep-questionnaires will be considered as missing values in the 
analyses.1,67 
 
Test-retest 
reliability 
reflects 
the 
consistency 
between 
repeated 
measurements of the same outcome in the same test conditions, but at 
different times. We will ascertain on individual response consistency over the 
study period. Scores of the first half-week will be correlated with scores of 
the second half-week. A test-retest reliability coefficient of more than 0.70 
will be considered adequate 29. 
 
Differences between OAB symptom scores assessed by the OAB-q / ICIQ-
FLUTS / IPSS and ESM could only be analysed on subject level, by paired 
sample t-test, due to lack of intra-subject variation in the OAB-q scores (only 
one measurement per subject). Scoring scales of the retrospective 
questionnaires and ESM will be harmonized by rescaling the ESM data from 
a 11-point to a 6-point and 5-point scale. In order to assess whether the 
rescaling affected the reliability of urological symptom related questions in 
ESM, a Cronbach’s a was calculated for the original and rescaled data. 
Subject-means (i.e. means over 7 days) of ESM data were calculated and 
compared to the corresponding OABq / ICIQ-FLUTS /IPSS scores.  
 
Following the COSMIN guidelines it should be aimed to assess the 
responsiveness of the ESM tool too. However, since responsiveness is the 
sensitivity of an instrument to detect difference between two points in time 
within groups68, this psychometric property, it is not meaningful to assess 
this, since the ESM measures repeatedly over a longer period of time (10 
times a day for 7 days). It is expected that there will be a fluctuation of 
symptoms during the assessment period, however ‘big’ differences that 
could be assessed with statistical analysis are not expected to occur. The 

 
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aim of this study is not to detect change between two groups with the use of 
statistical analysis. It is rather to evaluate symptom pattern recognition of the 
ESM tool. Therefore responsiveness will not be assessed as psychometric 
property in this study. 
A significance level (α) of 0.05 will be considered statistically significant. Data 
analysis will be performed using IBM SPSS Statistics software version 23.0 (IBM 
Statistics for Windows, Armonk, New York). 
 
 
6.2 Other study parameters 
 
Baseline characteristics / descriptives will be described as means and 
standard deviations (in case of normal distribution) or medians and 
interquartile ranges (in absence of a normal distribution) for continuous 
variables and frequencies for categorical variables. The following patient 
characteristics will be investigated: gender, age, race, length, weight, highest 
level of education, work status, smoking, alcohol use, drug use, caffeine use 
and medication. 
 
To investigate if certain patient characteristics lead to a different 
retrospective perception of urgency, possible predictors of a larger delta-
score (i.e. the differences in urgency reporting between ESM day-mean 
scores and the end-of-day SR-BD scores) will be tested: i.e. gender, age, 
presence of comorbid panic disorder, psychological symptoms (HADS) .   
 

 
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7.  ETHICAL CONSIDERATIONS 
7.1 Regulation statement 
This study will be conducted according to the Declaration of Helsinki (64th WMA General 
Assembly, Brazil, 2013), the Medical Research Involving Human Subjects Act (WMO) and 
EMA as well as FDA guidelines on the evaluation of treatments in OAB and development of 
patient-reported outcome measures.62,69,70  
 
7.2 Recruitment and consent 
7.2.1 
OAB patients 
 
Eligible patients are patients that are referred to the urologist by their general physician, 
other medical specialists or other hospitals with a differential diagnosis of OAB or urinary 
urgency incontinence.  Presently, all new patients that are seen in the outpatient clinic 
Urology in the MUMC+, the outpatient clinic Urology at Zuyderland Heerlen/Sittard and the 
outpatient clinic Urology at University Hospital Antwerp are triaged by the staff members of 
the urology department following the standard of care on the basis of the guidelines for 
urinary incontinence. 36,37 Patients that are referred with a differential diagnosis of OAB or 
urinary urgency incontinence receive SR-BDs and a HADS questionnaire by post, together 
with the information about the date of the outpatient clinic appointment in an information 
package. They are asked to fill these out and take these with them for their first urologist 
appointment.  
Since the patients already need to fill out these SR-BDs (and HADS) for their first regular 
urologist visit, patients will receive a recruitment letter within the information package   to 
inform them about the study (see ‘E3. Wervingstekst_ESM_Urologie_Versie 2.0 
(27.10.2017)’). They will also receive written information (see ‘E1. Proefpersoon 
informatie_ESM studie Versie 2.0(18.10.2017)’) about the purpose of the ESM study in this 
information package sent by the outpatient nurse. During the study, patients have to fill out a 
lot of questionnaires and repeated assessment of the ESM app. By contacting them prior to 
the first urology visit, there is no any additional burden of filling out an extra SR-BD (and 
HADS) for study purposes solely. Patients are asked to contact the coordinating investigator 
by email or telephone in case of interest in participation. If this is the case, the first visit will 
be scheduled with one week respite at the medical centre to sign the informed consent form 
(by the participant as well as the researcher) and to instruct the participant about the study 
procedures. No study procedures will be performed until the informed consent form is signed. 
After signing the informed consent form they will receive the login codes of the ESM app and 
the additional (retrospective) questionnaires.  This way of inclusion ensures that patients are 

 
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not entrusted with filling out an extra SR-BD for study purposes solely, since they already 
need to fill these out following the standard of care for their regular scheduled visit.  
  
7.2.2 
Healthy volunteers 
 
Healthy volunteers will be recruited by advertisements on bulletin boards at Maastricht 
University Medical Centre, other public bulletin board in Maastricht and on the website 
‘www.digiprik.nl’ (see ‘E4. Advertentie gezonde controles_ESM_Versie 2.0 (18.10.2017)’). 
Persons that are interested in participating after reading an advertisement are asked to 
contact the coordinating investigator via email and will then receive the written patient 
information letter and informed consent form  E1. Proefpersoon informatie_ESM_Vrijwilligers 
Versie 2.0(18.10.2017) and E2. IC_ESM_Versie 2.0 (18.10.2017)). One week after receiving 
this information, a telephone call will follow to answer any additional questions and to verify 
whether or not the subject is still interested in participating. If this is the case, the first visit will 
be scheduled at the medical centre to sign the informed consent form (by the participant as 
well as the researcher), receive the ESM login codes and additional retrospective 
questionnaires, and to instruct the participant about the study procedures. No study 
procedures will be performed until the informed consent form is signed. 
Healthy volunteers can report on the informed consent form if they want to be informed in 
case of a random “disease” finding. In case of random “disease” finding, patients will be 
treated with the standard care of treatment. 
 
7.3 Benefits and risks assessment, group relatedness 
Participating in this study does not bring along important risks, since subjects only have to 
complete questionnaires and there are no treatments or investigational products involved. 
Therefore, this is a low-risk study. However, completing the PROM several times a day might 
be quite burdensome and time-consuming for participants and will intervene with regular 
daily life. Completing the SR-BD by measuring the voided volumes with the use of a 
measuring cup is sometimes difficult to combine with professional or social life. Therefore, 
this could be considered a burden. However, new patients already need to fill out these SR-
BDs for their first regular urologist visit, so an extra completion of a SR-BD for study 
purposes solely will not be needed.  
Furthermore, since data are transferred via Internet and partly stored at a participant’s 
smartphone, there is a need for securing on an individual’s privacy. This is described into 
more detail in section 9.1 ‘Handling and storage of data and documents’. 

 
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During the study period, subjects will not directly benefit from participation, since they do not 
receive any interventional strategy. However, it is possible that completing the ESM 
questionnaires makes subjects more aware of their symptom patterns and possible 
provoking factors in daily life. Awareness could trigger symptoms and therefore be 
considered as a burden. Nevertheless, for the patients it could be beneficial too to know what 
triggers complaints, to cope better with their disease.  
All in all, the risks in this study are not disproportional in association with the benefits. 
Participants will be informed about the burdens before participating. 
7.4 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. 
 
7.5 Incentives  
Subjects will receive a 15 euro VVV-voucher compensation for participation in this study.  
Furthermore, travel expenses will be compensated. In UZA the VVV-vouchers are not valid, 
therefore an equal compensation will be given according to local guidelines. 

 
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8. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
8.1 Handling and storage of data and documents 
Obtained data will be coded for the protection of the privacy of the participants, in 
accordance with the Dutch Personal Data Protection Act (Wet Bescherming 
Persoonsgegevens, 2000). Data will be coded (“ESM_OAB_001”, “ESM_OAB_002” etc, 
The allocated number is associated with the order of entrance in the study. 
This way it is not convertible to the subject. This code is linked to the name, address, date 
of birth and telephone number of the subject. The principal investigator will keep the key 
of the code in a locked cabinet, to which only the PI has access. Access to the data will 
be permitted to all members of the project team, the IGZ, the medical-ethical committee 
(MEC) and assigned monitors from the Clinical Trial Center Maastricht (CTCM). The data 
will be stored for 15 years after the end of the study. 
Data that is collected on paper, i.e. the SR-BDs (see 9.1.1 ‘Retrospective symptom 
assessment – conventional questionnaires’), will be stored in a locked cabinet at SURO 
4.15 at MUMC+. The SR-BDs from Zuyderland Heerlen/Sittard and University Hospital 
Antwerp will be scanned and sent by e-mail, anonymized with the study ID for the 
protection of the privacy of the participants via Microsoft Outlook from one computer, 
protected with a password, to the other computer, protected with a password. The paper 
version of the SR-BDs will be stored in a locked cabinet in the office of drs. Kuenen and 
prof. dr. De Wachter. 
Data that is collected digitally, i.e. in- and exclusion criteria, demographic characteristics 
and (single-time) retrospective questionnaires (see 9.1.1 ‘Retrospective symptom 
assessment – conventional questionnaires’), will be collected using Castor EDC. 
Following, this data will be stored on the MIT server of the MUMC+. Backups will be 
automatically obtained every day, using the MIT server of MUMC+. 
All data obtained from the ESM application (i.e. downloaded on the participant’s 
smartphone) will be transferred to a certified and secured database using the local 
Internet network. Data is automatically encrypted and saved according to the NEN 7510- 
and ISO/IEC 27001/27002 guidelines, hereby respecting the Dutch Personal Data 
Protection Act (Wet Bescherming Persoonsgegevens, 2000) and Good Clinical Practice 
guideline. In case a participant completes an ESM assessment in the absence of an 
online Internet connection the obtained data are temporary stored at the concerning 
mobile device. For this, a specific asymmetric encryption using a logon procedure with 
individual username and password will be used to guarantee a subject’s privacy. Data will 
be transferred to the secured database as soon as there is an online Internet connection 
again. 

 
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8.2 Monitoring and Quality Assurance  
A qualified monitor of the CTCM will monitor the conduct of the study. A monitoring plan 
will be drafted after the first application to the METC. 
 
8.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
8.4 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.  
 
8.5 End of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. 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 
within 15 days, including the reasons for the premature termination. 
 
 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. 
 
8.6 Public disclosure and publication policy 
Publication will occur in accordance with the CCMO-statement on publication policy 
(CCMO-statement publicatiebeleid, 2002). Because publications on the validation of a 

 
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real-time symptom assessment method in OAB patients do not exist, the results of this 
study will be published in a peer reviewed journal.  

 
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