Early Versus Delayed Trial Without Catheter in Men With Acute Urinary Retention: a Randomized Controlled Trial (the RELIEF Study).
Phase: NA
Conditions: Acute Urinary Retention, Benign Prostate Obstruction, Benign Prostate Hyperplasia, Benign Prostate Hypertrophy(BPH)
Sponsor: Liselot Ribbert

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RESEARCH PROTOCOL  
RELIEF STUDY  
(May 2025) 
 
 
 
 
 
 
 
 

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PROTOCOL TITLE ‘Early Versus Delayed Trial Without Catheter in Men with Acute Urinary 
Retention: a Randomized Controlled Trial (the RELIEF study).’ 
 
Protocol ID 
NL-009284 
Short title 
RELIEF study 
Version 
1.1 
Date 
19-05-2025 
Coordinating investigator/project 
leaders 
 
Coordinating investigator: 
XX 
Project leaders: 
XX 
XX 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
 
Isala – XX 
 
Alrijne Ziekenhuis – XX 
Catharina Ziekenhuis – XX 
Canisius Wilhelmina Ziekenhuis – XX 
Martini Ziekenhuis – XX 
Maastricht UMC - XX 
Onze Lieve Vrouwe Gasthuis – XX 
Spaarne Gasthuis – XX 
St. Jansdal – XX 
Ziekenhuisgroep Twente – XX 
Zuyderland Ziekenhuis – XX 
 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Isala, afdeling Urologie  
 
 
 
Subsidising party 
ZonMw 
Independent expert(s) 
Dr. XX 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
XX 
 
 
 
Coordinating Investigator: 
XX 
 
Principal Investigator: 
XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS  
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 9 
2. 
OBJECTIVES ................................................................................................................11 
3. 
STUDY DESIGN ...........................................................................................................12 
4. 
STUDY POPULATION ..................................................................................................15 
4.1Population (base) .........................................................................................................15 
4.2Inclusion criteria ...........................................................................................................15 
4.3Exclusion criteria ..........................................................................................................15 
4.4Sample size calculation ................................................................................................15 
5. 
TREATMENT OF RESEARCH PARTICIPANTS ...........................................................16 
5.1Investigational product/treatment .................................................................................16 
5.2Use of co-intervention (if applicable) ............................................................................16 
5.3Escape medication (if applicable) .................................................................................16 
6. 
METHODS ....................................................................................................................17 
6.1Study parameters/endpoints ........................................................................................17 
6.1.1 
Main study parameter/endpoint .......................................................................17 
6.1.2 
Secondary study parameters/endpoints (if applicable) ....................................17 
6.1.3 
Other study parameters ...................................................................................17 
6.2Randomization, blinding and treatment allocation ........................................................18 
6.3Study procedures .........................................................................................................18 
6.3.1 
Catheter withdrawal.........................................................................................18 
6.3.2 
Follow-up ........................................................................................................18 
6.4Withdrawal of individual research participants ..............................................................19 
6.5Replacement of individual research participants after withdrawal .................................20 
6.6Follow-up of research participants withdrawn from treatment .......................................20 
6.7Premature termination of the study ..............................................................................20 
7. 
SAFETY REPORTING ..................................................................................................21 
7.1Temporary halt for reasons of research participant safety ............................................21 
7.2AEs, SAEs ...................................................................................................................21 
7.2.1 
Adverse events (AEs) ......................................................................................21 
7.2.2 
Serious adverse events (SAEs) .......................................................................21 
7.3Follow-up of adverse events ........................................................................................22 
7.4Data Safety Monitoring Board (DSMB) / Safety Committee ..........................................22 
8. 
STATISTICAL ANALYSIS .............................................................................................23 
8.1Primary study parameter(s) ..........................................................................................23 
8.2Secondary study parameter(s) .....................................................................................23 
8.3Other study parameters ...............................................................................................24 
8.4Interim analysis (if applicable) ......................................................................................24 
9. 
ETHICAL CONSIDERATIONS ......................................................................................25 
9.1Regulation statement ...................................................................................................25 
9.2Recruitment and consent .............................................................................................25 

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9.2.1 
Recruitment .....................................................................................................25 
9.2.2 
Informed consent procedures ..........................................................................25 
9.2.3 
Digital informed consent ..................................................................................26 
9.3Benefits and risks assessment, group relatedness .......................................................26 
9.4Compensation for injury ...............................................................................................27 
9.5Incentives (if applicable) ...............................................................................................27 
10. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................28 
10.1Handling and storage of data and documents ............................................................28 
10.2Monitoring and Quality Assurance..............................................................................28 
10.3Amendments ..............................................................................................................29 
10.4Annual progress report ...............................................................................................29 
10.5Temporary halt and (prematurely) end of study report ................................................29 
10.6Public disclosure and publication policy .....................................................................29 
11. 
REFERENCES ..........................................................................................................30 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
AUR 
Acute Urinary Retention 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
DM  
Diabetes Mellitus 
DRE 
Digital Rectal Examination 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
ICF 
Informed Consent Form 
ICIQ 
International Consultation on Incontinence Questionnaires 
IPSS 
International Prostate Symptom Score 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
PV 
Prostate Volume 
QoL 
Quality of Life 
Review 
committee 
Medical research ethics committee (MREC) or CCMO 
 
(S)AE 
(Serious) Adverse Event 
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. 
TUC 
Transurethral Catheter 
TWOC 
Trial Without Catheter 
UAVG 
Dutch Act on Implementation of the General Data Protection 
Regulation; in Dutch: Uitvoeringswet AVG 
UTI 
Uninary Tract Infection 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 

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SUMMARY 
Rationale: Management of acute urinary retention (AUR) with a transurethral catheter (TUC) 
lacks consensus on the optimal duration. Existing research shows conflicting results, and 
practice variation among urologists is high. A shorter catheterization period may reduce 
complications, improve patient comfort, and lower costs, whereas a longer duration may 
improve success rates of trial without catheter (TWOC). We hypothesize that a 3-day 
catheter duration is non-inferior to a 14-day duration regarding re-catheterization rates, with 
the potential for fewer complications and improved quality of life (QoL). 
Objectives: Main Objective: To determine whether the re-catheterization rate following a 
short (3-day) TUC duration is non-inferior to that following a long (14-day) TUC duration in 
men with acute urinary AUR treated with both TUC and alpha-blockers. Secondary 
Objectives: To assess differences in patient-centered outcomes (symptoms, QoL), process 
outcomes (complications), and resource outcomes (healthcare and societal costs) between 
the two catheter durations. 
Study design: Multicenter, randomized, controlled, non-inferiority trial with a 1:1 allocation to 
either a short or long catheter duration (ZonMw funded, dossiernummer: 10390032310057). 
Study population: Adult men with AUR treated with a TUC and alpha-blockers.  
Intervention: TWOC 3 days after catheter insertion. 
Main study parameters/endpoints: Re-catheterization rate immediately after TWOC 
(success vs. failure of spontaneous voiding).  
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: All participants undergo standard AUR procedures: TUC placement, 
alpha-blocker therapy, TWOC, and follow-up visits. A shorter catheter duration may reduce 
the risk of catheter-related infections and discomfort, while maintaining similar re-
catheterization rates. However, it may also increase the likelihood of early AUR recurrence. 
Both groups complete questionnaires on days 3 and 12, and at 1, 2, 3 and 6 months. This 
study is expected to offer a more efficient, evidence-based approach to AUR management, 
potentially improving patient well-being and reducing healthcare expenditures. 
 
 

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1. INTRODUCTION AND RATIONALE 
 
Acute urinary retention (AUR) in men is a urological emergency, defined as a sudden and 
painful inability to pass urine (1). It is widely acknowledged as a serious complication linked 
to the progression of benign prostatic hyperplasia (BPH). In The Netherlands alone, 
approximately 40,000 men experience AUR annually. Standard management typically 
involves the placement of a transurethral catheter (TUC) and the administration of an alpha-
blocker, followed by a trial without catheter (TWOC) to evaluate whether patients are able to 
resume spontaneous micturition. However, the optimal catheter duration prior to TWOC 
remains undetermined. 
 
Despite its high prevalence, AUR and its management have not been conclusively studied, 
leading to its identification as a knowledge gap in the Dutch Urological Society (NVU) 2020-
2024 agenda (2). Research on catheter duration has yielded conflicting results. Some 
publications suggest that a longer catheterization period may enhance TWOC success rates, 
while others find no significant difference (3-10). This inconsistency is reflected in clinical 
practice, where the duration of catheterization varies significantly. A recent Dutch cross-
sectional study (AUR-SNAPSHOT, ZonMw funded, dossiernummer: 10390092110026) 
reported TUC use ranging from 6 to 24 days (median 15 days), further highlighting the lack of 
consensus (11).  
 
This uncertainty places a significant burden on patients, as longer catheter use may cause 
discomfort, elevate the risk of infections, and increase healthcare costs (6,7,8,10,12,13). The 
AUR-SNAPSHOT study also underscores the need for further investigation into the impact of 
catheter duration on complications within the AUR population, such as hematuria (12.3%), 
urinary tract infections (10.3%), and urosepsis (4.3%) (11). These findings serve as a 
springboard for the RELIEF study, which aims to generate high-quality evidence to fill the 
existing gaps. 
 
The RELIEF study will focus on adult men presenting with AUR, the primary group affected 
by BPH-related urinary complications. Evidence suggests that alpha-blocker therapy 
enhances TWOC success, achieving steady-state levels around day three (14-19).  Among 
five guidelines (20-24), two (20,23) endorse a three-day catheterization period, largely based 
on expert consensus, while the others do not specify a recommendation on catheter 
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The absence of conclusive data and definitive guidelines underscores the necessity for a 
well-designed study to assess whether a shorter catheterization duration (3 days) is non-
inferior to a longer duration (14 days) in terms of re-catheterization rates. The RELIEF study 
will address this gap by systematically evaluating both clinical and patient-centered 
outcomes, including complications, quality of life (QoL), and healthcare expenditure. 
 
By directing attention to men with AUR, who frequently experience significant pain and 
discomfort, this research aims to determine the most effective, patient-centered, and cost-
efficient catheter duration in a population for which standardized care is urgently needed. 
Such findings may substantially refine clinical recommendations, reduce practice variation, 
and ultimately improve the well-being of men with AUR. 

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2. OBJECTIVES 
 
Primary Objective:  
To determine whether the re-catheterization rate after a short catheter duration (3 days) is 
non-inferior to that after a longer catheter duration (14 days) in men with AUR who are 
treated with a TUC and alpha-blocker therapy.  
This central question dictates the study design and required sample size.  
 
Secondary Objective(s):  
• 
Patient-Centered Outcomes: To compare the impact of a short (3-day) vs. long (14-
day) catheter duration on patient-reported symptoms and QoL. 
• 
Resource-Related Outcomes: To evaluate whether a shorter catheter duration reduces 
healthcare and societal costs compared to a longer duration. 
• 
Process-Related Outcomes: To assess differences in complication rates, such as 
hematuria, catheter-associated urinary tract infections (CAUTI), or catheter-related 
discomfort between the two catheter durations. 
 
Hypothesis 
It is hypothesized that a 3-day catheter duration will not be inferior to a 14-day catheter 
duration regarding re-catheterization rates. Furthermore, shorter catheterization is expected 
to yield fewer symptoms and complications, improved QoL and lower costs compared to 
longer catheterization in men with AUR. 
 

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3. STUDY DESIGN 
 
A multicenter, randomized, controlled, non-inferiority trial will be conducted with a 1:1 
allocation (computer-generated, variable block sizes). Due to the variation in catheter 
durations, blinding of participants and clinicians is not feasible during the trial. However, data 
analysts will remain blinded to the group assignments of each participant.  
A total of 11 Dutch hospitals will be participating. 
 
Justification for the design 
We conduct an RCT rather than an observational study, in which all patients would undergo 
a 3-day TWOC, followed by a 14-day TWOC for those who fail the initial attempt. An 
observational design would not allow for a direct comparison of primary and secondary 
outcomes between equivalent groups. 
The choice for a 3-day catheterization period is based on the pharmacodynamic profile of 
alpha-blockers. With daily administration, steady-state plasma levels are typically reached 
within 2 to 3 days (14-19). This corresponds with the time point at which the maximal 
therapeutic effect on alpha-1 adrenergic receptors in the bladder, prostate, and urethra is 
expected - leading to optimal smooth muscle relaxation and improved conditions for a 
successful TWOC. 
A non-inferiority design is the most suitable approach to assess whether a 3-day catheter 
duration is at least as effective as a 14-day duration in reducing the need for re-
catheterization. This design was selected over a superiority design, as we anticipate only a 
small difference in re-catheterization rates between the two study groups. 
 
Non-inferiority margin 
A non-inferiority margin of 12% was selected based on statistical considerations, clinical 
relevance, and the feasibility of achieving realistic sample sizes in the study arms. Three 
prior randomized controlled trials reported no significant differences in re-catheterization 
rates between short and long catheter durations, ranging from 11% to 16.4% (4,5,10). 
Additionally, the 12% margin was considered appropriate by an expert panel that contributed 
to the development of the study protocol. The panel discussed that when more frequent re-
catheterization in the study group occurs, the associated clinical risks are relatively low, and 
potential complications are generally mild and manageable.  A broader non-inferiority margin 
is deemed acceptable, as it is expected that the benefits of reduced catheter burden across 
the entire population, such as fewer complications and improved patient comfort, will 
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the implementation of a strict non-inferiority margin would result in a risk of Type II error, 
where the intervention might incorrectly be deemed inferior. 
Altogether, this margin offers a feasible and robust approach to addressing the primary 
research question. 
 
Duration and setting 
The follow-up period to capture the primary outcome, as well as short-term catheter-related 
complications and costs will last 6 months. An additional 12 months of medical record 
screening will be conducted to document any potential interventions for BPH, along with 
long-term complications (primarily urethral strictures). All TWOC procedures will be 
conducted in an outpatient or clinical setting. 

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Figure 1: Flow diagram - Patient inclusion  
 
 
 

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4. STUDY POPULATION 
 
4.1 Population (base)  
 
Adult men diagnosed with AUR and treated with a transurethral catheter (TUC) and alpha-
blocker therapy are eligible for inclusion in the study.  
 
4.2 Inclusion criteria 
 
To participate in this study, a subject must meet all of the following criteria:  
1. Adult man;  
2. Diagnosed with AUR treated with a transurethral catheter (TUC) and alpha-blocker 
therapy; 
3. Mentally competent and understanding of benefits and potential burden of the study;  
4. Written or digital informed consent. 
 
4.3 Exclusion criteria  
 
Patients who meet any of the following criteria will be excluded from participation in this 
study: a failed prior TWOC, urinary retention >1500ml, usage of an alpha-blocker other than 
tamsulosin, silodosin or alfuzosin, neurogenic bladder dysfunction (e.g. multiple sclerosis, 
spinal cord injury, spina bifida, vertebral disc prolapse), history of prostate cancer (ISUP 
grade group ≥ 2), active bladder cancer or undergoing follow-up for bladder cancer, urinary 
retention following surgery (within 72 hours post-operation), history of lower urinary tract 
surgery (e.g., bladder augmentation, urethral surgery, prostate surgery), bladder stones, 
suspected urethral stricture, clot retention, urosepsis or a contra-indication for alpha blocker 
therapy. 
 
4.4 Sample size calculation 
 
Based on previous studies (1,8,24), both groups are assumed to have a 50% re-
catheterization rate. With a one-sided alpha of 0.05 and a power of 80%, 215 participants per 
arm are needed to detect a predefined non-inferiority margin. Including an anticipated 10% 
dropout, the final requirement is 239 participants per arm.  
Given an annual incidence of approximately 40,000 AUR cases in the Netherlands and the 
participation of multiple hospitals, this sample size is considered feasible.  

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5. TREATMENT OF RESEARCH PARTICIPANTS 
 
5.1 Investigational product/treatment 
 
The proposed intervention involves performing a trial without catheter (TWOC) three days 
after catheter insertion in men with AUR. This study exclusively includes patients who 
continue or initiate alpha-blocker therapy as part of standard care. Multiple systematic 
reviews support the efficacy of alpha-blocker therapy prior to TWOC, leading to its 
recommendation in several guidelines (20-23). Thus, no medication is administered or tested 
within the scope of this study.  
 
5.2 Use of co-intervention (if applicable) 
 
Not applicable. 
 
5.3 Escape medication (if applicable) 
 
Not applicable.  
 
 
 

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6. METHODS 
6.1 Study parameters/endpoints 
6.1.1 
Main study parameter/endpoint 
Re-catheterization rate after TWOC. 
6.1.2 
Secondary study parameters/endpoints (if applicable) 
Patient important outcomes: 
1. Symptoms measured by 'International Prostate Symptom Score' (IPSS: voiding 
and storage symptoms) and International Consultation on Incontinence 
Questionnaire - Long-Term Catheter Quality of Life (ICIQ-LTCQoL: catheter 
symptoms and concern) on days 3 and 12, and at 1, 2, 3, and 6 months. 
2. QoL measured by EuroQol 5 Dimensions, 5 Levels questionnaire (EQ-5D-5L: 
general health and QoL) on days 3 and 12, and at 1, 2, 3, and 6 months. 
 
Process related outcomes:  
Catheter related complications (e.g., macroscopic hematuria, CAUTI, urosepsis, 
catheter related pain or other catheter related problems, urethral strictures), 
assessed through medical record review and telephone evaluation. All 
complications will be classified according to the Clavien-Dindo classification 
system.   
 
Resource related outcomes: 
1. Health care costs (e.g., costs of (re)catheterization, diagnosis and treatment of 
complications, and hospital admissions) over a 6-month time horizon, assessed 
through medical record review and the iMTA Medical Consumption Questionnaire 
(iMCQ) at 3 and 6 months. 
2. Social costs: productivity losses over a 1-month time horizon, assessed using 
the iMTA Productivity Cost Questionnaire (iPCQ) at 1, 2, 3 and 6 months. 
 
6.1.3 
Other study parameters  
 
Baseline characteristics will include age, weight, height, medical history (e.g., 
diabetes mellitus, cardiovascular disease, and neurological disorders), retention 
volume, and prostate volume (PV). 
 
 

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6.2 Randomization, blinding and treatment allocation 
 
Randomization will be automated and computer-generated using a 1:1 allocation ratio with 
variable block sizes through a secure, web-based randomization software, ensuring 
concealed allocation. Blinding of participants and medical staff during the trial is not feasible. 
To ensure an unbiased assessment, data analysts will remain blinded to the treatment 
assignments throughout the analysis phase. 
 
6.3 Study procedures 
6.3.1 
Catheter withdrawal  
 
Detailed recruitment and consent procedures are outlined in Chapter 9.2. Once 
consent is obtained, either the local or the coordinating investigator will randomize 
the participant and subsequently notify both the patient and the hospital planning 
team. All TWOC procedures will be conducted in an outpatient or clinical setting, 
with participating hospitals scheduling these procedures while adhering to the 
allocated catheter duration. If a TWOC procedure falls on a weekend, it will be 
rescheduled to the next working day, with this adjustment applied equally across 
both groups. 
If the TWOC is successful (generally defined as a voided volume over 100 ml and 
post-void residual volume under 200 ml), re-insertion of the catheter is not 
required. Patients may either return for follow-up or be discharged, depending on 
local hospital protocols. In case of an unsuccessful TWOC, a catheter will be 
reinserted, and the endpoint of re-catheterization is reached. Further steps will 
generally adhere to the European Association of Urology guidelines (22), although 
they may vary based on the local team’s approach and patient preferences. 
6.3.2 
Follow-up  
 
The primary outcome measure, re-catheterization following TWOC, will be 
obtained either 3 or 14 days after initial presentation with AUR. Most secondary 
outcomes, including patient-reported symptoms, QoL, short-term complications, 
medical costs, and societal costs, will be evaluated after 1, 2, 3, and 6 months. 
Long-term complications, along with routine follow-up care, will be monitored 
through passive data collection over an additional 12 months, yielding a total study 
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Telephone assessment 
The investigator will contact participants by phone 30 days after catheter removal / 
TWOC to document any short-term complications related to catheter use.  
 
Medical record review 
Data on long-term complications (primarily strictures) will be collected through 
medical record review over an 18-month follow-up period. Furthermore, all 
standard follow-up care participants receive after TWOC will be documented 
throughout this period. 
 
Questionnaires 
Patient-reported symptoms and QoL will be assessed using Dutch versions of 
three validated questionnaires. The EQ-5D-5L is a general QoL questionnaire 
evaluating five dimensions of health (25). The IPSS assesses urinary symptoms in 
patients with BPH (26), whereas the ICIQ-LTCQoL focuses on catheter-related 
symptoms and concerns (27). Validation of a Dutch version of the latter is currently 
being conducted. Patients will complete all three questionnaires three days post-
catheter insertion for baseline assessment. After 12 days and 1, 2, 3, and 6 
months, the IPSS will be administered to patients who no longer have a catheter, 
while the ICIQ-LTCQoL will be completed by patients with an indwelling catheter.  
 
Two additional questionnaires will be employed to contribute to a cost-
effectiveness analysis. The iPCQ quantifies productivity losses resulting from 
illness (28), and will be completed at 1, 2, 3 and 6 months post-enrollment. The 
iMCQ will be completed at 3 and 6 months post-enrolment to capture both direct 
medical costs, such as healthcare and medication use, and non-medical costs, 
including travel expenses and assistance provided by family or friends (29).  
 
All questionnaires will be completed digitally. For patients who are illiterate or lack 
digital skills, telephone interviews will be offered as an alternative. 
 
6.4 Withdrawal of individual research participants 
 
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 

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medical reasons, or if the medical condition of the patient changes and in- or exclusion 
criteria are no longer met.  
 
6.5 Replacement of individual research participants after withdrawal 
 
Subjects withdrawn from the study after recruitment (recruitment defined as signing of the 
informed consent form) will not be replaced. We anticipated a 10% drop-out rate during our 
power calculation. 
 
6.6 Follow-up of research participants withdrawn from treatment 
 
Patients withdrawn from the study will be followed-up by their treating physician conform 
standard treatment procedure. 
 
6.7 Premature termination of the study 
 
Premature termination of the study is not anticipated, as potential re-catheterization following 
an early catheter removal is not considered a severe medical intervention or complication. 
 
 

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7. SAFETY REPORTING 
 
7.1 Temporary halt for reasons of research participant 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. 
 
7.2 AEs, SAEs  
7.2.1 
Adverse events (AEs) 
 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to trial procedures. All AEs 
related to the catheter, TWOC, or potential re-catheterization will be recorded, 
whether reported spontaneously by the subject or observed by the investigator or 
his staff.  
7.2.2 
Serious adverse events (SAEs) 
 
A serious adverse event is any untoward medical occurrence or effect that  
- 
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; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
 
An elective hospital admission will not be considered as a serious adverse event. 
 
Due to the high amount of expected (serious) adverse events caused by treatment 
of the patients as part of standard care, only study related (S)EAs will be reported 
immediately. This means all (S)AEs related to participation in this study protocol, 

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meaning an early TWOC procedure and potential re-catheterization, will be 
reported. All other (S)AEs will not be reported, as no patient benefit is expected 
from this.  
 
Local investigators report all study-related SAEs to the sponsor without undue 
delay after obtaining knowledge of the events. The sponsor will subsequently 
report the SAEs through the web portal Research Portal 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 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. 
 
7.3 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.  
 
7.4 Data Safety Monitoring Board (DSMB) / Safety Committee 
 
Not applicable. 
 
 
 

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8. STATISTICAL ANALYSIS 
 
Statistical analyses will be performed using SPSS (IBM, version 26). All analyses will be two-
sided, and a p-value of less than 0.05 will be considered indicative of statistical significance. 
Baseline characteristics will be summarized and reported using frequency (percentage) for 
categorical variables, and mean ± standard deviation (SD) or median (interquartile range, 
IQR) for continuous variables. 
Randomization minimizes confounding. If any imbalance arises in baseline covariates, 
adjusted analyses will be performed.  
Due to potential loss to follow-up, we anticipate some missing data. We will assume the data 
is missing at random and handle it using multiple imputation with chained equations. This 
method will create 25 imputed datasets, with results subsequently pooled using Rubin's rules 
to ensure reliable analysis.  
 
8.1 Primary study parameter(s) 
 
For the primary outcome of this RCT, we will compare the percentage of patients undergoing 
re-catheterization after unsuccessful TWOC. Primarily, an intention-to-treat analysis will be 
performed, followed by an additional per-protocol analysis. If the 95% confidence interval for 
the difference in re-catheterization rates lies entirely within 12% (non-inferiority margin, as 
described in chapter 4.4), non-inferiority of the 3-day duration is declared. A mixed-effects 
model will be employed to account for the clustered data from the different participating 
hospitals.   
 
8.2 Secondary study parameter(s)  
 
Complications 
Complication rates at 21 days, 6 months, 12 and 18 months (e.g., hematuria, infection) will 
be compared using Fisher’s exact test. This statistical test will help determine if there is a 
significant disparity in complication rates. 
 
Patient reported outcomes  
Changes in QoL (measured by IPSS-Qol, ICIQ-LTCQoL, and EQ-5D-5L) will be analyzed 
with longitudinal covariance analysis. This analytical approach will enable us to investigate 
the evolution of QoL over time in the different treatment groups. 

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Cost analysis 
The economic evaluation will be performed alongside the clinical trial and is designed as a 
cost-effectiveness analysis from a societal perspective. The analysis will take a time horizon 
of 6 months after enrolment in the study. Bootstrapping will be used to calculate the 
distribution of the ICER, which will be shown in a cost-utility plane. 
 
8.3 Other study parameters 
 
Not applicable.  
 
8.4 Interim analysis (if applicable) 
 
No interim analysis is planned to minimize type I error (incorrectly rejecting the null 
hypothesis when it is true). 

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9. ETHICAL CONSIDERATIONS 
 
9.1 Regulation statement 
 
The study will be conducted according to the principles of the Declaration of Helsinki (date 
13th of December 2024, see for the most recent version: www.wma.net) and in accordance 
with the Medical Research Involving Human Subjects Act (WMO) and other guidelines, 
regulations and Acts.  
 
9.2 Recruitment and consent 
9.2.1 
Recruitment 
 
Participants will be identified upon presentation with AUR, either in the emergency 
department or at the urological outpatient clinic. Alternatively, patients may be 
enrolled following referral from their general practitioner or the GP emergency 
service (in Dutch: Huisartsenpost). 
9.2.2 
Informed consent procedures 
 
After catheterization, eligible patients will be informed about the study and receive 
a written Patient Information Form (PIF) from the attending physician. With the 
patient’s permission, contact details will be shared with the coordinating 
investigator or a delegated member of the study team, who will subsequently 
contact the patient by phone to answer any questions and provide further 
clarification. Detailed information about the study objectives and procedures is 
additionally available on the study’s website, along with an informative video. Each 
subject must be informed that participation in the study is voluntary and that refusal 
to provide consent will not affect the doctor-patient relationship.  
Given the acute nature of the condition and the potential need for a TWOC within 
three days, an efficient informed consent process is required. The traditional 
method of signing the ICF at home and returning it by postal mail is not feasible, as 
this process would exceed the three-day timeframe.  
 
Once the patient has received the study information, they will be given at least 24 
hours to consider participation. Following this reflection period, informed consent 
may be provided either by physically submitting the signed Informed Consent Form 
(ICF) to the hospital, or by completing a digital informed consent procedure via the 

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secure REDCap system. In the case of written consent, the local principal 
investigator or a delegated member of the study team will co-sign the ICF upon 
receipt. For digital consent, the coordinating investigator or a delegated team 
member will electronically countersign the form within the REDCap environment. 
Randomization will only occur after both the patient and the local or coordinating 
investigator (or their delegate) have signed the informed consent form. 
 
9.2.3 
Digital informed consent 
 
In compliance with privacy regulations, REDCap -a secure web-based application 
for managing online databases- is utilized. REDCap includes a specialized module 
that enables the secure transmission of digital PIFs and ICFs. Participants will 
provide their digital signatures using a computer mouse or touchscreen, depending 
on their device. 
To ensure the validity of electronic signatures, three key conditions are met: 
1. 
Identification. Digital ICFs will be provided exclusively to eligible patients 
following identification by their attending physician. Patients’ details, including 
email, will be securely transmitted to the coordinating investigator to ensure 
the correct individual receives the form. Access to the ICF will be restricted 
through two-factor authentication, utilizing the provided, personal email 
address. 
2. 
Document integrity. Signed forms are stored as immutable PDFs, preventing 
alterations. Participants receive electronic copies for their records.  
3. 
Timestamping. As REDCap includes an audit trail feature, all data related to 
the signing process will be systematically recorded. 
 
Study-related data will not be accessible to the service provider. Each participant 
will be assigned a unique REDCaP study ID. The Subject Identification Code List, 
which contains the participant's name, date of birth, and email address, will be 
stored separately from other study data. Access to this list will be restricted to 
study team members involved in study management. 
Details regarding the reliability and confidentiality of the e-consent process are 
provided in document 'K6. E-consent Questions and Answers CCMO-UMCG'. 
 
9.3 Benefits and risks assessment, group relatedness 
 

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The primary treatment for AUR is to drain the bladder using a TUC. This procedure offers 
immediate pain relief, decompresses the bladder, and prevents potential renal damage. It is 
regarded as a safe procedure and can be performed by trained nurses, GPs, (emergency) 
doctors, or urologists. TWOC is defined as removal of the catheter with subsequent 
observation of spontaneous micturition.  
 
Both study groups will undergo a TWOC, differing solely in timing. A 14-day catheterization 
duration aligns closely with the median duration observed in Dutch clinical practice (11). A 
potential burden for participants in the study group may be a higher likelihood of 
unsuccessful TWOC, leading to more frequent re-catheterization. However, the health risks 
associated with re-catheterization are considered to be of low impact or rare. Moreover, 
multiple studies have indicated that prolonged catheterization is associated with an increased 
risk of complications (6,7,8,10,12,13). Thus, shorter catheterization may reduce discomfort 
and complications without adversely affecting TWOC success. 
 
9.4 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 participants 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. 
 
9.5 Incentives (if applicable) 
 
Not applicable. 
 
 

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10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
10.1 Handling and storage of data and documents 
 
The handling of personal data complies with EU General Data Protection Regulation (GDPR) 
and the Dutch Act on Implementation of the General Data Protection Regulation (in Dutch: 
Uitvoeringswet AVG). A data management plan has been established, outlining procedures 
and protocols to ensure data integrity and compliance with EU GDPR. 
All collected data will be anonymized; however, patient identities will be accessible via a 
code list, as this is necessary for data collection. This list will be securely stored securely on 
the hospital’s internal network, accessible only to the coordinating investigator and local 
researchers. Patient coding will not involve the use of initials or dates of birth, and the code 
key will be securely kept by the investigator. 
Physical ICFs will be securely stored in a locked cabinet at the Department of Urology, 
accessible only to authorized personnel, while digital ICFs will be stored in the ReDCap 
system. Patients will receive a copy of the ICF via mail or email.  
Data will be retained for 15 years after study follow-up ends, and data collection will be 
managed through Research Manager. 
 
10.2 Monitoring and Quality Assurance 
 
Monitoring will be conducted in accordance with the NFU (Nederlandse Federatie van 
Universitair Medische Centra) guideline "Quality Assurance of Human Research 2.0". 
Independent, qualified monitors employed by the department of Innovation and Science at 
Isala will oversee the monitoring of the study. The risk classification for this study is 
considered "negligible", requiring thorough monitoring with a minimum of one visit each year. 
Additional visits may be conducted depending on the inclusion rate and any previously 
observed deviations.  
 
The monitor will verify compliance with standard operating procedures (SOPs), ensure the 
presence of mandatory documents, and perform source data verification on the research 
data.  Any findings identified during the monitoring visits will be communicated to the 
sponsor-investigator through a detailed monitoring visit report. The sponsor-investigator is 
responsible for addressing any findings, deviations, inquiries, or issues that arise and 
ensuring that appropriate follow-up actions are implemented. 

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10.3 Amendments  
 
Amendments are changes made to the research after a favourable opinion by the review 
committee has been given. All amendments will be notified to the review committee that gave 
a favourable opinion. Non-substantial amendments will not be notified to the review 
committee, but will be recorded and filed by the sponsor.  
 
10.4 Annual progress report 
 
The sponsor/investigator will submit a summary of the progress of the trial to the review 
committee once a year. Information will be provided on the date of inclusion of the first 
participant, numbers of participants included and numbers of participants that have 
completed the trial, serious adverse events, other problems, and amendments.  
 
10.5 Temporary halt and (prematurely) end of study report 
 
The investigator/sponsor will notify the review committee of the end of the study within a 
period of 8 weeks. The end of the study is defined as the end of the 18 month follow-up 
period of the last enrolled patient.  
The sponsor will notify the review committee 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 review committee 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 
review committee.  
 
10.6 Public disclosure and publication policy 
 
Data publication will adhere to CCMO guidelines, with all findings shared, regardless of the 
hypothesis outcome. Individual results will remain confidential. Efforts will be made to publish 
in peer-reviewed journals and present results at meetings, symposia and conferences. 
  

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