SteamOne - Prospective Database for Rezum Water Vapor Therapy of the Prostate
Conditions: Benign Prostate Obstruction (BPO)
Sponsor: University Hospital, Basel, Switzerland

 
SteamOne - Prospective Registry Database for Rezum water vapor therapy of the prostate 
Version 1.3, 10.02.2023 
 
 
 
 
SteamOne 
Prospective Registry Database for Rezum water vapor therapy of the 
prostate 
 
 
 
Research legislation: 
 Ordinance on human research with the exception of Clinical trials 
(HRO) (1). 
 
 
Type of Research Project: 
Research project involving human subjects  
 
 
Risk Categorisation:  
Risk category A acc. to ordinance HRO Art.7 
 
 
Project Leader: 
 
PD Dr. Jan Ebbing, MD 
University Hospital Basel 
Department of Urology 
Spitalstrasse 21 
CH-4031 Basel 
Switzerland 
Tel. 0041 61 32 87142 
Mail: jan.ebbing@usb.ch 
 
 
 

 
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PROTOCOL SIGNATURE FORM  
 
 
Study Title 
SteamOne 
Prospective Registry Database for Rezum water vapor 
therapy of the prostate 
 
The project leader (main center) and the investigator (at the local center/site) have approved the 
protocol version 1.3 dated 10.02.2023 and confirm hereby to conduct the project according to the 
protocol, the Swiss legal requirements (1,2), the current version of the World Medical Association 
Declaration of Helsinki (3) and the principles and procedures for integrity in scientific research 
involving human beings. 
 
 
Project leader (lead center/site) and investigator (local center/site) 
 
University Hospital Basel - Department of Urology – Spitalstrasse 21 – CH-4031 Basel, 
Switzerland 
 
Name: Jan Ebbing, MD 
 
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 
The statistician of the Clinical Trial Unit (CTU) of the Department of Clinical Research (DKF) has 
checked and approved the statements and data in chapters 4 and 4.1 of the protocol version 1.3 
dated 10.02.2023 
 
DKF statistician 
 
University Hospital Basel – Department of Clinical Research (DKF) – Spitalstrasse – CH 4031 
Basel, Switzerland 
 
Name: _________________________ 
 
Date: 
_________________________  
Signature:  ___________________________  
 
 
 
 

 
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TABLE OF CONTENTS 
TABLE OF CONTENTS 
3 
GLOSSARY OF ABBREVATIONS 
5 
1 BACKGROUND AND PROJECT RATIONALE 
7 
2 PROJECT OBJECTIVES AND DESIGN 
8 
2.1 Hypothesis and primary objective 
8 
2.2. Primary and secondary endpoints 
8 
2.2.1 
Primary endpoint 
8 
2.2.2 
Secondary endpoints in terms of efficacy of Rezum to improve micturition 9 
2.2.3 
Further questions / endpoints of special interest in the context of a Rezum 
treatment 
9 
2.2.3.1 
Efficacy of Rezum to preserve sexual function (erection, ejaculation, 
orgasm, sexual satisfaction) 
9 
2.2.3.2 
Surgical safety and side effects of Rezum 
9 
2.2.3.3 
Anesthesia 
9 
2.2.3.4 
Quality of Life (QoL) 
9 
2.2.3.5 
Patients´perception of pain during and after Rezum treatment 
10 
2.2.3.6 
Patients´ satisfaction with clinic treatment 
10 
2.2.3.7 
Antimicrobial prophylaxis 
10 
2.2.3.8 
Patients´ preferences, motivations and expectations for Rezum  
 
treatment 
10 
2.2.3.9 
Doctors´preferences, motivations and reasons to use Rezum 
10 
2.2.3.10 
Influence of steam injection number and injection points 
10 
2.2.3.11 
Patients with pressure-flow studies (urodynamic investigations) 
11 
2.2.3.12 
Patients with MRI investigations 
11 
2.2.3.13 
Patients with prostate cancer 
11 
2.3 
Project design 
11 
2.3.1 Assessment of clinical and patient reported outcomes using heartbeat 
ONE 
12 
2.3.2 Kesem Health iUFlow medical uroflowmetry device 
12 
2.3.3 Study centers 
13 
3 PROJECT POPULATION AND STUDY PROCEDURES 
14 
3.1 Project population, inclusion and exclusion criteria 
14 
3.2  Recruitment, screening and informed consent procedure 
15 
3.3 
Study procedures 
15 
3.3.1 Use of Patient Reported Outcomes Measures (PROMs) and Clinical Reported 
Outcome Measures (CROMs) 
15 
3.3.1.1 Explanation of questionnaires used in the study 
18 
3.3.1.2 Surgical safety classifications used in the study 
21 
3.3.1.3 Patients with pressure-flow studies (urodynamic investigations) 
22 
3.3.1.4 Patients with MRI investigations 
24 
3.4 Withdrawal and discontinuation 
24 
4 STATISTICS AND METHODOLOGY 
24 
4.1. Statistical analysis plan 
24 
4.1.1 Primary analysis 
24 
4.1.2 Secondary analyses 
25 
4.1.3 Subgroup analyses 
26 
4.1.4 Sample size reestimation 
27 
4.1.5 Safety analysis 
27 

 
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4.1.6 Deviation(s) from the original statistical plan 
27 
4.1.7 Handling of missing data and dropouts 
27 
4.1.8 Handling of patients, that will get retreatment 
27 
5 REGULATORY ASPECTS AND SAFETY 
27 
5.1 Local regulations / Declaration of Helsinki 
27 
5.2 Notification of safety and protective measures (HRA Art. 15, HRO Art. 20) 
28 
5.3 Serious events (HRO Art. 21) 
28 
5.4 Amendments 
28 
5.5 End of project 
28 
5.6 Insurance 
28 
6 FURTHER ASPECTS 
28 
6.1 Overall ethical considerations 
28 
6.2 Risk-Benefit Assessment 
29 
7 QUALITY CONTROL AND DATA PROTECTION 
30 
7.1 Quality measures 
30 
7.2 Data recording and source data 
30 
7.2.1 heartbeat ONE database system description 
31 
7.2.2 Entering Patient Reported Outcomes (PROs) 
34 
7.2.3 Entering Clinician Reported Outcomes (CROs) 
34 
7.2.4 Kesem Health iUFlow Clinical Portal 
34 
7.3 Confidentiality and coding 
35 
7.3.1 Data security heartbeat ONE database 
35 
7.3.2 Data security Kesem Health  iUFlow App and Clinical Portal database 
36 
7.4 Retention and destruction of study data 
36 
8  FUNDING / PUBLICATION / DECLARATION OF INTEREST 
36 
9 REFERENCES 
38 
Appendix 22 
1 
Table 3: Schedule of assessments (summary) (V1.0) 
1 

 
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GLOSSARY OF ABBREVATIONS 
 
AES 
 
Advanced Encryption Standard 
ASP 
 
Application Service Provider 
BASEC 
 
Business Administration System for Ethical Committees 
BCI 
 
 
Bladder Contractility Index  
BOO   
 
Bladder Outlet Obstruction  
BOOI  
 
Bladder Outlet Obstruction Index  
BPH 
 
 
Benign Prostate Hyperplasia 
BPO   
 
Benign Prostate Obstruction 
CNS   
 
Central Nervous System  
CRF 
 
Case report form 
CROM  
 
Clinical Reported Outcome Measure  
DA  
 
 
Detrusor under activity  
DO 
 
 
Detrusor over activity 
DPA 
 
 
Data Protection impact Assessment 
EAU   
 
European Association of Urology  
FOPH 
 
Federal Office of Public Health 
GDPR  
 
General Data Protection Regulation 
HRA 
 
Human Research Act 
HRO  
 
Ordinance on Human 
IC/ICU  
 
Intensive Care Unit 
ICIQ-MLUTS 
International Consultation on Incontinence Questionnaire for male lower 
urinary tract symptoms  
ICIQ-MLUTSsex 
International Consultation on Incontinence Questionnaire Male Sexual 
Matters Associated with Lower Urinary Tract Symptoms Module 
ICIQ-S 
International Consultation on Incontinence - Satisfaction 
ICS  
 
 
International Continence Society  
IPSS   
 
International Prostate Symptom Score 
LUTS  
 
Lower Urinary Tract Symptoms 
MRI  
 
 
Magnetic Resonance Imaging 
MSAM  
 
Multinational Survey on the Aging Male 
MSHQ  
 
Male Sexual Health Questionnaire 
NRS   
 
Numeric pain Rating Scale 
PI-RADS  
 
Prostate Imaging-Reporting and Data System  
PROM  
 
Patient Reported Outcome Measure 
PROMIS 
 
Patient-Reported Outcomes Measurement Information System 
PVR   
 
Post Voiding Residual 
Qmax  
 
Maximum urine flow rate 
QoL 
 
 
Quality of Life 
QoR-15GE  
 
Quality-of-Recovery-Score (German Version) 
RCT 
 
 
Randomised Controlled Trials 
SaaS  
 
Software-as-a-Service 
UTI 
 
 
Urinary Tract Infection 
 
 
 
 

 
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1 
BACKGROUND AND PROJECT RATIONALE  
Due to its minimally invasive character, the Rezum - water vapor therapy of the prostate for the 
treatment of lower urinary tract symptoms (LUTS) associated with benign prostate obstruction 
(BPO) is attracting increasing attention from both the urological experts and from patients.  
Rezum is an approved treatment procedure for the treatment of BPO related male LUTS and is 
reimbursed by health insurance companies. 
Rezum is performed transurethral by steam injections into the central or transitional zone of the 
enlarged prostate. The 103°C hot steam is produced by a generator and injected into the prostate 
tissue via a disposable handpiece with a retractable needle. About 1 injection is needed per 10ml 
of prostate tissue to achieve desobstruction. The single injection takes only 9 seconds. The 
thermal energy contained in the water vapor can develop evenly and freely in the intercellular 
space of the prostate by convection. This is a unique technique in the surgical desobstruction of 
the prostate. The steam condenses and releases the stored thermal energy to the cell 
membranes, which then denature. As a result, the prostate tissue shrinks about 30% in the first 
three months after the Rezum treatment. The shrinkage process therefore does not occur 
immediately, but with a time delay. The minimally invasive character results from the short 
operation time, the potential of Rezum to preserve sexual function (both ejaculation and erection) 
and the possibility to perform the Rezum procedure also in local anesthesia or analgosedation. 
Data on efficacy, durability of efficacy, safety/complications and groups of indications are still 
limited and refer to relatively small numbers of cases in cohort studies  (4–14) and one sham 
comparison study (15,16). The European Association of Urology (EAU) mentions Rezum under 
alternative ablative techniques under investigation without giving any recommendations in the 
use of Rezum in its guideline "Management of Non-neurogenic Male LUTS" (17). The guideline 
panel gives practical considerations and demands randomised controlled trials against a 
reference technique to confirm the first promising clinical results and to evaluate mid- and long-
term efficacy and safety of water vapor energy treatment. 
However, randomised controlled trials (RCTs) often examine idealized patients using outlined 
inclusion and exclusion criteria. Therefore, it may be difficult to draw conclusions for other patient 
groups or for patients in routine practice. Thus, “real life” data are just as important to determine 
the role of Rezum water vapor therapy in the treatment of BPO and male LUTS. 
The recent development of novel minimally invasive treatment options for LUTS due to BPO, 
including Rezum, has increased patients´ options, and thus increased the importance of 
assessing and incorporating both patients´ values and preferences and physicians´ attitude and 
behavior towards the treatment of male LUTS, and the influence that this has on patient 
preferences and treatment choice. This need for considering values and preferences exits both 
for optimal treatment of individual patients and for the development of trustworthy clinical practice 
guidelines. In addition, the best or most beneficial form of anesthesia and the most beneficial form 
of antibiotic prophylaxis to prevent from postoperative symptomatic urinary tract infections (UTI) 
when performing Rezum have not yet been studied. 
Furthermore, no data currently exist that show the effect of desobstruction achieved by the Rezum 
treatment on urodynamic pressure-flow studies. 
Therefore, the study aims to record and follow-up Rezum patients prospectively in a multicenter, 
German-language, web-based database. We want to collect patient reported outcome measures 
(PROMs) and examine clinical reported outcome measures/data (CROMs) on different subgroups 
of patients treated with Rezum as a clinical routine treatment option for BPO related male LUTS 
in terms of efficacy of the procedure, outcome of sexual function and surgical safety. In addition, 
we want to analyse patients´ tolerance of the chosen form of anesthesia, patients´ recovery from 

 
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the chosen anesthesia, effectiveness of the chosen antimicrobial prophylaxis to prevent 
postoperative symptomatic UTI, physicians' and patients' preference/motivation to use Rezum in 
BPO and LUTS treatment, patients´ satisfaction with the Rezum treatment, patients´quality of life 
before and after Rezum treatment, and the effect of the Rezum treatment on urodynamic 
pressure-flow parameters and on magnetic resonance imaging (MRI) investigations of the 
prostate. 
 
 
 
2 
PROJECT OBJECTIVES AND DESIGN  
2.1 Hypothesis and primary objective  
a)  
To assess the available promising clinical data of Rezum – water vapor therapy in patients with 
BPO and male LUTS in terms of efficacy, durability and safety in a large, prospective, multi-center 
cohort consisting of 1000 “real-life” patients with a follow-up of 5 years. 
 
b)  
To answer questions/endpoints of special interest in the context of a Rezum treatment (see 
chapter 2.2.2 and 2.2.3.1 – 2.2.3.13: 
 
What factors influence the effect on micturition improvement and effect duration of Rezum 
(e.g. prostate size, localization of injection sites, anticoagulation, comorbidities etc.)? 
 
How well is sexual function (erection, ejaculation, orgasm, sexual satisfaction) preserved 
rather influenced by Rezum? 
 
What factors influence periinterventional complications in Rezum treatment and what are 
typical side effects of a Rezum? 
 
How do urodynamic values in pressure-flow studies change due to the Rezum treatment? 
 
What changes show up in MRI scans after Rezum treatment? 
 
What is the rate of Rezum patients who have concurrent prostate cancer or who are 
diagnosed with prostate cancer during the course following Rezum treatment? 
 
How quickly do patients recover after Rezum treatment depending on the type of anesthesia 
chosen and what is the patients´ perception of pain during and after Rezum treatment? 
 
How does the form of antibiotic prophylaxis during Rezum treatment affect the rate of 
postinterventional urinary tract infections? 
 
What are patients' expectations of surgical treatment of BPO and of Rezum treatment and 
why do patients choose Rezum treatment? 
 
What are reasons that a practitioner uses the Rezum treatment on a patient? 
 
How satisfied are patients with the Rezum treatment? 
 
How does Rezum influence quality of life? 
 
The majority of questions/endpoints have never been investigated in a study before. 
 
2.2. Primary and secondary endpoints 
2.2.1  Primary endpoint 
The primary endpoint is change in the International Prostate Symptom Score (IPSS) five years 
after treatment with Rezum. IPSS is validated and available in German (18,19). The IPSS 
questionnaire is shown in Appendix 1. The minimal clinical difference is 5.2 points improvement. 

 
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2.2.2 Secondary endpoints in terms of efficacy of Rezum to improve micturition 
• 
Improvement of maximum urinary flow rate (Qmax) measured by uroflowmetry.  
• 
Decrease of post voiding residual volume (PVR) measured by ultrasound. 
• 
Decrease of prostate size measured by ultrasound or magnetic resonance imaging (MRI). 
• 
Retreatment rate (medical (drugs), bladder catheter and surgical) 
• 
Improvement of International Consultation on Incontinence Questionnaire for male lower 
urinary tract symptoms (ICIQ-MLUTS). ICIQ-MLUTS is validated and available in German 
(20,21). The ICIQ-MLUTS questionnaire is shown in Appendix 2. 
 
2.2.3 Further questions / endpoints of special interest in the context of a Rezum 
treatment 
2.2.3.1 Efficacy of Rezum to preserve sexual function (erection, ejaculation, 
orgasm, sexual satisfaction) 
      is investigated by questionnaires for patient surveys: 
• 
Male Sexual Health Questionnaire (MSHQ) (validated and available in German) (22–24). 
Erection scale, ejaculation scale and satisfaction scale are mandatory. Additional items 
(sexual activity and desire) are voluntary. The MSHQ questionnaire is shown in Appendix 
3. 
• 
International Consultation on Incontinence Questionnaire Male Sexual Matters Associated 
with Lower Urinary Tract Symptoms Module (ICIQ-MLUTSsex) (validated and available in 
German (25,26). The ICIQ-MLUTSsex questionnaire is shown in Appendix 4. 
 
2.2.3.2 Surgical safety and side effects of Rezum 
Surgical safety is investigated by analysing intraoperative complications classified by ClassIntra 
(27–29) and 30-days postoperative complications defined by the Clavien-Dindo classification 
(30). The ClassIntra classification is shown in table 4, the Clavien-Dindo classification is shown 
in table 5. 
Typical side effects of the Rezum treatment like hematopsermia, dysuria and hematuria, as well 
as the use of pain medication, are investigated by a self-designed patient questionnaire (Appendix 
5) as part of PROMs in the first 90 days after intervention. 
 
2.2.3.3 Anesthesia 
Investigation of type of anesthesia (general anesthesia, spinal anesthesia, local anesthesia, 
analgosedation) incl. reason for type of anesthesia and postoperative recovery using the validated 
German version of the Quality-of-Recovery-Score (QoR-15GE) at the first postoperative day and 
two weeks after discharge from hospital. 
The QoR-15 provides a valid, reliable, responsive and easy-to-use method of measuring the 
quality of a patient's postoperative recovery. Compared with the QoR-40 (31), it covers the same 
elements of quality of recovery but with fewer items and thus is more efficient in evaluating the 
patient's postoperative quality of recovery (32,33). The QoR-15 questionnaire is shown in 
Appendix 6. This endpoint has never been investigated in a study related to Rezum. 
2.2.3.4 Quality of Life (QoL) 

 
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Investigation of QoL changes associated with the Rezum treatment using the PROMIS Global 
Health 10 questionnaire (34). This endpoint has never been investigated in a study related to 
Rezum. The questionnaire is shown in Appendix 19. 
 
2.2.3.5 Patients´perception of pain during and after Rezum treatment 
Investigation of patients’ perception during Rezum procedure in case of local anesthesia and/or 
anagosedation and after Rezum treatment using Numeric pain Rating Scale (NRS) at baseline 
and at the first postoperative day. The NRS has the following scale: from 0 – 10 (no pain - worst 
pain imaginable). This is intended to query both the pain sensation during the Rezum treatment 
and postoperatively at day of surgery and at the first postoperative day. This endpoint has never 
been investigated in a study related to Rezum. 
 
2.2.3.6 Patients´ satisfaction with clinic treatment 
The ICIQ-S (International Consultation on Incontinence – Satisfaction) will be used to evaluate 
patient’s satisfaction after urological surgery (35). The full questionnaire is answered by patients at 2 
weeks, 6 weeks and 3 months. Only question 1-6 are to be answered at 6 months, 12 months and 
annually after surgery (Appendix 7). This endpoint has never been investigated in a study related to 
Rezum. 
 
2.2.3.7 Antimicrobial prophylaxis 
Investigation of the effectiveness of the chosen antimicrobial prophylaxis by analysing the rate of 
postoperative symptomatic urinary tract infections (UTI) within the first 30 days after surgery as 
part of the Clavien-Dindo classification.  
Definition of symptomatic UTI is based on clinical diagnosis supported by measured bacteriuria 
of ≥105 cfu/ml treated with antimicrobial agents. 
This endpoint has never been investigated in a study related to Rezum. 
 
2.2.3.8 Patients´ preferences, motivations and expectations for Rezum 
treatment 
Investigation of patients’ reasons for preference/choice of Rezum and associated expectations 
using self-designed questionnaires (Appendix 8  (8.1 (baseline),8.2 (follow-up 3 months), 8.3 
(follow-up 6 months) and 8.4 (follow-up 1-5 years)) considering measurement tools (36–38). This 
endpoint has never been investigated in a study related to Rezum. 
 
2.2.3.9 Doctors´preferences, motivations and reasons to use Rezum 
Investigation of doctors´ reasons for preference/choice of using Rezum in a patient using self-
designed questions. This endpoint has never been investigated in a study related to Rezum. 
 
2.2.3.10 Influence of steam injection number and injection points 
We will use a drawing in the database where practitioners can accurately draw the water vapor 
injection points on the prostate so that the influence of steam injection number and Injection points 
arrangement on outcome parameters, e.g. micturition parameters (IPSS, ICIQ-MLUTS), sexual 
function (MSHQ, ICIQ-MLUTSsex) prostate size, side-effects, complications can be investigated. 
This endpoint has never been investigated in a study related to Rezum. 

 
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2.2.3.11 Patients with pressure-flow studies (urodynamic investigations) 
We like to analyse urodynamic (invasive) pressure-flow studies investigating bladder outlet 
obstruction index (BOOI), bladder contractility index (BCI) and detrusor (bladder muscle) 
overactivity (DO) before and/or after Rezum treatment in order to  
1.) show the effect of Rezum on pressure-flow parameters resulting from desobstruction and 
investigate the relationship with PROMs (IPSS, ICIQ-MLUTS),  
2.) in case of treatment failure in patients with chronic urinary retention to show that this is a result 
of detrusor underactivity (DU) instead of insufficient desobstruction of the prostate. 
 
Two groups of patients are conceivable for analyzing urodynamic (invasive) pressure-flow 
investigations as part of study-independent routine perioperative diagnostics: 
a.) Patients with available preoperative pressure-flow studies (not older than 6 months): 
postoperative routine diagnostics will probably not be performed in this patient group if the 
patient can micturate well postoperatively. 
b.) Patients that might get a pressure-flow study postoperatively because of insufficient 
micturition (treatment failure). This group will primarily consist of patients who were 
preoperatively catheter dependent. 
 
We would like to ask patients of group a), despite satisfactory micturition after Rezum treatment, 
to allow one further urodynamic investigation 3-6 months after Rezum therapy so that the effect 
of Rezum on pressure-flow values can be studied. 
For patients of group b) suffering from treatment failure (unsuccessful catheter removal after 
surgical desobstruction of the prostate) the EAU recommends to perform urodynamic 
investigation (17). Therefore, urodynamics should be considered in this situation regardless of 
the study. Therefore, we encourage study participants to have urodynamics performed in this 
situation. 
This endpoint has never been investigated in a study related to Rezum. 
 
2.2.3.12 Patients with MRI investigations 
MRI data not older than 12 months at time of Rezum treatment and MRI data in the follow-up 
period of 5 years are investigated in terms of prostate size, ablative lesions (lesions caused by 
Rezum) (39), PI-RADS (prostate imaging-reporting and data system) lesions (40). This endpoint 
has never been investigated in a study related to Rezum. 
 
2.2.3.13 Patients with prostate cancer 
Both the rate of patients under active surveillance with prostate cancer and the rate of prostate 
cancer detected by positive prostate biopsy in the 5 years of follow-up after treatment with Rezum 
is documented. This endpoint has never been investigated in a study related to Rezum. 
 
 
 
2.3 
Project design  

 
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It is a prospective, observational multicenter study recruiting patients in Switzerland, Germany 
and Austria. 
2.3.1 Assessment of clinical and patient reported outcomes using heartbeat ONE 
The study uses a web-based German-language registry database called “heartbeat ONE” by 
heartbeat medical solutions GmbH (Berlin, Germany) that provides both clinical reported outcome 
measures (CROMs) and patient reported outcome measures (PROMs). PROMs are investigated 
by validated questionnaires: IPSS/QoL, ICIQ-MLUTS, MSHQ, ICIQ-MLUTSsex, PROMIS Global 
Health 10, NRS, QoR-15GE and by home urine flow measurement (iUFlow) as well as by self-
designed questionnaires to assess patients´ preferences and expectations for Rezum and for 
surgical therapy of the prostate, satisfaction with the Rezum therapy, side effects of the Rezum 
therapy, (re)medication to treat BPO and LUTS, and reoperations after Rezum therapy. The 
“heartbeat ONE” database is the main database of this study. 
 
2.3.2 Kesem Health iUFlow medical uroflowmetry device 
If patients have a smartphone with app function (Android or Apple), they will be provided with a 
certified and approved home uroflowmetry medical device (iUFlow from Kesem Health) at study 
entry. This should enable patients to measure their urine flow conveniently from home and thus 
be independent of the medical consultation (automated home bladder monitoring solution). 
Experience has shown that patients often do not manage to take an adequate urine flow 
measurement during the consultation in the clinic. Home uroflowmetry will probably improve data 
quality. Two iUFlowTM devices are provided for each patient in order to be able to cover the entire 
observation period. It is planned that the centers will be continuously supplied with devices. The 
devices are then handed out to the patients during the recruitment phase or hospitalization and 
patients are instructed by the study staff. The device-specific app, which connects to the device 
via bluetooth is in German language incl. the Privacy Policy (Appendix 20). When the patient 
opens the app for the first time, he can select the University Hospital Basel as the study clinic and 
insert his personal study number that he has received. The second device is shipped to the 
patient´s home address 24 months after the Rezum treatment and covers year 3-5 of the follow-
up period. The reason for two devices is the fact that the disposable battery of the first device will 
be empty after two years and cannot be replaced.  The devices can be disposed of via the usual 
battery disposal by the patient.  
iUFlowTM is marketed by Kesem Health Pty Ltd, 5A Hartnett Cl, Mulgrave VIC 3170, Australia. 
The Device is FDA and CE approved and is approved to be used in the EU and Switzerland (see 
certificates in (Appendix 9). The software component of the iUFlow system is part of the medical 
device and is developed in accordance with the standard EN 62304:2006 / AC:2008 Medical 
Device Software – Software Life Cycle Processes. The development, maintenance and other 
relevant details are reported in SWD-002 iUFlow Software Development and Maintenance 
Procedure and related documents. 
Every time a patient is using the device urine flow measurement data and additional voluntary 
parameters entered by the patient (micturition protocol, drinking protocol) will be send to the 
Kesem Health iUFlow study database via mobile internet or WLAN internet of the patient. The 
iUFlow study database is called “iUFlow Clinical Portal”, which works independently of the 
heartbeat ONE study database, which is the main study database that collects all CROMS and 
PROMS. iUFlow data is manually transferred from the iUFlow Clinical Portal to the main heartbeat 
ONE database by the study stuff of the University Hospital Basel (see Figure 1). Unfortunately, 

 
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an automated interface is currently not possible. If patients don’t use a smartphone uroflowmetry 
will be performed during routine clinical follow up visits. 
 
2.3.3 Study centers 
Up to 20 Rezum centers are supposed to collect baseline data, perioperative and surgical data, 
clinical follow-up data (CROMs and PROMs) from the Rezum patients using the heartbeat ONE 
database. The data from 1000 baseline patients recruited in Switzerland, Germany and Austria 
are to be collected and followed up over a period of 5 years. Patients who are to be included in 
the database must be operated by certified urologists, that have successfully performed a Rezum 
training course. Clinics qualify as study sites if they have already performed more than 50 Rezum 
procedures and see potential to recruit 50 patients within a 12–18-months period. 
In order to a) promote heterogeneity of the patient cohort and b) to increase the interest of centers 
to enter the study at an early stage and c) to promote centers to recruit patients quickly the 
following efforts are formulated beside the fact that a maximum of 20 centers can recruit 1000 
patients in total:  
 
Study centers will get financial compensation for each patient in the study. In order to 
strengthen the centers' incentive to also collect the follow-up data, the compensation 
payments are paid out gradually. 
 
At least one center should recruit in each country (Switzerland, Germany, Austria).  
 
The number of recruiting centers per country should be equally distributed (33.3%).  
 
The number of patients that a single center can include is a dynamic process and  
is calculated on the basis of the respective number of active centers using this formula: (1000 
patients − already recruited patients) ÷ number of active centers.  
 
In order to ensure that the recruiting phase does not unnecessarily exceed the desired period of 
18 months, each center is given the following minimum default values (Table 1). 
Table 1 Recruitment rate  
 
 
If the required minimum number of recruited patients is not reached according to table 1, the 
site is reproved.  
 
If a site is reproved twice in a row, it is up to the PI to exclude a site from further recruitment.  
 
If a site has recruited the required minimum number of 35 patients 15 months after initiation, 
the site is not reproved anymore and can recruit patients until the total number of 1000 study 
patients is reached. 
 
A regular newsletter will inform the sites about the recruitment progress. 
 
Months 
from 
initiation of site 
Intended average number of 
recruited patients 
Required 
minimum 
number 
of 
recruited patients (default values) 
3 
9 
7  
6 
18 
14  
9 
27 
21  
12 
36 
28 
15 
45 
35 
18 
50 
No required minimum 

 
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In addition to the establishment of the heartbeat ONE database at each of the participating study 
centers by the heartbeat company itself, each study center is planned to be initiated on site by a 
study nurse/coordinator and/or the PI itself. This ensures that the heartbeat database is mastered 
and that the responsible staff members on site are aware of the course of the study and the study 
protocol. The on-site training includes instruction in the iUFlow uroflowmetry, as well as in a 
provided tablet. Patients can use the tablet to fill out baseline and follow-up questionnaires 
(PROMs) at time of recruitment in the clinic, during hospitalization or during clinical follow-up visits 
in the clinic.  
 
3 
PROJECT POPULATION AND STUDY PROCEDURES 
3.1 Project population, inclusion and exclusion criteria  
This study recruits patients who are treated with Rezum – water vapor therapy of the prostate 
due to benign prostate obstruction (BPO) or male lower urinary tract symptoms (LUTS) as part of 
routine clinical practice. This study aims to recruit and follow-up 1000 patients prospectively in a 
maximum of 20 study sites in Switzerland, Germany and Austria. The follow-up time is going to 
be 5 years. The study is going to start in May 2022. We expect recruitment to end 18-24 months 
later and the trial to end a further 5 years after that (May 2029). 
 
Inclusion criteria: 
- 
All male patients who are treated with Rezum due to prostate obstruction and LUTS in the 
participating study centers can be included if certain inclusion criteria are met and some 
exclusion criteria are not present. 
- 
The indication to perform Rezum needs to be made independently from the study. The 
decision for Rezum treatment is the responsibility of each individual practitioner and patient. 
- 
Age ≥ 18 years 
- 
Operated or supervision of surgery by a certified urologist 
- 
Subgroups of special interest are e.g. catheter-dependent patients, patients with oral 
anticoagulation, patients with preoperative urodynamic pressure-flow investigation (not older 
than 6 months) or patients with prostates bigger than 80 ml 
 
Exclusion criteria: 
- 
Missing informed consent 
- 
Lack of ability to answer questionnaires in German language or mentally by oneself (e.g. in 
dementia, mental disability). 
- 
Patient does not have a personal email address available and the survey cannot be completed 
via a relative's email address and the patient is not willing to complete the survey on the tablet 
at the clinic.  
- 
Known or suspected neurogenic bladder dysfunction in e.g. Parkinson's disease, multiple 
sclerosis or other neurological diseases with possible effects on bladder function 
- 
History of malignant bladder tumor in the last two years (including CIS) or currently present 
malignant bladder tumor at time of Rezum treatment (including CIS) 
- 
Previous operation(s) on the prostate, except prostate biopsy, if this was performed more than 
4 weeks ago at time of Rezum treatment 
- 
Previous operation(s) on the bladder neck 
- 
Presence of bladder neck stenosis requiring treatment at time of Rezum treatment 

 
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- 
Planned combination of Rezum treatment concurrently with another urologic * or non-urologic 
procedure. 
 
* also the combination with a planned transurethral procedure is not allowed except for bladder 
stone removal 
3.2  Recruitment, screening and informed consent procedure 
Patients will be recruited within the participating study hospitals as part of regular patient care 
after an indication for Rezum treatment has been made independent of the study. According to 
the EAU (European Association of Urology) guideline “Non-neurogenic Male LUTS” 
urethrocystoscopy in men with LUTS prior to minimally invasive/surgical therapies is 
recommended if the findings may change treatment (17). Due to the fact that not all prostate 
configurations should be treated with Rezum, such as an isolated steep bladder neck, this EAU 
recommendation should also apply to Rezum, but is in the responsibility of each practitioner and 
no obligation for recruitment. 
Once Rezum therapy has been determined for a patient, if all inclusion and exclusion criteria are 
met, the patient will be asked if he is interested in participating in the study. Since Rezum is a 
highly elective surgery and will be performed on a scheduled basis, the patient has ample time to 
read the informed consent letter and ask questions, as is customary for any elective surgery 
informed consent. Study participants do not receive any compensation. There are no additional 
costs for patients and health insurers as a result of the study.  
 
3.3 
 Study procedures 
The study ends with the 5-year follow-up of the last included patient out of a total of 1000 patients 
to be recruited. It is estimated that the 20 participating centers will each recruit an average of 50 
patients in an estimated time of 18-24 months. We believe that a delay of 12 months is to take 
into account until initiation of the last recruiting center has been successfully finished. In summary, 
the study will probably end no later than 84 months (May 2029) after recruitment of the first patient 
(May 2022). 
Patient reported outcome measures (PROMs) incl. iUFlow data will be collected during hospital 
stay and perioperatively, 2 weeks, 6 weeks, 3 months, 6 months, 12 months, and then annual 
until the 5th follow-up year (table 2). 
Clinical reported outcome measures (CROMs) are collected as part of routine clinical 
examinations. Table 3 in Appendix 22 gives an overview about the collected CROMs and PROMs. 
The detailed database template with all parameters in German language is shown in Appendix 
23. Fixed follow-up visits do not exist, but the study centers are encouraged to also see the study 
patients after completion of the perioperative phase at 3 months, 6 months, 12 months and then 
annually until completion of the 5th year of follow-up, or to obtain the necessary data from the 
physicians who continue to treat the patients. 
From experience with patients who have already been treated with Rezum at the University 
Hospital in Basel, the time points mentioned correspond to realistic routine follow-up intervals, as 
they would also be carried out independently of an observational study. 
 
3.3.1 Use of Patient Reported Outcomes Measures (PROMs) and Clinical Reported 
Outcome Measures (CROMs) 

 
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Patients' data, CROMs and PROMs are collected at baseline before Rezum therapy, 
perioperatively (at day of surgery, at first postoperative day, during hospitalization course, at day 
of catheter removal), 2 weeks, 6 weeks, 3 months, 6 months, and annually after surgery for 5 
years using the heartbeat ONE database provided and supported by heartbeat medical solutions 
and the Clinical Portal supported by Kesem Health. CROMs will be assessed at baseline before 
Rezum is performed at day of surgery and after Rezum treatment during clinical follow-up visits. 
Clinical data are manually entered into the heartbeat ONE database at each study center.  
Follow-up visits are scheduled according to the routine practices of the respective 
country/hospital. From our own practice, it can be said that routine clinical controls usually 
correspond to the time periods mentioned above. Since the study is intended to be observational, 
there are no study-dependent, strict guidelines for follow-up controls. However, practitioners are 
encouraged to follow up their patients on a regular basis in their own interest to check the quality 
of outcome of the performed Rezum treatment. The mentioned follow-up times can serve as a 
guideline. Table 3 in Appendix 22 shows a summarized listing of all CROMs and PROMs with 
corresponding time points, which are collected in the heartbeat ONE database. The detailed 
database template with all parameters in German language is shown in Appendix 23. However, 
the vast majority of study data to meet study endpoints are provided by PROMs rather than 
CROMs. Two important clinical outcome parameters are prostate size and post void residual urine 
(PVR), both of which are determined by sonography. However, both parameters are part of 
routine follow-up examinations. 
Patient questionnaires (PROMs) will be preferred collected via the heartbeat service provider by 
a linked e-mail invitation, alternatively by a provided tablet (iPad) during a hospital visit if a patient 
does not use e-mail. Detailed data flow of PROMs via e-mail invitation into the heartbeat ONE 
database is described in chapter 7.2 “data recording and source data”.  
Home urine flow measurement data using the iUFlow device including the smartphone App are 
collected by a separate study database (iUFlow Clinical Portal) provided by Kesem Health for this 
study. IUFlow data is manually transferred from the iUFlow Clinical Portal to the heartbeat ONE 
database by the study stuff of the University Hospital Basel. The exact data flow via the iUFlow 
device into the Kesem Health Clinical Portal is described in chapter 7.2 “data recording and 
source data”. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 2 PROMs and patient questionnaires at baseline and in follow-up 
 
 
Before 
Rezum 
                                                             After 
                                                            Rezum 
 
1 
day 
2 
weeks 
6 
weeks 
3 
months 
6 
months 
1 
year 
2 
years 
3 
years 
4 
years 
5 
years 
Survey point 
a 
b 
c 
d 
e 
f 
g 
h 
i 
j 
k 
Questionnaires 
 
 
IPSS/QoL 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
ICIQ-MLUTS 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
MSHQ 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
ICIQ-MLUTSsex 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
QoR-15 
x 
x 
x 
 
 
 
 
 
 
 
 
PROMIS Global 
Health 10 * 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Numerical pain 
rating scale (NRS) 
** 
x 
x 
 
 
 
 
 
 
 
 
 
Satisfaction with 
 treatment (ICIQ-S) 
***  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Side effects of 
Rezum treatment 
and pain 
medication 
 
 
x 
x 
x 
 
 
 
 
 
 
Patients´ 
preferences and  
expectations for 
Rezum treatment 
x 
 
 
 
x 
x 
x 
x 
x 
x 
x 
BPH/LUTS 
medication 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Re-operations 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
Bladder catheter 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
Completion time in 
minutes 
31 
3 
16 
25 
31 
28 
28 
28 
28 
28 
28 
 
 
 
Home urine flow measurement 
 
iUFlow 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Completion time in 
minutes 
15 
Min. 
 
5 
Min. 
5 
Min. 
5 
Min. 
5 
Min. 
5 
Min. 
5 
Min. 
5 
Min. 
5 
Min. 
5 
Min. 
* contains a Numeric Pain Rating Scale (NRS); ** same NRS like in PROMIS Global Health 10; *** full 
questionnaire until 3 months; 6 months, 12 months and year 1-5 only questions 1-6 
 
Time windows for data collection at each survey point: 
a. 
   4 weeks prior to Rezum surgery – 1 day prior to Rezum surgery. 

 
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b. 
   1 day after Rezum surgery – 3 days after Rezum surgery. 
c. 
   2 weeks after Rezum surgery – 4 weeks after Rezum surgery. 
d. 
   6 weeks after Rezum surgery – 8 weeks after Rezum surgery. 
e. 
   3 months after Rezum surgery – 4 months after Rezum surgery. 
f. 
   6 months after Rezum surgery – 7 months after Rezum surgery. 
g. 
 12 months after Rezum surgery – 14 months after Rezum surgery. 
h. 
 22 months after Rezum surgery – 26 months after Rezum surgery. 
i. 
 34 months after Rezum surgery – 38 months after Rezum surgery. 
j. 
 46 months after Rezum surgery – 50 months after Rezum surgery. 
k. 
 58 months after Rezum surgery – 62 months after Rezum surgery. 
 
3.3.1.1 Explanation of questionnaires used in the study 
Validated symptom score questionnaires for urination/draining 
- IPSS/QoL = International Prostate Symptom Score / Quality of Life, completion time: 1-2 minutes 
- ICIQ-MLUTS = International Consultation on Incontinence Questionnaire for male lower urinary 
tract symptoms, completion time: 4-5 minutes 
The EAU (European Association of Urology) guideline “Non-neurogenetic Male LUTS” (17) 
recommends use of validated symptom score questionnaires including bother and quality of life 
assessment during the assessment of male LUTS and for re-evaluation during and/or after 
treatment. The two most widely used questionnaires are IPSS/QoL and ICIQ-MLUTS. 
The IPSS is an eight-item validated questionnaire, consisting of seven symptom questions and 
one QoL question (18,19). The IPSS score is categorised as ‘asymptomatic’ (0 points), ‘mildly 
symptomatic’ (1-7 points), ‘moderately symptomatic’ (8-19 points), and ‘severely symptomatic’ 
(20-35 points). Limitations include lack of assessment of incontinence, post-micturition symptoms, 
and bother caused by each separate symptom. The IPSS/QoL questionnaire is shown in 
Appendix 1. 
The ICIQ-MLUTS was created from the International Continence Society (ICS) Male 
questionnaire (20). It is a widely used and validated patient completed questionnaire including 
incontinence questions and bother for each symptom It contains thirteen items, with subscales 
for nocturia and overactive bladder (OAB). The ICIQ-MLUTS questionnaire is shown in Appendix 
2. 
 
Validated sexual function questionnaires 
- MSHQ = Male Sexual Health Questionnaire (erection scale and ejaculation scale, satisfaction 
scale), completion time: 2-3 minutes 
- ICIQ-MLUTSsex = International Consultation on Incontinence Questionnaire Male Sexual 
Matters Associated with Lower Urinary Tract Symptoms Module, completion time: 1-2 minutes 
Epidemiological studies have also demonstrated consistent evidence for an association between 
lower urinary tract symptoms (LUTS)/Benign Prostatic Hyperplasia (BPH) and sexual dysfunction, 
regardless of age, other comorbidities and various lifestyle factors (41). The Multinational Survey 
on the Aging Male (MSAM-7) study - performed in the USA, France, Germany, Italy, Netherlands, 
Spain, and the UK - systematically investigated the relationship between LUTS and sexual 
dysfunction in > 12,000 men aged 50-80 years. From the 83% of men who self-reported to be 
sexually active, the overall prevalence of LUTS was 90%, with the overall prevalence of ED being 
49%, and a reported complete absence of erection in 10% of patients. Moreover, the overall 

 
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prevalence of ejaculatory disorders was 46% (42). Effects on erectile function and ejaculation 
function vary according to the type of surgery performed in men with LUTS/BPH (43). 
Rezum is probably currently one of the procedure with the least impact on sexual function in the 
surgical treatment of BPO. Currently, the rate of retrograde ejaculation is thought to be as low as 
3% and no negative impact on erectile function is reported so far following Rezum treatment 
(15,44). However, BPO/Male LUTS drugs such as alpha-blockers are also known to negatively 
impact sexual function on a regular basis. However, the exact significance of sexual function 
preservation with Rezum remains to be systematically tested with our study. 
The EAU guideline “Male Sexual Dysfunction” (45) recommends the use of validated 
questionnaires related to sexual dysfunction to assess all sexual function domains and the effect 
of a specific treatment modality. 
The MSHQ questionnaire was validated in 56 men with moderate to severe LUTS and control 
subjects with no sexual problem and mild or no LUTS (23,24). The MSHQ long form includes 3 
domains: Erection scale (3 items), Ejaculation scale (7 items), Sexual satisfaction scale (6 items) 
+ 9 additional items (2 items measuring bothersome linked to erection and ejaculation and 7 items 
measuring sexual activity and desire). The 7 items on sexual activity and desire are to be filled in 
voluntarily. MSHQ questionnaire is shown in Appendix 3. 
The ICIQ-MLUTSsex is a patient-completed questionnaire for detailed evaluation of male sexual 
matters associated with their lower urinary tract symptoms and impact on quality of life (QoL) in 
research and clinical practice. The ICIQ-MLUTSsex is derived from the fully validated ICS male 
questionnaire and provides robust measure to assess the impact of sexual matters on outcome. 
It is composed of 4 sections (erection, ejaculation, pain/discomfort during ejaculation, impact of 
urinary symptoms) (26). The ICIQ-MLUTSsex questionnaire is shown in Appendix 4.  
 
Validated physical recovery questionnaire 
- QoR-15 = Quality of Recovery-15, completion time: 2-3 minutes 
Rezum is said to be a minimal-invasive surgical treatment for BPO related LUTS which can be 
performed both under general anesthesia and local anesthesia (spinal anesthesia, local prostatic 
bloc or analgosedation). No data exist about postoperative quality of recovery after Rezum 
treatment. The QoR-15 provides a valid, reliable, responsive and easy-to-use method of 
measuring the quality of a patient's postoperative recovery. Compared with the QoR-40 (31), it 
covers the same elements of quality of recovery but with fewer items and thus is more efficient in 
evaluating the patient's postoperative quality of recovery (32,33,46). The QoR-15 questionnaire 
is shown in Appendix 6. CROMs will protocol the type of anesthesia, anesthetic drugs, 
premedication and postoperative use of pain killers. 
 
Validated quality of life questionnaire 
- PROMIS (Patient-Reported Outcomes Measurement Information System) 
 Global Health 10, completion time: 2-5 minutes 
The Global Health 10 Score is part of the PROMIS (Patient-Reported Outcomes Measurement 
Information System) and thus belongs to the latest generation of patient-related outcome 
measures (47). It is a measure of overall health-related quality of life based on a patient sample 
of 21,133 people. The questionnaire consists of a combination of 10 questions that assess both 
the physical and mental health status of adult patients independent of their individual medical 
situation. Patients subjectively rate their own health, quality of life and social aspects of their lives. 
It is designed to be a basic assessment of a patient's health that can be used for a variety of 

 
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conditions. Patients subjectively rate their own health, quality of life and social aspects of their 
lives. The items are measured using a five-point response matrix that includes physical function, 
fatigue, pain, emotional distress and social health (34). No data exist about changes of quality of 
life in the context of a Rezum treatment. The questionnaire is shown in Appendix 19. 
 
 
Validated satisfaction questionnaire 
- ICIQ-S = International Consultation on Incontinence Questionnaire - Satisfaction, completion 
time: 1-2 minutes 
The ICIQ-S assesses aspects of experience, expectations, and outcomes to evaluate satisfaction 
after urological surgery (35). Question items consist of: outcome success, comparison of 
symptoms, return to ‘normal life’, same situation, same choice, recommend, current symptoms, 
preparation for surgery, satisfaction of explanation, pain after surgery, satisfaction of pain relief, 
current pain, complications/side effects, result of surgery and satisfaction with surgery. The ICIQ-
S questionnaire is shown in Appendix 7. 
 
Further questionnaires  
- Questionnaire "Numerical Pain Rating Scale" (NRS), completion time :0.5 minutes 
This is intended to query the pain sensation during the Rezum treatment and in the postoperative 
course. Data should be matched with the type of anesthesia and the anesthesiologic drugs used. 
Study results might be able to give a recommendation for the best form of anesthesia used in a 
Rezum procedure. The "Numerical Pain Rating Scale" questionnaire has a scale from 0 – 10 (no 
pain - worst pain imaginable). NRS is also part of PROMIS Global Health 10. 
 
- Questionnaire "Rezum side effects and pain medication", completion time: 2-3 minutes 
This questionnaire is self-designed. Typical side effects must be seen and investigated 
independently of treatment complications in order to provide patients with the best possible advice 
and information. The need for pain medication will be evaluated in a time context as well. 
Typical side effects of Rezum treatment include discomfort (burning/stinging) in the 
pelvis/abdomen, hematuria, hematospermia or urinary urgency.  Rezum side effects have only 
been studied in small cohorts, but not in a larger collective of patients. The questionnaire is shown 
in Appendix 5. 
 
- Questionnaire "Preferences & expectations of Rezum treatment", completion time: 5-7 minutes   
  (baseline questionnaire), 3 minutes (follow-up questionnaire) 
The recent development of novel minimally invasive treatment options for LUTS due to BPO, 
including Rezum, has increased patients´ options, and thus increased the importance of 
assessing and incorporating both patients´ values and preferences and physicians´ attitude and 
behaviour towards the treatment of male LUTS, and the influence that this has on patient 
preferences and treatment choice. This need for considering values and preferences exits both 
for optimal treatment of individual patients and for the development of trustworthy clinical practice 
guidelines. 
This self-designed questionnaire, which is currently under psychological evaluation, considers 
measurement tools related to BPH/Male LUTS treatment (36–38) and aims to investigate patients' 
motivations, expectations and preferences for surgical desobstruction of the prostate due to BPO 
in general but also in particular in relation to the Rezum treatment. This will attempt to better 

 
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understand patient attitudes in order to improve future counseling of patients regarding minimally 
invasive procedures for the treatment of BPO related male LUTS. The questionnaires are shown 
in Appendix 8 (8.1 – baseline, 8.2 – follow-up 3 months, 8.3 – follow-up 6 months, 8.4 follow-up 
1 – 5 years). 
 
 
 
- Questionnaire "BPH (Benign Prostate Hyperplasia) medication", completion time: 1-2 minutes 
- Questionnaire "Re-Operation", completion time: 1-2 minutes 
- Questionnaire “Bladder catheter”, completion time: 1-2 minutes 
All three questionnaires are self-designed. The purpose of the questionnaires is to get relevant 
information, not to score the questionnaires. Only one study with 197 patients has investigated 
the resumption of drug therapy and the reoperation rate due to BPO related LUTS over an 
observation period of 5 years. This study also included only patients with prostates between 30-
80 ml. This study showed a reoperation rate at 5 years of 4.4% and re-treatment with BPH 
medications of 11.1% (15).  
A very limited number of other studies have examined the efficacy of Rezum on larger prostates, 
but with only a very short follow-up period of one year (5,6). 
Therefore, it is very interesting to prospectively observe these two outcome parameters in a 
larger, heterogeneous cohort of patients and with a longer follow-up. The questionnaires are 
shown in Appendix 15 (BPH/LUTS medication), Appendix 16 (Re-operation) and Appendix 21. 
 
3.3.1.2 Surgical safety classifications used in the study 
Surgical safety is investigated by analysing intraoperative complications classified by ClassIntra 
(27–29) and 30-days postoperative complications defined by the Clavien-Dindo classification 
(30). 
ClassIntra® - classification of intraoperative adverse events 
The classification defines intraoperative adverse events as any surgery or anesthesia-related 
deviation from the ideal intraoperative course occurring between begin of anesthesia and end of 
anesthesia (Table 4).  
 
Table 4 ClassIntra® - Classification of intraoperative adverse events 
Grade 0 
No deviation from the ideal intraoperative course 
Grade 1 
Any deviation from the ideal intraoperative course without the need for any 
additional treatment or intervention; patient asymptomatic or mild 
symptoms 
Grade 2 
Any deviation from the ideal intraoperative course with the need for any 
additional minor treatment or intervention; patient with moderate 
symptoms, not life-threatening and not leading to permanent disability 
Grade 3 
Any deviation from the ideal intraoperative course with the need for any 
additional moderate treatment or intervention; patient with severe 
symptoms, potentially life-threatening and/or potentially leading to 
permanent disability 
Grade 4 
Any deviation from the ideal intraoperative course with the need for any 
additional major treatment or intervention; patient with life-threatening 
symptoms and/or leading to permanent disability 

 
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Grade 5 
Any deviation from the ideal intraoperative course with intraoperative death 
of the patient 
The following events are not defined as intraoperative complications: sequelae, failures of cure, 
events related to the underlying disease, wrong-site or wrong-patient surgery or errors in 
indication. 
 
 
Clavien-Dindo classification of postoperative complications within 30 days 
The classification defines postoperative adverse events occurring after the patient has left the 
recovery room until 30 days after surgery (Table 5). 
 
  Table 5 Clavien-Dindo classification for postoperative complications 
  Grade I 
Any deviation from the normal postoperative course without the need for 
pharmacological treatment or surgical, endoscopic and radiological 
intervention. 
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, 
analgetics, diuretics and electrolytes and physiotherapy. This grade also 
includes wound infections opened at the bedside. 
  Grade II 
Requiring pharmacological treatment with drugs other than such allowed 
for grade I complications. 
Blood transfusions and total parenteral nutrition are also included  
  Grade III 
Requiring surgical, endoscopic or radiological intervention 
IIIa Intervention not under general anaesthesia 
IIIb Intervention under general anaesthesia 
  Grade IV 
Life-threatening complication (including CNS complications)* requiring 
IC/ICU 
IVa Single organ dysfunction (incl. dialysis) 
IVb Multi organ dysfunction 
  Grade V 
Death of a patient 
  Suffix ‘d’ 
If the patient suffers from a complication at the time of discharge, the suffix 
‘d’ (for ‘disability’) is added to the respective grade of complication.  
* brain haemorrhage, ischaemic stroke, subarachnoidal bleeding, but excluding transient 
ischaemic attacks (TIA); IC: Intermediate care; ICU: Intensive care unit 
Note: A (re)-catheterization of the urinary bladder is not defined as a complication if it occurs due 
to a bladder emptying disorder. If, on the other hand, the (re)-catheterization occurs due to, for 
example, a symptomatic urinary tract infection or hematuria, this is to be classified at least as 
Clavien Dindo grade IIIa. The definition of symptomatic UTI is based on a clinical diagnosis 
accompanied by a measured bacteriuria of ≥105 cfu/ml and treated with at least one 
antimicrobial agent. A symptomatic UTI is classified as at least Clavien Dindo grade II. 
 
3.3.1.3 Patients with pressure-flow studies (urodynamic 
investigations) 
Uroflowmetry and postvoid residual urine volume (PVR) are simple tests that can raise or lower 
the suspicion of bladder outlet obstruction (BOO), but neither can make a definitive diagnosis. 
Decreased uroflow can result from impaired detrusor (bladder muscle) contractility (detrusor 
underactivity (DU)) or obstruction, e.g. BPO. Without the synchronous measurement of detrusor 
pressure (Pdet), uroflow is unable to distinguish between these two entities. Furthermore, there 

 
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are no features of the uroflow curve that allow a definitive distinction between outlet obstruction 
and DU. The prevalence of DU in men with LUTS is about 40% (48,49). Similarly, a normal uroflow 
does not exclude outlet obstruction (50). Urodynamics with pressure-flow studies remain the gold 
standard for diagnosing BOO, like BPO and other voiding and storage abnormalities responsible 
for LUTS and voiding dysfunction. Currently, no urodynamic data are published for the Rezum 
treatment. 
Both the BOOI - Bladder Outlet Obstruction Index (former Abrams-Griffiths normogram) and BCI 
- Bladder Contractility Index can be simply calculated without the use of computer programs or 
even the nomogram for that matter: 
 
BOOI is represented by the equation: BOOI = Pdet @ Qmax − 2 Qmax (Pdet = detrusor pressure; 
Qmax = maximum flow rate) 
Using  the ICS - International Continence Society nomogram, men can be divided into obstructed, 
equivocal, and unobstructed according to their BOOI: BOOI > 40 = obstructed; BOOI 20−40 = 
equivocal; and BOOI < 20 = unobstructed (50) 
 
The BCI is represented by the following formula: BCI = Pdet Qmax + 5 Qmax.  
Using this formula, contractility can be divided into strong > 150, normal 100–150, and weak < 
100 (50). 
Therefore, we like to analyse urodynamic (invasive) pressure-flow studies investigating BOOI and 
BCI before and/or after the Rezum intervention in order to  
1.) show the effect of Rezum on pressure-flow parameters resulting from desobstruction and 
investigate the relationship with PROMs (IPSS, ICIQ-MLUTS), and 
2.) in case of treatment failure in patients with chronic urinary retention to show that this is a result 
of detrusor underactivity instead of insufficient desobstruction. 
In addition, we like to analyse detrusor overactivity (DO) urodynamically during storage phase 
and correlate DO pre- and postoperatively with PROMs (IPSS, ICIQ-MLUTS). 
 
Two patient groups are of scientific interest for the analysis of urodynamic (invasive) pressure-
flow studies: 
a) Patients with preoperative pressure-flow studies (not older than 6 months): postoperative 
routine diagnostics will probably not be performed in this patient group if the patient can 
micturate well postoperatively, but it is scientifically very valuable to study the effect of Rezum 
on the urodynamic indices for the reasons described above. 
b) Patients that might get a pressure-flow study postoperatively because of insufficient 
micturition (treatment failure). This group will primarily consist of patients who were 
preoperatively catheter-dependent. 
Centers should be encouraged to perform a urodynamic (invasive) follow-up pressure flow study 
three to six months after the Rezum intervention in patients in group a) or in case of treatment 
failure in group b).  
Postoperative treatment failure is defined as at least two unsuccessful trials to remove the 
transurethral catheter with the last trial not having been performed earlier than 30 days and not 
later than 90 days after the Rezum intervention. 
In case of treatment failure (group b) unsuccessful catheter removal, no voiding possible) the 
EAU recommends to perform a urodynamic pressure-flow study (17). Therefore, it should be 
covered by the insurance of the patient.  
If postoperative urodynamic (invasive) pressure-flow studies are performed in the context of the 
study protocol, additional informed consent of each patient is necessary. 

 
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3.3.1.4 Patients with MRI investigations 
It is assumed that some patients will have had an MRI (magnetic resonance imaging) of the 
prostate prior to the Rezum treatment or will get an MRI of the prostate in the follow-up years 
after the Rezum treatment. Reasons for this can be an investigation for the presence of prostate 
cancer or the fact that a patient is under active surveillance for prostate cancer.  
Patients are going to be encouraged to provide MRI images in order to examine parameters that 
may have been changed after Rezum treatment like ablative steam lesions (39), prostate size or 
PI-RADS lesions (40). The MRIs are going to be reviewed in the Department of Radiology of the 
University Hospital Basel. 
Patients will be asked to sign an additional consent form giving permission to request a copy of 
the MRI images of the prostate for the study, together with the written report from the radiology 
institute that produced the images. Any costs incurred for the requested images will be paid by 
the study. 
 
 
3.4 Withdrawal and discontinuation 
Patients participating in this research project are asked to adhere to the specifications and 
requirements of the research project through the PROMs protocol (Table 3).  
In case of non-compliance with the protocol (Table 3), the project management or the 
investigator/investigator of the local institution may exclude patients from participation in the 
research project. If a patient's health condition no longer permits participation in the research 
project, the project management or the investigator/investigator of the local institution may also 
exclude the patient from the study project, not only in the interest of the patient's health. Data 
collected up to study exclusion will be analyzed. 
Study participants can withdraw from the research project at any time. In this case, however, the 
data collected up to that point will still be analyzed in encrypted form. 
After evaluation, the data are anonymized. The key allocation is destroyed so that afterwards no 
one can find out that the data originally came from a particular study participant. This is primarily 
for data protection purposes. 
 
 
 
4 STATISTICS AND METHODOLOGY 
4.1. Statistical analysis plan 
 
Detailed methodology for summaries and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan. The statistical analysis plan will be finalized 
before database closure and will be under version control at the CTU of the DKF. 
 
4.1.1 Primary analysis 
The primary endpoint of the study is symptom reduction from baseline to five-year follow-up as 
measured by the international prostate symptom score (IPSS). The IPSS is scored on a 0 to 35 
scale with higher scores indicating greater frequency of BPH symptoms (18,19).  

 
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The mean difference between IPSS at five years follow-up and at baseline will be assessed using 
a linear mixed effects model with IPSS score as the outcome. The measurement time point will 
be measured as a fixed effect, and patient ID (possibly nested within center ID) will be included 
as a random effect. For the subgroup analyses, the group membership will be included as an 
interaction with measurement time point. 
 
4.1.2 Secondary analyses 
The primary endpoint, i.e., change in IPSS, will be assessed at each other measurement time 
point (after three months, six months, and annually over five years) in secondary analyses. 
The following secondary outcomes will also be assessed: 
• 
Quality of life score (QoL) from the IPSS questionnaire (18,19) (Appendix 1) 
• 
Questionnaire for male lower urinary tract symptoms (ICIQ-MLUTS) (20) (Appendix 2) 
• 
Urinary flow rate measured using iUFlow uroflowmetry (automatic uroflow at home) 
• 
Post voiding residual volume (PVR) 
• 
Prostate size (in ml) 
• 
Reoperation rate (Appendix 16) 
• 
Remedication with BPO/LUTS drugs (Appendix 15) 
• 
Recatherization rate (Appendix 21) 
• 
Sexual function, including erection, ejaculation, orgasm and sexual satisfaction measured 
using the following questionnaires: 
– Male Sexual Health Questionnaire (MSHQ) (23,24) (Appendix 3) 
– International Consultation on Incontinence Questionnaire Male Sexual Matters 
Associated with Lower Urinary Tract Symptoms Module (ICIQ-MLUTSsex) (26) 
(Appendix 4) 
• 
Type of anesthesia used, including reason for type of anesthesia and postoperative 
recovery using the following questionnaire: 
– Quality-of-Recovery-Score (QoR-15) (32,33,46) (Appendix 6) 
• 
Quality of life from PROMIS Global Health 10 questionnaire 
• 
ICIQ-S to evaluate patients’ satisfaction with clinic treatment (46) (Appendix 7) 
• 
In case of local anesthesia/analgosedation, the patients’ perception of pain during the 
Rezum procedure by using a Numeric pain rating scale (NRS) from 0 to 10 
• 
Effectiveness of the chosen antimicrobial prophylaxis (infection vs. no infection) 
• 
Patients’ preferences and expectations for Rezum treatment using self-designed 
questionnaires (Appendix 8) and validated preference measurement tools (36–38)  
• 
Changes in bladder outlet obstruction index (BOOI) bladder contractility index (BCI) and 
detrusor overactivity (DO) among those who underwent pressure flow studies (50) 
• 
Change of MRI investigations (ablative lesions, PI-RADS lesions, prostate size) among 
those who show a MRI of the prostate 
• 
Intraoperative (ClassIntra classification, table 4) (27–29) and postoperative complications 
(Clavien-Dindo classification, table 5) (30) 
• 
Rezum side-effects and need for pain medication (Appendix 5) 
• 
Influence of steam injection number and Injection points arrangement on outcome 
parameters, e.g. micturition parameters (IPSS, ICIQ-MLUTS), sexual function (MSHQ, 
ICIQ-MLUTSsex) prostate size, side-effects, complications. 
 
We will use both statistical models and descriptive statistics to answer our questions. 

 
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We will summarise the parameters for each time point to allow us to explore changes over time. 
In relation to the subgroup analyses, we will identify factors that influence the endpoints. 
The endpoints described above will be assessed using the same mixed models framework that 
will be used for assessing the primary outcome. We will use linear mixed models for the 
continuous outcomes and mixed logistic regression models for the binary outcomes.  
In addition, we will examine the relationship between changes in the bladder outlet obstruction 
index (BOOI) as well as the bladder contractility index (BCI) after undergoing Rezum and changes 
in the clinical outcome parameters IPSS and MCIQ-MLUTS among patients who undergo pre- 
and post-operative pressure flow examinations using linear regression models. For these 
analyses, we will use the outcome measurements taken closest to the time of the post-Rezum 
pressure flow examination. 
 
 
4.1.3 Subgroup analyses 
The main subgroup analyses of interest for the outcomes “reduction of IPSS”, “reduction of ICIQ-
MLUTS”, “improvement of uroflow”, “reduction of PVR volume”, “reduction of prostate size” and 
“reoperation rate” are the following: 
•  Larger prostate size of > 80 ml (expected in about 20% of the study population) 
• Chronic urinary retention, i.e., catheter-dependence (expected in about 10-15% of the 
population).  
 
The main subgroup analysis of interest for the outcomes “reduction of ICIQ-MLUTSsex” and 
“reduction of MSHQ” is the following: 
•  Larger prostate size of > 80 ml (expected in about 20% of the study population) 
 
In addition, subgroups based on the following characteristics will be examined for surgical safety 
outcomes, i.e., intra- and post-operative complications: 
•   Anticoagulation 
•   Age ≥ 80 years 
•  Fragility or comorbidities identified by the Charlson Comorbidity Index (51) (making patients 
only eligible for local anesthesia or analgosedation) 
Furthermore, we will examine the relationship between changes in the bladder outlet obstruction 
index (BOOI) as well as the bladder contractility index (BCI) after undergoing Rezum and changes 
in the clinical outcome parameters IPSS and MCIQ-MLUTS among patients who undergo pre- 
and post-operative pressure flow examinations using linear regression models. For these 
analyses, we will use the outcome measurements taken closest to the time of the post-Rezum 
pressure flow examination. 
 
Determination of sample size 
 
As alluded to above, one of the motivations behind recruiting a large cohort is the ability to conduct 
subgroup analyses. Given that 15% of patients are expected to drop out each year, 920 patients 
should be recruited into the study in order to have 408 patients left after five years. The CTU of 
the DKF recommend to round this number to 1000 due to uncertainty in the assumptions made 
and because adding center as a random effect into the model could further reduce the power. 
 

 
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4.1.4 Sample size reestimation  
After 18 months the state of recruitment will be assessed. If the number of patients recruited is 
far below the 1000 patients planned, we will conduct an interim sample size reassessment. 
Several of the assumptions used to calculate the sample size, including size of subgroups, intra-
patient correlation, variance, etc., will be examined using the patients for whom data have already 
been collected. The sample size simulations will be rerun using the updated assumptions. If fewer 
patients are required to perform the most important subgroup analyses under the updated 
assumptions, the sample size will be updated. 
 
4.1.5 Safety analysis 
Surgical safety will be assessed by recording intraoperative complications defined by the 
ClassIntra classification (27–29) as well as 30-day postoperative complications defined by the 
Clavien-Dindo classification (30). 
 
4.1.6 Deviation(s) from the original statistical plan 
If substantial deviations of the analysis as outlined in these sections are needed for whatever 
reason, the protocol will be amended. All deviations of the analysis from the protocol or from the 
detailed analysis plan will be listed and justified in a separate section of the final statistical report. 
 
4.1.7 Handling of missing data and dropouts 
We expect 15% dropout per year. This has been accounted for in the sample size calculation. 
The analyses will be conducted at each planned assessment time point using the available cases. 
We will quantify the dropout each year and calculate summary statistics of baseline 
characteristics and last measurements taken prior to dropout for those who drop out compared 
to those who remain in the study. 
 
4.1.8 Handling of patients, that will get retreatment 
It may happen that during the 5-year follow-up of the patients, further therapy is carried out due 
to new micturition complaints. This can be drug treatment or surgical reintervention due to BPO 
recurrence or surgical treatment because of complications, e.g. bladder neck stenosis or urethra 
stricture. BPO drug or surgical retreatment rate will be described at each planed assessment 
point. Patients that need retreatment of BPO will continue to be followed up as part of the study, 
but will be statistically evaluated separately from the patients without retreatment. Factors that 
influence BPO retreatment will be analysed. 
 
 
 
5 
REGULATORY ASPECTS AND SAFETY 
5.1 Local regulations / Declaration of Helsinki 
This research project will be conducted in accordance with the protocol, the Declaration of 
Helsinki [3], the principles of Good Clinical Practice, the Human Research Act (HRA) and the 
Human Research Ordinance (HRO) [1] as well as other locally relevant regulations. The Project 
Leader acknowledges his responsibilities as both the Project Leader and the Sponsor. 
 

 
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5.2 Notification of safety and protective measures (HRA Art. 15, HRO Art. 20) 
If, during the research project, circumstances arise which could jeopardise the safety or health of 
the participants or lead to a disproportionate relationship between the risks and burdens and the 
benefits, all the measures required to ensure protection are to be taken without delay. 
The project leader is promptly notified (within 24 hours) if immediate safety and protective 
measures have to be taken during the conduct of the research project. The Ethics Committee will 
be notified via BASEC of these measures and of the circumstances necessitating them within 7 
days. 
 
 
5.3 Serious events (HRO Art. 21) 
If a serious event occurs, the research project will be interrupted and the Ethics Committee 
notified on the circumstances via BASEC within 7 days according to HRO Art. 211. 
 
5.4 Amendments 
Substantial changes to the project set-up, the protocol and relevant project documents will be 
submitted to the Ethics Committee for approval according to HRO Art. 18 before implementation. 
Exceptions are measures that have to be taken immediately in order to protect the participants.  
 
5.5 End of project 
Upon project completion or discontinuation, the Ethics Committee is notified within 90 days. After 
the final data analysis of the project, the data will be kept for another 10 years to have the 
possibility to answer further scientific questions that might arise.  
 
5.6 Insurance 
In the event of project-related damage or injuries, the Sponsor will be liable, except for damages 
that are only slight and temporary; and for which the extent of the damage is no greater than 
would be expected in the current state of scientific knowledge (Art. 12 HRO). For sites outside 
Switzerland, local regulations apply. 
 
 
 
6 
FURTHER ASPECTS 
6.1 Overall ethical considerations 
The study is an observational study. Common outcome questionnaires, such as the IPSS, ICIQ-
MLUTS, ICIQ-MLUTSsex or MSHQ which would normally be collected during the routine medical 
follow-up consultation, are, however, made available to the patients in a structured manner and 
if wished by the patient independently of a medical consultation. The same applies to the urine 
flow measurement (iUFlow), which the patient can perform at home independently of a medical 
                                                        
1 A serious event is defined as any adverse event where it cannot be excluded, that the event is attributable to the 
sampling of biological material or the collection of health-related personal data, and which: 
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital stay; 
b. results in permanent or significant incapacity or disability; or 
c. is life-threatening or results in death. 

 
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consultation. This means that the patient is not under pressure to perform the measurement on 
command during a medical consultation. This often does not work (bladder already empty, 
micturition not possible during consultation) and data would be correspondingly incomplete. The 
results are accessible to both the Rezum practitioner and the study stuff via the heartbeat ONE 
study database. In our opinion, however, this type of data collection still corresponds to the 
character of an observational study; the data collection is merely shifted to the home environment, 
which we think will generate better and more complete data quality. In our opinion, the results 
provided do not influence the practitioners with regard to the treatment of their patients, as the 
outcome data would also be collected independently of the study during the routine follow-up 
visits. 
Centers should be encouraged to perform a urodynamic (invasive) follow-up pressure flow study 
three to six months after the Rezum treatment in patients in group a) or in case of treatment failure 
in group b) according to chapters 2.2.3.11 and 3.3.1.3. “Patients with pressure-flow studies 
(urodynamic investigations)”. Although there is no benefit of postoperative pressure-flow study 
for patients with successful Rezum treatment (group a)), the results are scientifically very valuable 
to better measure the efficiency of Rezum treatment in terms of desobstruction of the prostate. 
However, indication for pressure-flow study in group b) is justified by the recommendation of the 
EAU guideline “Management of Non-neurogenic Male LUTS” (17). 
The time commitment of the study participants is very manageable (table 2). Additional, study-
based medical consultations in addition to routine, study-independent follow-up visits are not 
foreseen, except for postoperative urodynamics if necessary, despite treatment success (group 
a)), as described above. However, postoperative urodynamics is not a prerequisite for study 
participation, is purely voluntary and requires the explicit consent of the patient, who is already 
aware of the examination. 
In the true sense, incidental findings collected via the study are not expected, as this is an 
observational study investigating an approved treatment. 
Study patients have full right to see their study data. Participation in the study is voluntary and 
can be withdrawn at any time. 
 
6.2 Risk-Benefit Assessment  
In general, there are no risks involved in participation in this study. Study-related activities are 
restricted to filling in questionnaires, which are used via secured, well-established platforms, 
which have been widely used in clinical trials. Filling in questionnaires can be time consuming, 
what can be perceived as a burden.  Furthermore, the uroflowmetry measurements (iUFlow) are 
also approved for usage by patients at home and bear no risks. All other data collected within this 
study are part of routine Rezum treatment and follow-up of patient with BPO retated LUTS. 
Patients with existing pressure-flow study (urodynamic investigation) before the Rezum treatment 
may be asked if they would allow a control pressure-flow study on a purely voluntary basis.  
Individual patients may not have a benefit in participating.  
However, patients can have a direct benefit from participation, as they have a continuous self-
assessment of their health status (PROMIS Global Health 10) in relation to their lower urinary 
tract (urinary bladder and prostate) and sexual function with the questionnaires on urination 
(IPSS/Qol, ICIQ-MLUTS) and sexual function (ICIQ-MLUTSsex, MSHQ), as well as with the urine 
flow measurement at home (iUFlow). This will allow patients to assess and visualize for 
themselves the effects of the Rezum treatment over time. 

 
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In addition, by participating, patients will help to further investigate the benefits of Rezum 
treatment, potential risks and side effects, and the effect on sexual function and quality of life for 
different groups of males. By doing so, study participants will give future patients the chance to 
be better advised by physicians regarding Rezum treatment with the data obtained from this 
study. 
 
 
 
 
 
7 
QUALITY CONTROL AND DATA PROTECTION 
7.1 Quality measures  
For quality assurance the Ethics Committee may visit the research sites. Direct access to the 
source data and all project related files and documents must be granted on such occasions.  
We aim to engage one full-time study nurse/coordinator (100%) for the duration of the study. 
The 100% will be split if necessary. 
Tasks performed by study nurse(s)/coordinator(s) are as followed: 
 
Initiation of the study center including explanation of the heartbeat ONE database 
      and the study protocol as well as the devices used (iUFlow, IPad tablet) 
 
Monitoring of recruitment at each study site 
 
Monitoring of the timely dispatch of uroflowmetry devices (iUFlow) to patients 
 
Monitoring of data entry and follow-up at each study site incl. return of clinical data, iUFlow 
uroflow data and questionnaires 
 
Ensuring continuous support for the study centers in the event of problems or queries 
 
Supporting patients and responding to patient queries or problems 
 
7.2 Data recording and source data 
All project data is directly recorded via the main database “heartbeat ONE” (CROMs and PROMS) 
except of the home uroflowmetry data which will be collected first via the Kesem Health Clinical 
Portal connected to the Kesem iUFlow App. Data electronically collected in the Kesem Health 
Clinical Portal will be manually transferred into the heartbeat ONE database by study staff of the 
main study center of the University Hospital Basel.  
Clinical baseline and follow-up data (CROMs) are entered manually into the heartbeat ONE 
database by the respective study centers. The heartbeat ONE database offers a user-friendly 
interface so that data can be entered efficiently, in a structured and fully comprehensive but time-
saving manner.  
Patient questionnaires (PROMS) are basically designed so that they can be answered 
electronically, e.g. via a tablet or e-mail link. Each study center will be provided with a tablet that 
patients can use to complete the questionnaires. There is also a direct electronic way to fill in the 
questionnaires in the follow-up from home. If patients provide an e-mail, the questionnaires will 
be sent to them via an e-mail invitation with a link to the questionnaires. Alternatively, the survey 
can be completed via a relative’s email address or via tablet in the clinic. 

 
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Figure 1 shows the data flow. Sub-center can only see data of their own patients in the heartbeat 
ONE database and Kesem Health Clinical Portal, whereas the study stuff at the main study center 
at the University Hospital Basel can see study data from all study centers. 
 
 
 
 
 
 
 
 
Figure 1: Flow of study data 
 
* CROMs are entered into the local database by local study stuff (study nurses, surgeon, local PI), PROMs 
(questionnaires) can be answered electronically by patients via heartbeat Portal (e-mail) or via heartbeat Bridge 
(iPad/tablet).  
** USB study stuff can authorize study stuff of local sub-centers to see iUFlow data in the Kesem Health Clinical 
Portal just from their study patients. 
 
The following description contains technical, clinical and legal information about the heartbeat 
ONE database. heartbeat medical can provide comprehensive information material, technical 
system descriptions (hosting, API, etc.) and data protection-related documents (data protection 
impact assessment, TOMs, etc.) upon request. 
 
7.2.1 heartbeat ONE database system description 
Data entry into heartbeat ONE: All content (PROM scores and clinical documentation forms 
(CROMs) will be implemented into heartbeat ONE by heartbeat’s medical content team according 
to the project specifications (Assessment Schedule_V1.0, see Appendix 23). Pathway specific 
task lists define survey and documentation time points according to the study/registry design. The 
implementation process takes into account any licensing for PRO instruments and is MDD 
heartbeat ONE
main database
Location: University Hospital Basel (USB)
heartbeat ONE
local database
in study subcenter 1
heartbeat ONE
local database
in study subcenter 2
heartbeat ONE
local database
in study subcenter 3
Kesem Health
Clinical Portal
for iUFlow data
Location: USB **
Patient 1
CROMs, PROMs 
and iUFlow data
Patient 2
CROMs, PROMs 
and iUFlow data
Patient 3
CROMs, PROMs 
and iUFlow data
manually transfered
by USB
iUFlow App
iUFlow
App
iUFlow App
*
*
*

 
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(Medical Device Directive) compliant, including compliance with IEC 62304, IEC 62366-1, ISO 
14971 and ISO 13485.  
heartbeat ONE can be used with and without an HL7-integration with the local hospitals 
information system (HIS). An integration allows for the automation of administrative processes 
(create patient, start survey processes, return data, etc.). 
To collect data according to the study and/or registry protocol, each participating site receives its 
own instance of the platform heartbeat ONE (described as local database in Figure 1) to comply 
with local data and IT protection obligations (Figure 2). The preferred mode of operation is 
Software-as-a-Service (SaaS) but an on-Premise installation is also available upon request. 
heartbeat ONE SaaS instances for participants in Switzerland are operated in the Green data 
center in CH-5242 Lupfig, Zurich-West, certified according to ISO 5001 and ISO 27001 and for 
participants in Germany and Austria the instances are operated in the diva-e data center in D-
60388 Frankfurt a.M. Kruppstraße 105 certified according to ISO 9001 und ISO 27001. Each 
customer receives a fully separated virtual machine on which the system is running. 
 
Figure 2 Decentralised data collection by own instances - GDPR (General Data Protection 
Regulation of the European Union (EU))-compliant, data can only be viewed by study staff 
 
 
 
 
 
 
Only authorised study personnel have access to the heartbeat ONE database, which is password 
protected. The extent of access to the heartbeat ONE database can be controlled by the PI and 
study stuff of the main study center of the study (USB) who have full administration rights. PI and 
study stuff of a local sub-center have only local administration rights. As soon as a patient's master 
data is entered into heartbeat ONE, he receives a personalised study number.  Only study 
personnel who are authorised to enter data into the heartbeat ONE database have the key to the 
identifying master data. Data output or data viewing can be selected/set by the PI in such a way 
that no reference can be made between the identifying master data (key) and the study data. 
 
Heartbeat consists of three central components (see Figure 3):  
University Hospital Basel
(USB)
(heartbeat ONE)

 
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1) Heartbeat ONE is a browser application for medical staff to access and manage the data 
collection of their patients on an individual and group level. PRO data arriving from 
heartbeat Portal (e-mail) and heartbeat Bridge (iPad) is processed and stored. CROs can be 
entered via heartbeat ONE. 
 
2) The patient portal provides one option for delivering patient surveys. This option is used 
when the patient is outside the hospital in a public network. Patients receive an encrypted 
link via email for their survey and, without installing an app, can answer the survey in a 
browser of their personal device survey after successful verification. The link itself in the e-
mail has no direct reference to the person being surveyed, but links exclusively to a survey. 
 
3) heartbeat Bridge is a tablet app, which allows patients to enter their PRO data at the 
study/registry site without their own device. heartbeat Bridge is integrated into the clinical 
network. 
 
The main system as well as the patient portal are separated from each other via different 
zones. Communication between the two zones takes place via an IPsec tunnel. All patient-
identifying data is stored in encrypted form. Further detailed information about the system 
architecture is available on request. 
 
Figure 3 Heartbeat ONE SaaS setup.  
 
 
 

 
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7.2.2 Entering Patient Reported Outcomes (PROs) 
 
Study staff access heartbeat ONE database via a browser. From there, study staff can initiate 
patient surveys and document clinical parameters. 
 
A patient survey can be conducted in two ways:  
 
 
iPad App - The survey via tablet app is conducted on site. After initiation, the patient receives 
a 4-digit verification token from the study staff. The token allows the patient to access the 
initiated survey on the tablet app. After a subsequent additional verification with the date of 
birth, the patient can conduct the survey. 
 
E-mail - After initiation, the patient receives an e-mail in the name of the hospital. The e-mail 
address and e-mail templates (logo, subject, text, contact) are configured according to study 
site preferences. The e-mail contains an encrypted link which directs the patient to its browser 
based patient portal. After verification via birth date, the patient can access the survey and 
enter their PRO data. 
 
Once the patient has left the site, an automatic e-mail follow-up function helps to survey patients 
at defined points in time. Study staff activate these e-mail follow up (so called autopilots) by 
entering a reference date. The system automatically sends up to three reminders per follow up if 
surveys are not answered by patients. 
 
7.2.3 Entering Clinician Reported Outcomes (CROs) 
 
The relevant clinical parameters that are to be collected in the course of the study can be 
documented intuitively via documentation forms by study stuff of each sub-center (study nurse, 
surgeon, local PI). Dashboards and task lists remind and support study staff to keep 
documentation completeness and data quality at a high level.  
 
7.2.4 Kesem Health iUFlow Clinical Portal 
 
The purpose of the iUFlow Kesem Health Clinical Portal is to allow study staff accessing clinical 
iUFlow data of authorised study patients. The Clinical Portal offers a real time visibility of patients´ 
home uroflow tests and bladder diary. When the patient opens the device specific app for the first 
time, he can select the University Hospital Basel as the study clinic and insert his personal study 
number that he has received. Once patients connect their app to the iUFlow device, data is 
immediately available on the portal. The Kesem Health Clinical Portal does not contain any 
master data of the patient, identification is exclusively via the assigned study number. Thus, data 
are fully coded in the Kesem Health Clinical Portal.  
The Clinical Portal supports download of data (PDF, Comma Separated Value file (CSV/Excel)) 
to be used for statistical analysis. Both outputs can be downloaded and used in real time. 
Customized messages can be sent to patients to provide real time feedback and/or reminder to 
perform their uroflow tests. 
The Kesem Clinical Portal database has no direct connection to the heartbeat ONE main 
database. Data from Kesem Clinical Portal is continuously and manually transferred from the 
Kesem Health Clinical Portal to the heartbeat ONE main database by study stuff of the University 
Hospital Basel. Study stuff of the main study center of the USB will see all study patients in the 
Kesem Health Clinical Portal, whereas sub-centers are only authorized to see results of their 
patients in the Clinical Portal (Figure 1). 

 
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7.3 Confidentiality and coding 
Project data will be handled with uttermost discretion and is only accessible to authorized 
personnel who require to fulfill their duties within the scope of the research project. On the CRFs 
and other project specific documents including the iUFlow Kesem Health Clinical Portal outside 
the secured heartbeat ONE database, participants are only identified by a unique participant 
number. PI and study staff of the main study center at the University Hospital Basel have access 
to all data and full administration rights for the heartbeat One database. PI and study staff of 
subcenters have only local access to their own patient data and have local administration rights 
concerning their own patients within the heartbeat ONE database. Only the main study center 
(USB) has administration rights for the Kesem Health Clinical Portal. Subcenters can only access 
the Clinical Portal to view data of their own patients without any administration rights.  
Only the GCP-compliant heartbeat ONE database, secured with personalized authorization 
passwords, keeps the study participant identification lists. Thus, the respective PI and authorized 
study staff of a subcenter has access only to the subcenter specific local study participant 
identification list. The PI and authorized study of the main study center (USB) have access to the 
entire study participant identification list for all participating centers. Hence, the complete study 
participant identification list is kept at the University Hospital in Basel. Safety back-ups are 
provided on different hardware storage media within the study centers. The hardware access is 
always password secured.  
Backups are created hourly and kept for 24 hours. In addition, it is possible to create offsite 
backups.  
Some data will be shared with representatives and affiliates of Boston Scientific in 
pseudonymised/aggregated form for internal development, analysis, regulatory evidence, 
marketing or educational purposes. The data will be stored on a server in the USA, while obeying 
Swiss and European data protection regulations. The provided data includes: 1. Patient age range 
within 5-year bands e.g. 40-45, 46-50, 2. Prostate volume, 3. Rezum delivery parameters, as 
documented in the study database, 4. Relevant comorbidity, as documented in the study 
database, 5. IPSS, 6. Qmax, 7. Procedure-related adverse events, as documented in the study 
database. 
 
 
7.3.1 Data security heartbeat ONE database 
Heartbeat medical guarantees by contract the GCP-conformity of the heartbeat ONE database 
and accordingly will control the heartbeat ONE database in a validation process. An audit trail is 
implemented in heartbeat ONE, which will allow tracking of any user generated inputs and 
changes to the database. 
 Over the course of collaboration with more than 200 institutions, (multi-center) research projects 
and registries, heartbeat medical has established a comprehensive data protection concept 
including a mature data protection impact assessment (DPA) as well as technical and 
organizational measures. This concept covers all requirements in Germany, Austria and 
Switzerland.  
Data entered by the patient is only available to system users on a read-only basis. Modification 
is not possible. Medical documentation can be created and edited by system users. Full access 
including user administration (see also User administration below) is only possible for selected 
system users. Access is not possible without a system account and therefore also not for 

 
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employees of heartbeat medical. Patients do not have direct access to the system, but the 
physician / study staff can share and discuss the results with patients. 
All patient-identifying data entered or created in heartbeat ONE is secured by a password 
assigned by the customer using 256 bit AES encryption. Access to this data is only possible with 
a user account including password. Heartbeat Medical is further obligated to take appropriate 
precautions to prevent unauthorized access by third parties to the customer's information and 
data. All patient-identifying data is send and stored in encrypted form. 
heartbeat ONE offers a user and permissions management system to create and manage user 
accounts and permissions. Individual permissions are grouped into roles and can then be 
assigned to the user (-groups). 
7.3.2 Data security Kesem Health  iUFlow App and Clinical Portal database 
Kesem Health is using Amazon Web Services (AWS) as an infrastructure partner. AWS holds the 
following security and compliance certifications: SOC1/ISAE 3402, SOC2, SOC 3, FISMA, 
DIACAP, FedRAMP, PCI DSS Level 1, ISO 9001, ISO 27001, ISO 27017, ISO 27018. 
Data that is collected and stored by Kesem Health is encrypted at rest. All data in transit is 
encrypted. Customer identifying data and clinical data is encrypted in transit using TLS 1.1 and 
1.2. All Kesem endpoints support HTTPS for encrypting data in transit. In general, all identification 
data (in this case only the study number) is kept separate from clinical data. To further increase 
anonymity and data security, the user of the iUFlow app is only asked to enter his study number 
assigned by the study team and the location of the study "University Hospital Basel" during the 
initial registration in the app. No personal identifying data is necessary for registration and 
activation of the Kesem Health iUFlow app. The Kesem Health Privacy Policy is shown in 
Appendix 20. Study participants will be given the Kesem Health Privacy Policy in writing as part 
of the study consent process. When registering in the iUFlow app, this will be displayed again 
and must be confirmed. 
The Kesem Health Clinical Portal database is password secured. Only study staff of the main 
center at the University Hospital Basel (USB) has administration rights. Study stuff of sub-centers 
need to get authorized by the USB to see iUFlow data of their respective patients in the Kesem 
health Clinical Portal, but sub-centers have no administration rights. 
 
7.4 Retention and destruction of study data 
After termination of the study, all data from the heartbeat ONE main database will be archived by 
Heartbeat in line with GCP-conformity criteria, which was contracted between Heartbeat and USB 
for a period of at least 10 years.  The Kesem Clinical Portal of the study will be closed and deleted, 
including all data inside, after data has been monitored and fully transferred to the heartbeat ONE 
database. 
 
 
 
8  FUNDING / PUBLICATION / DECLARATION OF INTEREST 
The project is funded by Boston Scientific (BSC) International S.A. a French corporation, Parc 
dÀffaires Le Val Saint-Quentin, 2 rue René Caudron, 78960 Voisins-le-Bretonneux, France with 
a maximum total funding of 1,634,444 ONE MILLION six hundred and thirty-four thousand four 
hundred and forty-four euros. The basis of funding is a contract agreement (Appendix 10.1) 
following the principle Investigator's (PD Dr. J. Ebbing) successful application to BSC's 
Investigator Sponsored Research Program. Funding is distributed on a staggered basis according 

 
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to the achievement of timelines (goals). Appendix 18 shows the items in the estimated study 
budget in chronological order. 
At least one year of follow-up data and then updates at annual intervals until the 5th follow-up 
year will be published in reputable peer-reviewed journals. 
The study will be registered at the following study registers:  
- 
kofam: Portal für klinische Versuche in der Schweiz (SNCTP) 
- 
swissethics: Registry of All Reseach Projects (RAPS) 
- 
European Clinical Trials Database (EudraCT) 
- 
Europäische Studienregister (EU Clinical Trials Register) 
- 
US National Institutes of Health NIH: (ClinicalTrials.gov) 
- 
WHO: International Clinical Trials Registry Platform (ICTRP) 
Collaboration with participating sub-study centers will be governed by a study sub-contract. 
(Appendix 14) 
 
The following contracts form the basis of this study or are applied within the scope of the study: 
1. Main contract with funder of the study, Boston Scientific International S.A. a French 
corporation, Parc dÀffaires Le Val Saint-Quentin, 2 rue René Caudron, 78960 Voisins-le-
Bretonneux, France (Appendix 10.1). 
Chapters of the current BSC contract relating to the transfer of data to BSC and the use 
of data by BSC will be renegotiated by amendment. It is planned that pseudonymised data 
will be passed on to BSC. 
BSC would like to use this data for regulatory submissions and internal research purposes. 
Completely anonymised data, as required by BSC in the current BSC contract, by 
definition do not allow usable statistical evaluations. This contradiction will be regulated 
by passing on pseudonymised/aggregated data to BSC which will be contracted by 
amendment (Appendix 10.2). 
 
2. Contract with manufacturer of the iUFlow (home uroflometry device), Kesem Helath Pty 
Ltd, 5A Hartnett Close, Mulgrave, Victoria 3170, Australia. (Appendix 11) 
 
3. Contract with Heartbeat (HRTBT) Medical Solutions GmbH, Greifswalder Str. 212, 10405 
Berlin, Germany, which provides and supports the main database “heartbeat ONE”. 
(Appendix 12) 
 
3.1   heartbeat enters into a separate application service provider (ASP) contract with each  
        participating site (Appendix 13). Those ASP contracts regulate  
        rights and obligations between the two parties and include a Service Level Agreement  
        and a Data Processing Agreement. 
              In the course of the project, the participating centers are not charged any usage costs.  
              These costs are borne by the central study unit (USB) and set out in a separate offer. 
 
4. Study subcontract with participating study centers. (Appendix 14) 
 
All contracts were reviewed and approved for contract signature by either Unitectra, Technology 
Transfer, Universities of Basel, Bern and Zürich, Scheuchzerstrasse 21, 8006 Zürich or by the 
legal department of the University Hospital Basel (USB). 
 

 
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Appendix 22  
 
Table 3: Schedule of assessments (summary) (V1.0) 
 
Parameter 
T0 
(Baseline) 
T – 
iUFlow-
device 
T – 
Dropout 
from 
study 
T1 
 (intra- 
operative) 
T2  
(peri- 
operative) 
T3  
(1d 
postop) 
T4 
(12w 
postop) 
T5 
(day of 
catheter 
removal) 
T6  
(2w 
postOP) 
T7  
(6w 
postOP) 
T8 
 (3m 
postOP) 
T9 
 (6m 
postOP) 
T10  
(12m 
postOP) 
T11 
(2-5y 
postOP) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Reported Outcome 
Measures (PROMs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IPSS/QoL 
x 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
ICIQ-MLUTS 
x 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
ICIQ-MLUTSsex 
x 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
MSHQ 
x 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
PROMIS Global Health 10 
x 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
QoR-15GE 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
NPRS (Numeric pain rating 
Scale)  
x 
 
 
 
 
x 
 
 
 
 
 
 
 
 
ICIQ-S 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Rezum side effects and pain 
medication patient 
questionnaire 
 
 
 
 
 
 
 
 
x 
x 
x 
 
 
 
Patients’ preferences and 
expectations for Rezum 
treatment questionnaire -  
x 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Questionnaire BPH/LUTS 
medication 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
Questionnaire re-operations 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Questionnaire bladder 
catheter 
 
 
 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
Questionnaire Uroflow 
x 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Clinical Reported Outcome 
Measures (CROMs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study ID 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient characteristics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comorbidities 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urological Anamnesis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Catheterization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Operations/interventions of the 
lower urinary tract 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prostate biopsy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History of cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic urethrocystoscopy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urodynamic evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uroflowmetry (not iUFlow) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Micturition-related medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood and urine 
examination 
x 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Laboratory blood 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory urine 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anticoagulation 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reason for Rezum (Doctor) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgery planning 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
iUFlow-device 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Dropout from study 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
Surgery 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Anesthesia 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Premedication 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Anesthetics used in the 
course of the intervention 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Hospitalization time 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
Postoperative analgesia 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 

 
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Postoperative catheter 
management 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
Transurethral catheter 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suprapubic catheter 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Follow-up 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Cancer history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnostic urethrocystscopy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical imaging 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urodynamic evaluation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uroflowmetry (not iUFlow) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Micturition-related medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anticoagulation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bladder catheter 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reoperation lower urinary 
tract 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complications/ 
Circumstances 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Side effects 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complications