Impact of Peri-operative tEstosterone Levels on oNcological and Functional Outcomes in RadiCal prostatEctomy
Phase: PHASE3
Conditions: Prostatic Neoplasms, Hypogonadism, Testosterone Deficiency
Sponsor: Canisius-Wilhelmina Hospital

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
1 
 
 
 
 
 
 
 
 
 
Clinical trial protocol: 
Impact of peri-operative tEstosterone levels oN Functional 
and oncological Outcomes following RadiCal 
prostatEctomy (ENFORCE) 
 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
2 
Impact of peri-operative tEstosterone levels oN Functional and oncological Outcomes 
following RadiCal prostatEctomy (ENFORCE)  
Protocol ID 
NL74362.091.20 
Short title 
ENFORCE 
EudraCT number  
2020-003012-27  
Version 
2.6 
Date 
8-12-2020 
Coordinating investigator/project 
leader 
 
D.J.H. Baas, MD
Canisius Wilhelmina Ziekenhuis
Department of Urology
Weg door Jonkerbos 1006532 SZ Nijmegen
Phone: 024-3658832 / 06-42633257
E-mail: d.baas@cwz.nl 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
Leading centre: 
D.M. Somford, MD PhD
Canisius Wilhelmina Ziekenhuis (CWZ)
Department of Urology  
Weg door Jonkerbos 100
6532 SZ Nijmegen
Phone: 024-3658832
E-mail: r.somford@cwz.nl 
 
Canisius Wilhelmina Ziekenhuis (J.P. van Basten) 
Radboud UMC (M. Sedelaar)
Catharina Ziekenhuis Eindhoven (E. Vrijhof) 
St Antonius Nieuwegein (H. van Melick) 
Zuijderland (M. Bruins) 
NKI/AvL (P. van Leeuwen) 
Jeroen Bosch Ziekenhuis (R. Wijn) 
Sponsor (in Dutch: 
Canisius Wilhelmina Ziekenhuis 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
3 
verrichter/opdrachtgever) 
 
 
Subsidizing party 
TBD 
Independent expert (s) 
Drs. Berends (CWZ) 
Department of Medical Oncology 
 
 
 
 
Laboratory sites  
CWZ 
 
 
Pharmacy  
N/A 
 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
4 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
 
Principal Investigator: 
Dr. D.M.Somford  
 
18-11-2020 
 
 
 
 
 
 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
5 
TABLE OF CONTENTS 
1. INTRODUCTION AND RATIONALE ......................................................................................... 11 
2. OBJECTIVES ............................................................................................................................ 13 
3. STUDY DESIGN ....................................................................................................................... 14 
Time and event schedule 1: Prescreening, screening, procedures and assessments ................. 20 
Time and event schedule 2: treatment and follow-up phase ......................................................... 21 
 ...................................................................................................................................................... 21 
4. STUDY POPULATION .............................................................................................................. 22 
4.1 
Population (base) .......................................................................................................... 22 
4.2 Prescreening eligibility criteria ............................................................................................. 22 
4.3 
Inclusion criteria ............................................................................................................ 22 
4.4 
Exclusion criteria ........................................................................................................... 22 
4.5 
Sample size calculation ................................................................................................ 23 
5. TREATMENT OF SUBJECTS ................................................................................................... 24 
5.1 
Investigational product/treatment .................................................................................. 24 
5.2 
Use of co-intervention ................................................................................................... 24 
5.3 
Escape medication ....................................................................................................... 24 
6. INVESTIGATIONAL PRODUCT ............................................................................................... 25 
6.1 
Name and description of investigational product(s) ...................................................... 25 
6.2 
Summary of findings from non-clinical studies ............................................................. 25 
6.3 
Summary of findings from clinical studies ..................................................................... 25 
6.4 
Summary of known and potential risks and benefits .................................................... 25 
6.5 
Description and justification of route of administration and dosage .............................. 26 
6.6 
Dosages, dosage modifications and method of administration .................................... 26 
6.7 
Preparation and labelling of Investigational Medicinal Product .................................... 26 
6.8 
Drug accountability ....................................................................................................... 27 
7. NON-INVESTIGATIONAL PRODUCT ...................................................................................... 28 
8. METHODS ................................................................................................................................ 29 
8.1 
Study parameters/endpoints ......................................................................................... 29 
8.2 
Randomization, blinding and treatment allocation ........................................................ 31 
8.3 
Study procedures .......................................................................................................... 31 
8.4 
Withdrawal of individual subjects .................................................................................. 32 
8.5 
Replacement of individual subjects after withdrawal .................................................... 32 
8.6 
Follow-up of subjects withdrawn from treatment .......................................................... 32 
8.7 
Premature termination of the study ............................................................................... 32 
9. SAFETY REPORTING .............................................................................................................. 33 
9.1 
Temporary halt for reasons of subject safety ................................................................ 33 
9.2 
AEs, SAEs and SUSARs .............................................................................................. 33 
9.3 
Annual safety report ...................................................................................................... 34 
9.4 
Follow-up of adverse events ......................................................................................... 35 
9.5 
Data Safety Monitoring Board (DSMB) ......................................................................... 35 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
6 
10. STATISTICAL ANALYSIS ....................................................................................................... 36 
10.1 
Primary study parameter(s) .......................................................................................... 36 
10.2 
Secondary study parameter(s) ..................................................................................... 36 
10.3 
Other study parameters ................................................................................................ 36 
10.4 
Interim analysis ............................................................................................................. 36 
11. ETHICAL CONSIDERATIONS ................................................................................................ 37 
11.1 
Regulation statement .................................................................................................... 37 
11.2 
Recruitment and consent .............................................................................................. 37 
11.3 
Objection by minors or incapacitated subjects (if applicable) ....................................... 37 
11.5 
Compensation for injury ................................................................................................ 37 
11.6 
Incentives ...................................................................................................................... 38 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ..................................... 39 
12.1 
Handling and storage of data and documents .............................................................. 39 
12.2 
Monitoring and Quality Assurance ................................................................................ 39 
12.3 
Amendments ................................................................................................................. 39 
12.4 
Annual progress report ................................................................................................. 39 
12.5 
Temporary halt and (prematurely) end of study report ................................................. 40 
12.6 
Public disclosure and publication policy ....................................................................... 40 
14. 
REFERENCES ................................................................................................................. 42 
 
 
 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
7 
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the 
application form that is required for submission to the accredited 
Ethics Committee; in Dutch: Algemeen Beoordelings- en 
Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
AMI 
Acute Myocardial Infarction 
BCR 
Biochemical Recurrence 
CA 
Competent Authority 
CABG 
Coronary Artery Bypass Grafting 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
CVA 
Cerebrovascular Accident 
CT 
Computed Tomography 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 
EBRT 
External Beam Radiation Therapy 
ED 
Erectile dysfunction 
EPIC-26 
Expanded Prostate Cancer Index Composite – short form  
EU 
European Union 
EudraCT 
European drug regulatory affairs Clinical Trials  
FSH 
Follicle-stimulating hormone 
FT 
Free Testosterone  
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
Hb  
Hemoglobin 
HT 
Hematocrit 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product  
IMPD 
Investigational Medicinal Product Dossier  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
8 
ISUP 
International Society of Urological Pathology 
LH 
Luteinising hormone 
LRP 
Laparoscopic Radical Prostatectomy 
MACE 
Major Adverse Cardiovascular Events  
METC  
 
Medical research ethics committee (MREC); in Dutch: medisch-
ethische toetsingscommissie (METC) 
MRI 
Magnetic Resonance Imaging 
MSKCC 
Memorial Sloan Kettering Cancer Center 
ORP 
Open Radical Prostatectomy 
PCa 
Prostate Cancer 
PCI 
Percutaneous Coronary Intervention  
PE 
Pulmonary Embolism  
PRL 
Prolactine 
PROM 
Patient Reported Outcome Measure 
PSA 
Prostate Specific Antigen 
PSM 
Positive Surgical Margin 
PLND 
Pelvic Lymph Node Dissection 
QoL 
Quality of Life  
RARP 
Robot Assisted Radical Prostatectomy  
RP 
Radical Prostatectomy 
(S)AE 
(Serious) Adverse Event  
SHBG 
Sex Hormone Binding Globuline 
SPC 
Summary of Product Characteristics; in Dutch: officiële 
productinformatie IB1-tekst 
Sponsor 
The sponsor is the party that commissions the organization or 
performance of the research, for example a pharmaceutical 
company, academic hospital, scientific organization or investigator. A 
party that provides funding for a study but does not commission it is 
not regarded as the sponsor, but referred to as a subsidizing party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TT 
Total Testosterone 
TRT  
Testosterone Replacement Therapy 
UAVG 
Dutch Act on Implementation of the General Data Protection 
Regulation; in Dutch: Uitvoeringswet AVG 
UI 
Urinary incontinence 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
9 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet 
Medisch-wetenschappelijk Onderzoek met Mensen 
 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 10 
SUMMARY 
Rationale: Radical prostatectomy (RP) is currently the most common treatment for non-metastatic 
prostate cancer (PCa). Two frequent side effects of this procedure are urinary incontinence and 
erectile dysfunction, both having a significant negative impact on quality of life.  
Additionally, it is known that with age the testosterone level in men declines. This does not lead to 
symptoms in all men (asymptomatic testosterone deficiency). Both testosterone deficiency (TD) and 
radical prostatectomy are well-established to have a significant negative impact on sexual 
performance and are likely to add up in patients with a low testosterone following RP.  
Objective: The aim of this study is to assess the effect of testosterone replacement therapy (TRT) on 
functional and oncological outcomes in testosterone deficient men following RP for PCa.  
Study design: This study is a phase 3 prospective, randomized, placebo-controlled, single-blind 
clinical trial.  
Study population: All men over 18 years old diagnosed with non-metastatic prostate cancer who are 
scheduled for RP within three months as primary treatment, can be prescreened for inclusion. Prior to 
the RP, serum testosterone will be determined. Subsequently, within six weeks after the RP, serum 
testosterone will be determined again and patients will be screened for inclusion. If necessary, a third 
measurement of testosterone will be done. Eligible patients meet the criteria for TD and other inclusion 
criteria.  
Intervention: Patients will be randomized for testosterone replacement therapy (TRT) or placebo as a 
daily administered topical gel starting within 8 weeks after RP. Patients will receive TRT or placebo for 
one year following RP and will be monitored for another year for functional outcomes and for four more 
years to establish 5-year biochemical recurrence (BCR) free survival.  
Main study parameters/endpoints:  
The primary study endpoint is a clinically relevant (12 points or more) difference in the EPIC-26 
domain for sexual functioning 12 months after RP in favor of testosterone deficient men receiving TRT 
compared with testosterone deficient men receiving placebo. Secondary endpoints include: urinary 
incontinence score, hormonal functioning score and BCR-free survival. 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  
The number of visits and blood drawings are equal to standard of care follow-up after RP, with the 
exception of two or three extra blood samples at the first prescreening visit and within six weeks 
following RP. We ask patients to remain with their hospital for 24 months after RP for follow-up and to 
complete online questionnaires for the given visits. The five-year biochemical recurrence (BCR) free 
survival will be obtained through patient’s medical records and if insufficient, through the Dutch Cancer 
Registry (NKR). 
Patients who receive TRT or placebo can experience local side-effects such as itching, rash and/or 
irritation at the site of application. In addition, patients who receive TRT can experience systemic side-
effects are gain of weight, hot flashes, acne and an increase in red blood count level.  
Furthermore, TRT might improve sexual functioning, urinary continence, hormonal functioning and 
BCR-free survival, but this is not certain and is subject of research in this study.  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 11 
1. INTRODUCTION AND RATIONALE 
Prostate cancer 
Prostate cancer (PCa) is the most prevalent solid malignancy in men in the Western world. In the 
Netherlands, over 13.000 men were diagnosed with prostate cancer in 20191. If the disease is limited 
to the prostate or locally advanced, several treatment options are available such as active 
surveillance, surgery, external beam radiotherapy (EBRT) or brachytherapy. The most common 
treatment for non-metastatic PCa is surgical removal of the prostate; a radical prostatectomy (RP). In 
the Netherlands an estimated 2.500 procedures are performed on a yearly basis. Two common side-
effects of this procedure are urinary incontinence (5-27%) and erectile dysfunction (ED) (57-89%) 
which have a significant negative impact on the quality of life2 3 4 5. These functional results can 
improve up until 12 months after surgery, but remain mostly stable after 12-24 months. Patient 
Reported Outcome Measures (PROMs) are used to objectively document these functional outcomes. 
The Expanded Prostate cancer Index Composite-26 (EPIC-26) is a commonly used and validated 
PROM to assess the five domains; urinary incontinence, urinary obstructive, bowel, sexual and 
hormonal functioning in men who underwent treatment for prostate cancer 6 7. Following RP most 
patients have an undetectable PSA, which is an indicator of successful treatment of PCa. However, up 
to one-third of patients experience a rising PSA during follow-up, an event known as biochemical 
recurrence (BCR)8. A BCR is therefore a common event and associated with worse overall survival, 
especially in high-risk cases9.  
 
Testosterone deficiency in aging men   
It is known that serum testosterone levels decline with age. At the age of 70, around 30% of men are 
testosterone deficient (TD)10. This does not necessarily lead to symptoms. Late-onset hypogonadism 
is defined as the combination of TD and the presence of at least three symptoms11. The 
Massachusetts Male Aging Study (MMAS) collected data of aging men in the late 1980s and 1990s, 
they found a prevalence of symptomatic testosterone deficiency between 6% and 12%12. A few years 
later the same research group verified these findings with the data from the Boston Area Community 
Health (BACH) survey and found that 28.1% of men above 50 years had a low total testosterone and 
6.6 % of men above 50 years symptomatic testosterone deficiency13. The number of symptomatic men 
increases with age; in men 70-79 years they found a prevalence of 18.4%.  
 
Testosterone replacement therapy 
The current EAU guideline on late-onset hypogonadism states that testosterone replacement therapy 
(TRT) is indicated in adult men with low testosterone and concomitant signs and symptoms of TD 
following unsuccessful treatment of obesity and comorbidities 14. TRT has been shown to improve 
sexual functioning in hypogonadal men15 16. The aim of TRT is to restore testosterone to physiological 
levels. Several agents are available; oral preparations, intramuscular injections and transdermal gels. 
Testosterone gel is a commonly used agent and widely available.  
 
Testosterone and prostate cancer  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 12 
In 1941, Charles B. Huggins described the association between testosterone and PCa, a discovery for 
which he received the Nobel Prize in 196617. He discovered the positive effect of castration (i.e. 
testosterone depletion) on metastatic prostate cancer, which is as of today the cornerstone of the 
treatment of patients with metastatic PCa. More recently there has been a challenge to this paradigm 
of lowering testosterone levels in PCa patients, as two studies demonstrated the potential beneficial, 
but counterintuitive, effect of supraphysiological levels of testosterone in men with advanced prostate 
cancer18 19. In addition, another study showed that men with preoperative low serum testosterone 
levels had worse pathological outcomes and a higher rate of BCR following radical prostatectomy20. 
The interaction between testosterone and PCa therefore remains complex, not fully understood and 
requires more research.  
 
Testosterone and RP  
Several studies evaluated the safety of TRT in TD men after initial local treatment of PCa. Recently, 
an extensive systematic review and meta-analysis was published analyzing 21 studies in which 
patients received TRT following definitive local therapy for non-metastatic PCa21. Overall, they did not 
find an increased rate of BCR in all groups. Nor did subgroup analysis of patients who underwent RP 
show an increased BCR rate. More specifically, subgroup analyses showed that patients who had 
undergone a RP experienced lower (though not significant) BCR rates than those who underwent a 
non-surgical treatment. This is possibly explained by the differences in patient population and disease 
characteristics such as tumor stage and grade, time of TRT and the definition of BCR, which was not 
standardized among included studies. Several comments are made by the authors. The studies 
included in the review varied widely in terms of design, methods, interventions and follow-up duration. 
Secondly, their analysis included patients who were eligible for testosterone replacement therapy and 
thus at lower risk for BCR. A more recent study retrospectively analyzed 850 patients who underwent 
RP22. Preoperative testosterone levels were determined, 152 patients (18%) with low preoperative 
calculated free testosterone and delayed post-operative sexual function recovery, were placed on TRT 
and matched to control cases. A significant lower BCR rate in the TRT group was established. 
Furthermore, they found that the time to BCR was delayed by approximately 1.5 years. Due to the 
non-randomized nature of this study, the authors recommend a multi-center, prospective randomized 
trials, as we now propose in this protocol. 
 
Conclusion of rationale 
Testosterone replacement therapy in (a)symptomatic testosterone deficient men after RP is safe and 
may improve functional and oncological outcomes but is not common practice. Further research is 
warranted to evaluate its potential benefits.   

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 13 
2. OBJECTIVES 
 
Primary Objective:  
To evaluate if TRT in (a)symptomatic testosterone deficient men with prostate cancer undergoing RP, 
leads to better outcomes in the domain of sexual functioning 12 months after RP compared to 
testosterone deficient men who receive placebo therapy.  
 
Secondary Objectives:  
1. Evaluate if TRT in (a)symptomatic testosterone deficient men with prostate cancer undergoing RP 
leads to better outcomes in the domain of sexual functioning 3 months after RP. 
2. Evaluate if TRT in (a)symptomatic testosterone deficient men with prostate cancer undergoing RP 
leads to better outcomes in the domain of sexual functioning 24 months after RP. 
3. Evaluate if TRT in (a)symptomatic testosterone deficient men with prostate cancer undergoing RP 
leads to better outcomes in the domain of hormonal functioning 12 months after RP.  
4. Evaluate if TRT in (a)symptomatic testosterone deficient men with prostate cancer undergoing RP 
leads to better outcomes in the domain of hormonal functioning 24 months after RP.  
5. Evaluate if TRT in (a)symptomatic testosterone deficient men with prostate cancer undergoing RP, 
leads to both a reduction of and longer interval to BCR following RP, at 1, 2 and 5 years after RP.  
 
Exploratory objective:  
6. Evaluate if TRT in (a)symptomatic testosterone deficient men with prostate cancer undergoing RP 
leads to better outcomes in the domain of urinary continence 12 months after RP.  
7. Evaluate if TRT in (a)symptomatic testosterone deficient men with prostate cancer undergoing RP 
leads to better outcomes in the domain of urinary continence 24 months after RP.  
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 14 
3. STUDY DESIGN 
This study is a phase 3 prospective, randomized, placebo-controlled, single-blind clinical trial to 
evaluate the effect of TRT on sexual functioning in testosterone deficient men following RP.  
The study will consist of four phases; a prescreening phase before RP, a screening phase after RP, a 
treatment phase and a follow-up phase. During the prescreening phase testosterone levels will be 
determined pre-operatively and within six weeks post-operatively for all patients. If both values are not 
in concordance with each other, another measurement will be done. At six weeks after RP patients will 
be screened for inclusion. Only TD men will be included and asked for written informed consent. Men 
who have normal testosterone levels cannot proceed in the study, but will be asked to give permission 
to use their oncological and functional outcomes as a reference cohort. Randomization will take place 
(TRT vs. placebo) on a 1:1 ratio. Patients will enter a 1-year treatment phase, followed by a 1-year 
follow-up phase for functional outcomes.  
 
Prescreening phase 
In participating centers all patients who are scheduled for RP will be asked to participate in this study. 
If a patient is eligible for prescreening according to inclusion and exclusion criteria, they will be 
informed about the study. After written informed consent, a blood sample (drawn in het morning 
between 07:00-11:00, in a fasting state) will be collected to determine serum testosterone (free and 
total) and SHBG. Clinical data (age, weight, height, BMI, medical history, ECOG-performance status, 
ASA classification, non-age adjusted Charlson Comorbidity Score, marital status) will be collected 
from the electronical patient record. Disease specific data (clinical T and MRI stage, initial PSA, 
maximum Gleason score/ISUP grade at biopsy, prostate volume on imaging) will be collected as well. 
Patients must have a minimum baseline score of 40 points for the sexual functioning domain, as this 
reflects a minimally satisfactory sexual functioning.  
 
RP 
The RP will take place as scheduled, but within three months following written informed consent for 
prescreening. Operative parameters such as technique (robot-assisted (RARP), laparoscopic (LRP) or 
open (ORP)), nerve sparing (no/unilateral/bilateral), use of NeuroSafe (intra-operative frozen section), 
pelvic lymph node dissection (PLND), blood loss, total time of surgery, and intra-operative 
complications will be recorded in the database. The prostate and if applicable lymph nodes will be 
examined by the pathologist conform normal practice. The pathology report must include: pT-stage, 
Gleason score/ISUP grade, presence of positive surgical margins (PSM) as well as location and 
length, and in case of PLND: number of nodes removed, presence of nodal involvement and number 
of positive nodes. These items will be recorded in the database as well.  
 
After RP 
Within six weeks after RP an additional blood test for PSA, free and total testosterone, SHBG, 
hemoglobin (Hb), hematocrit (HT), liver function, and lipid profile will be done. When preoperative total 
testosterone was <8 nmol/l, or between 8-12 nmol/l with a free testosterone <225 pmol/l, LH will be 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 15 
determined subsequently to confirm the diagnosis of late-onset hypogonadism. If LH is below its 
normal limit, the patient is not eligible for the study and referred to the endocrinologist for further 
investigation. Again, this test has to be taken between 07:00 and 11:00 in the morning in a fasting 
state.  
 
Third testosterone measurement  
Patients who had a normal testosterone before RP, but a testosterone deficiency after RP need to 
have a confirmation measurement of testosterone and LH. Patients who were testosterone deficient 
on two previous occasions and with a normal or elevated LH do not need additional testing at this 
moment.  
 
Screening phase 
At six weeks after RP the prescreening phase will end and patients will be screened for inclusion at 
the screening visit. If patients meet the eligibility criteria for TRT following RP (see the criteria bellow), 
patients will be asked to participate in the study. Patients will be asked to sign a second informed 
consent form for the study. Patients with testosterone deficiency defined as a total testosterone <8.0 
nmol/l or total testosterone 8-12 nmol/l and free testosterone < 225 pmol/l will be included.  
 
Patients with normal testosterone levels 
Patients who were eligible for prescreening but have a normal testosterone level are not eligible for 
further participation in the trial. We do ask them to give consent to use their functional and oncological 
outcomes as a reference for testosterone deficient patients. Functional outcomes are measured with 
the EPIC-26 up to two years after surgery and oncological outcomes are defined as the occurrence of 
a biochemical recurrence up to five years after surgery.  
 
Eligible for testosterone replacement therapy: 
1. Testosterone deficiency: total testosterone < 8nmol/l OR total testosterone 8-12 nmol/l and 
free testosterone < 225 pmol/l, measured at two separate occasions and normal or elevated 
LH.  
2. Unmeasurable PSA level (<0.1) within six weeks of follow up 
3. pT2-T3a after RP  
4. ISUP 1-3 independent of surgical margin status or ISUP 4-5 with negative surgical margins  
5. No metastatic lymph nodes if a PLND has been done  
6. No general contra-indications for testosterone therapy 
7. At least one-sided nerve-sparing procedure 
8. A minimum baseline score of 40 points for the sexual functioning domain as measured by the 
EPIC-26 questionnaire.  
 
Randomization and treatment phase 
Patients will be randomized for TRT or placebo and start with daily application of TRT/placebo after 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 16 
randomization, within eight weeks after RP at latest.  
 
Evaluation of testosterone level and dosage adjustment 
Patients will visit their physician at 3, 6 and 9 months after RP. Serum testosterone level will be 
measured before the visit. The measurement must take place in the morning before application of the 
gel. For patients who receive testosterone gel, their serum testosterone level should be within 17-20 
nmol/l. If the current testosterone level is below that value, the daily dosage should be increased with 
one pump actuation. If the testosterone level is above 20 nmol/l the daily dosage should be decreased 
with one pump actuation. The daily dosage should not exceed 4 pump actuations.  
If patients exceed the upper limit of 20nmol/l with one dosage actuation, they should stop with the 
treatment.  
Patients who receive placebo gel will also have their testosterone level measured as a reference, but 
there will be no dosage adjustment in the placebo group.  
 
Penile rehabilitation  
All participants are allowed to use additional medication for penile rehabilitation if they request. The 
following protocol can be used:  
1. PDE-5 inhibitor (sildenafil or tadalafil) on demand or daily use 
2. Intracavernous (phenatolamine/papaverine) or intra-urethral (alprostadil) injections 
 
The use of additional medication for penile rehabilitation will be registered in the eCRF.  
 
Continuation of testosterone therapy after treatment phase 
If patients who were treated with TRT, experience worsening of their symptoms after TRT stops, it is 
allowed for those men to continue treatment after evaluation of their testosterone levels. This will be 
registered in the eCRF.  
 
Safety of treatment 
The safety of treatment of patients in will be evaluated at 3-, 6- and 9-months following RP. 
Withdrawing a patient from treatment is indicated if any of the following events occur:  
1. Detectable serum PSA  
2. Hematocrit ³ 54%  
3. Any adverse event (AE) that leads to substantial changes in risk-benefit consideration 
according to the local investigator  
4. Delay of drug administration of more than 28 days for any reason  
5. Elevation of ALAT 1.5x above its normal value  
6. Exceeding the upper limit of 20 nmol/l testosterone with one dosage actuation   
See paragraph 8.4.1 for a full list of withdrawal criteria.  
 
Testosterone half-life time and antihormonal treatment after TRT  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 17 
The half-life time of testosterone gel is around 10-100 minutes. Therefore, in case a biochemical 
recurrence is found and there is an indication for antihormonal treatment, patients should stop 
immediately with the application of testosterone gel. After 72-96 hours the serum testosterone level is 
back to its baseline level.   
 
Evaluation of major adverse cardiovascular events  
During treatment and follow-up, patients will be evaluated if any of the following Major Adverse 
Cardiovascular Events (MACE) as defined for this study did occur:  
1. Myocardial infarction (MI) 
2. Cerebrovascular Accident (CVA) 
3. Hospitalization because of heart failure  
4. Cardiac interventions including percutaneous coronary intervention (PCI) and coronary artery 
bypass grafting (CABG).   
5. Pulmonary embolism (PE) 
6. Deep-venous thrombosis (DVT)  
7. Death; if no cause is known, cardiac death will be assumed.  
 
Checks and visits: 
3-month FU 
• 
Laboratory tests: PSA, TT, FT, SHBG, Hb, HT, lipid profile and ALAT 
• 
Evaluate safety criteria to continue TRT or placebo 
• 
In patients who receive TRT: serum testosterone level will be evaluated and if required 
adjustments to the application dosage will be made.  
• 
Completion of EPIC-26  
• 
Registration of cardiovascular events.  
• 
Completion of eCRF 
 
6-month FU  
• 
Laboratory tests: PSA, TT, FT, SHBG, Hb, HT, lipid profile and ALAT 
• 
Evaluate safety criteria to continue TRT or placebo 
• 
In patients who receive TRT: serum testosterone level will be evaluated and if required 
adjustments to the application dosage will be made.  
• 
Completion of EPIC-26  
• 
Registration of cardiovascular events.  
• 
Completion of eCRF 
 
9-month FU 
• 
Laboratory tests: PSA, TT, FT, SHBG, Hb, HT, lipid profile and ALAT 
• 
Evaluate safety criteria to continue TRT or placebo 
• 
In patients who receive TRT: serum testosterone level will be evaluated and if required 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 18 
adjustments to the application dosage will be made.  
• 
Completion of EPIC-26  
• 
Registration of cardiovascular events.   
• 
Completion of eCRF 
 
12-month FU 
• 
Laboratory tests: PSA, TT, FT, SHBG, Hb, HT, lipid profile and ALAT 
• 
Completion of EPIC-26  
• 
Registration of cardiovascular events.  
• 
Completion of eCRF 
• 
Stop application of testosterone/placebo gel.  
 
 
18-month FU 
• 
Laboratory tests: PSA, TT, FT, SHBG, LH 
• 
Completion of EPIC-26 
• 
Registration of cardiovascular events.  
• 
Completion of eCRF 
 
24-month FU  
• 
Laboratory tests: PSA, TT, FT, SHBG, LH 
• 
Completion of EPIC-26  
• 
Registration of cardiovascular events.  
• 
Completion of eCRF 
 
 
24-60 months  
Resume oncological follow-up conform local protocol. 
 
60-month FU 
5-year BCR free survival rate: The 5-year BCR-free survival will be established through revision of the 
medical records. 
 
 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 19 
 
 
 
 
 
 
 
 
 
 
Pre-screening phase  
Randomization (1:1) 
RARP (+/- PLND) (standard care) 
Inclusion 
Control group:  
 
Start Placebo 
 
 
Screening phase 
Intervention group:  
 
Start TRT 
 
Men with prostate cancer scheduled for RARP as primary treatment 
Informed consent (2) 
Diagram 1: flow-chart of phases  
Informed consent (1) 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
20 
Time and event schedule 1: Prescreening, screening, procedures and assessments  
Phase: 
Prescreening 
 
 
Screening 
Assessment 
Prior to RP 
<6 weeks after RP 
<6 weeks after RP 
6-weeks after RP 
Informed consent 
X 
 
 
X 
PSA 
X 
X 
 
 
TT, FT, SHBG1 
X 
X 
X3 
 
LH 
 
X2 
X3 
 
Lipid spectrum 
 
X 
 
 
ALAT 
 
X 
 
 
Hb, HT 
 
X 
 
 
Prescreening 
comedication check 
X 
 
 
 
Prescreening criteria 
X 
 
 
 
Inclusion/exclusion criteria 
check 
X 
 
 
X 
Demographics 
X 
 
 
 
Medical history 
X 
 
 
 
EPIC-26 
X 
 
 
 
RP data  
 
 
 
X 
Pathology data 
 
 
 
X 
Doctor visit 
X 
 
 
X 
Inclusion 
 
 
 
X 
1laboratory tests must be taken between 07:00-11:00 in the morning in a fasting state.  
2In case a low testosterone is found prior to RP; LH will be measured after RP. 
3If a low testosterone is found after RP; a confirmation test will be done.   

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 
21 
   
 
 Time and event schedule 2: treatment and follow-up phase 
 
Phase: 
Treatment 
 
 
 
 
Follow-up 
 
 
Assessment  
6-8-weeks 
after RP 
3-months 
after RP  
6-months 
after RP 
9-months 
after RP 
12-months 
after RP 
18-months 
after RP 
24-months 
after RP 
5-years 
after RP 
Randomization 
X 
 
 
 
 
 
 
 
Doctor visit 
X 
X 
X 
X 
X 
X 
X 
 
PSA  
 
X 
X 
X 
X 
X 
X 
X 
TT, FT, SHBG1 
 
X 
X 
X 
X 
X 
X 
 
ALAT 
 
X 
X 
X 
X 
 
 
 
Hb, HT 
 
X 
X 
X 
X 
 
 
 
Lipid profile 
 
X 
X 
X 
X 
 
 
 
Adjustment of 
application dosage 
based on serum TT 
level 
 
X 
X 
X 
 
 
 
 
Assessment of safety 
of TRT/placebo 
 
X 
X 
X 
 
 
 
 
EPIC-26 
 
X 
X 
X 
X 
X 
X 
 
Cardiovascular Events 
Questionnaire 
 
X 
X 
X 
X 
X 
X 
 
Assessment of BCR 
 
X 
X 
X 
X 
X 
X 
X 
1Blood collection during treatment should be taken before application of the gel in the morning.  
  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 22 
 
4. STUDY POPULATION 
4.1 
Population (base)  
All men who are diagnosed with non-metastatic prostate cancer who are scheduled for RP as 
primary treatment are eligible for prescreening for this study. The diagnosis of prostate cancer must 
be confirmed by either biopsy (transperineally or transrectal) or found in prostate tissue after 
transurethral resection of the prostate (TURP) for assumed benign prostate hyperplasia (BPH). 
Patients must have completed the current standard of care diagnostic path to exclude visceral or 
bone metastasis if suspected. This may include additional imaging (CT-thorax/abdomen, bone 
scintigraphy, and/or PSMA-scan) at the physician’s discretion.  
 
4.2 Prescreening eligibility criteria 
1. Signed informed consent form 1 (IC) 
2. Age > 18 years 
3. Histologically confirmed prostate cancer 
4. Scheduled for RP as primary treatment with intention of at least a one-sided nerve-sparing 
procedure.   
5. Non-metastatic disease (cN0M0)  
6. Willing to provide blood samples to determine testosterone level 
7. A pre-operative minimal sexual function defined as 40 points (out of 100) for the EPIC-26 
sexual functioning domain.  
 
Prescreening exclusion criteria:  
1. Any previous treatment for prostate cancer, for example but not limited to: anti-hormonal 
therapy, radiotherapy or brachytherapy (active surveillance is allowed).  
2. Previous use of testosterone therapy for any reason 
3. History of male breast cancer 
4. History of liver tumor  
5. Uncontrolled hypertension 
6. Allergy for components in the testosterone therapy agent or placebo 
7. Use of vitamin-K antagonists (acenocoumarol or fenprocoumon)  
8. BMI > 30 
 
4.3 
Inclusion criteria 
1. All of the above prescreening eligibility criteria 
2. Signed informed consent form 2 (ICF)  
3. Undetectable PSA level within six weeks after RP 
4. At least one-sided nerve-sparing procedure 
 
4.4 
Exclusion criteria 
1. pT3b or pT4 
2. Positive surgical margin (PSM) and ISUP 4 or 5  
3. Metastatic lymph nodes if a PLND has been done 
 
Following medical conditions require extra consideration regarding TRT:  
Inclusion at discretion of the caregiver. 
• 
Heart failure, history of ischemic cardiac disease, altered renal- or liver functioning, 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 23 
epilepsy, migraine (risk of fluid retention) 
• 
Diabetes mellitus (risk of increased glucose tolerance) 
• 
Obesity or COPD (risk of induction or worsening of sleep-apnea syndrome) 
• 
Thrombophilia or high-risk for DVT 
 
4.5 
Sample size calculation 
To calculate the sample size, the clinical minimally important difference for the EPIC-26 within the 
domain of sexual functioning was used. Based on the Dutch ProZIB report on prostate cancer in 2019 
the mean score [0-100] within the sexual functioning domain for patients who underwent RARP at T0 
was 63, with a standard-deviation of 26. At T12 for the same group, the mean was 26 with an SD of 
226. Skolarus et al demonstrated in previous research that a clinical relevant difference (minimal 
important difference, MID) in the domain of sexual functioning is considered 12 points or more23. This 
means that we expect patients who receive TRT who have clinically relevant improvement will have a 
mean score of at least 38. A sample size calculation using the following parameters was performed:  
Power (β-1) = 0.80  
Significance level (α) = 0.05 
Two-sided testing 
Group 1: mean 26 SD: 22Group 2: mean 38   
This results in a sample size of 53 patients in each group. 
 
The university of Michigan, who developed the EPIC-26 questionnaire, suggests when studying one 
domain as primary endpoint, a sample size of 64 patients per treatment group should be used24.  
We assume that 10% of our patients will discontinue treatment, therefore we establish the sample size 
for each group at 70 patients, 140 in total. To reach inclusion of 140 testosterone deficient patients, we 
will prescreen 700 patients who are scheduled for RP, assuming that 25% of our population meets the 
criteria for TD and 80% will be eligible for inclusion after RP (700*0.25*0.8 = 140 patients).  
 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 24 
5. TREATMENT OF SUBJECTS 
 
 
 
 
5.1 
Investigational product/treatment 
Patients will be randomized 1:1 between receiving testosterone gel (TRT) or placebo.  
Testosterone gel (Androgel®) will be given as a gel for topical application.  
 
Placebo gel will contain the same components as testosterone gel, except for the testosterone.   
 
5.2 
Use of co-intervention 
Concomitant administration of testosterone and ACTH or corticosteroids may increase the risk of 
developing edema. As a result, these medicinal products should be administered cautiously, 
particularly in patients suffering from cardiac, renal or hepatic disease. 
Interactions with laboratory tests: androgens may decrease levels of thyroxin binding globulin, 
resulting in decreased T4 serum concentrations and in increased resin uptake of T3 and T4. Free 
thyroid hormone levels, however, remain unchanged and there is no clinical evidence of thyroid 
insufficiency. 
Changes in insulin sensitivity, glucose tolerance, glycemic control, blood glucose and glycosylated 
hemoglobin levels have been reported with androgens. In diabetic patients, antidiabetics' medication 
might need reduction. 
Application of sunscreen or lotion does not reduce efficacy. 
Washing 2 hours after application does not have significant effect on blood testosterone levels. 
Patients are allowed to use 5-alpha-reductase inhibitors (sildenafil, tadalafil) if requested.  
5.3 
Escape medication  
Not applicable 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 25 
6. INVESTIGATIONAL PRODUCT  
 
6.1 
Name and description of investigational product(s) 
Androgel 16.2 mg/g gel. One gram of gel contains 16.2 mg testosterone. One pump actuation delivers 
1.25 g of gel containing 20.25 mg of testosterone.  
 
 
6.2 
Summary of findings from non-clinical studies 
Please see section 5.3 of the attached Summary of Product Characteristics (SPC) of Testosterone gel. 
 
6.3 
Summary of findings from clinical studies 
Several clinical studies have demonstrated the efficacy and safety of TRT in patients with TD. Several 
testosterone formulations are available; oral, topical gel and through intramuscular injection. The use 
of testosterone gel is the most frequent used. After absorption by the stratum corneum, creating a 
reservoir, from which testosterone is continuously is delivered for 24 hours after daily application. 
Topical applications have shown to normalize testosterone levels with an excellent safety profile26. A 
recent multicenter, randomized, double-blind placebo-controlled trial studied the efficacy and safety of 
testosterone gel in several dosages compared to placebo (6:1 ratio) in 274 hypogonadal men27 over 
182 days. They found that over 80% over the men treated had an adequate testosterone level after 
titration with a good safety profile.  
 
 
 
6.4 
Summary of known and potential risks and benefits 
Testosterone replacement therapy is associated with an elevation of the serum PSA and increased 
prostate volume. However, before inclusion there must be no sign of residual prostate cancer following 
RP. Therefore, we consider it safe to treat patients who have been successfully treated with RP, as 
mentioned before. The potential risks include known side-effects, as listed below.  
 
Undesirable effects 
Most frequent undesirable effects are skins reactions (10%), reaction at the application side, 
erythema, dry skin.  
Adverse drug reactions reported in 1 - <10% of patients treated with Androgel in the controlled clinical 
trials are listed in the following table: 
 
Organ system class  
Common adverse reactions (>1/100,<1/10) 
Blood and lymphatic system disorders  
Changes in laboratory tests (polycythaemia, lipids), 
Haematocrit increased, Red blood cell count increased, 
Haemoglobin increased 
General disorders and administration site conditions 
Headache 
Renal and urinary disorders 
Prostatic disorders 
Reproductive system and breast disorders 
Gynaecomastia, mastodynia 
Nervous system disorders 
Dizziness, paraesthesia, amnesia, hyperaesthesia 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 26 
Psychiatric disorders 
Mood disorders 
Vascular disorders 
Hypertension 
Gastro-intestinal disorders 
Diarrhoea 
Skin and subcutaneous disorders 
Alopecia, urticaria 
Gynaecomastia, which may be persistent, is a common finding in patients treated for hypogonadism. 
Because of the alcohol contained in the product, frequent applications to the skin may cause irritation 
and dry skin. 
 
6.5 
Description and justification of route of administration and dosage 
Transdermal use.  
The application should be administered by the patient himself, onto clean, dry, healthy skin over right 
and left upper arms and shoulders.  
The gel should be simply spread on the skin gently as a thin layer. It is not necessary to rub it on the 
skin. Allow to dry for at least 3-5 minutes before dressing. Wash hands with soap and water after 
application, and cover the application site(s) with clothing after the gel has dried. Wash the application 
site thoroughly with soap and water prior to any situation where skin-to-skin contact of the application 
site with another person is anticipated. For more information regarding post dose washing see section 
4.4 (subsection Potential for testosterone transfer).  
Do not apply to the genital areas as the high alcohol content may cause local irritation.  
To obtain a full first dose, it is necessary to prime the canister pump. To do so, with the canister in the 
upright position, slowly and fully depress the actuator three times. Safely discard the gel from the first 
three actuations. It is only necessary to prime the pump before the first dose.  
After the priming procedure, fully depress the actuator once for delivering 1.25 g of ANDROGEL 16.2 
mg/g into the palm of the hand and then apply to the upper arms and shoulders.  
 
6.6 
Dosages, dosage modifications and method of administration 
The recommended dose is two pump actuations of gel (i.e. 40.5 mg of testosterone) applied once 
daily at about the same time, preferably in the morning. The daily dose should be adjusted by the 
doctor depending on the clinical or laboratory response in individual patients, not exceeding four pump 
actuations or 81 mg testosterone per day. The adjustment of posology should be achieved by 
increments of one pump actuation of gel.  
The dose should be titrated based on the pre-dose morning testosterone blood levels. Steady state 
blood testosterone levels are reached usually by the second day of treatment with ANDROGEL 16.2 
mg/g. In order to evaluate the need to adjust the testosterone dosage, blood testosterone levels 
should be measured in the morning before application of the product, after the steady state is reached. 
Testosterone blood levels should be assessed periodically. The dose may be reduced if the 
testosterone blood levels are raised above the desired level. If the levels are low, the dosage may be 
increased stepwise, to a daily administration of 81 mg of testosterone (four actuations of gel) per day.  
Therapy should be discontinued if the blood testosterone levels consistently exceeds the normal range 
at the lowest daily dose of 20.25 mg (1.25 g gel, equivalent to one pump actuation) or if blood 
testosterone levels in the normal range cannot be achieved with the highest dose of 81 mg (5 g gel, 
equivalent to four pump actuations).  
 
6.7 
Preparation and labelling of Investigational Medicinal Product 
Preparation and labelling of the investigational medicinal products will be done according to GMP 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 27 
guidelines.  
 
6.8 
Drug accountability 
At start of the study, the local the investigational products will be delivered to the principal investigator 
authorized designee of the participating hospital. The designee will check and record the amount and 
condition of the received products. The products will come with an enclosed packing slip, which must 
be signed and returned to the delivered to verify the reception of the investigational product. An 
investigational product dispensation record will be kept, which will contain the following information: 
• 
Patient record id  
• 
Date and quantity of product dispensed  
• 
Date and quantity of product returned to pharmacy/investigator (if applicable) 
• 
Date and quantity of accidental loss or damaged product (if applicable)  
These logs must be kept for inspection of the study. At the end of the study these the monitor will 
collect these records as well.  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 28 
7. NON-INVESTIGATIONAL PRODUCT 
 
Not applicable.  
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 29 
8. METHODS 
8.1 
Study parameters/endpoints 
Most of the study’s endpoints will be functional outcomes, which will be registered with Patient 
Reported Outcome Measures (PROM).  
 
8.1.1 
Main study parameter/endpoint 
The main endpoint for this study is the total sexual domain score coming from the EPIC-26 
questionnaire, 12 months after RP. Calculation of this domain score is done by calculating the average 
of the Standardized Values for items 57-60, 64 and 68 (with 5 non-missing items needed to compute 
score). Corresponding with questions 8a, 8b, 9, 10, 11 and 12. This results in a number between 0 
and 100. A change of 12 points in this domain is considered clinically relevant.   
Calculation of the different domain scores is done according to the instructions provided by University 
of Michigan28. 
8.1.2 
Secondary study parameters/endpoints  
 
1. EPIC-26 sexual functioning domain score [0-100] at 3 months after RP. A difference of 12 points 
or more is considered clinically relevant.  
2. EPIC-26 sexual functioning domain score [0-100] at 24 months after RP. A difference of 12 points 
or more is considered clinically relevant.  
3. EPIC-26 urinary incontinence domain score [0-100] at 12 months after RP. A difference of 9 points 
or more is considered clinically relevant. 
4. EPIC-26 urinary incontinence domain score [0-100] at 24 months after RP. A difference of 9 points 
or more is considered clinically relevant. 
5. EPIC-26 hormonal functioning domain score [0-100] at 12 months after RP. A difference of 6 
points or more is considered clinically relevant. 
6. EPIC-26 hormonal functioning domain score [0-100] at 24 months after RP. A difference of 6 
points or more is considered clinically relevant. 
7. Occurrence of biochemical recurrence (two times detectable PSA > 0.2 ng/ml) 
8. In case of biochemical recurrence, time to recurrence in months.  
 
8.1.3 
Other study parameters  
Baseline characteristics:  
- 
Date of birth 
- 
Age at time of surgery 
- 
Date of histological diagnosis 
- 
Weight 
- 
Height 
- 
BMI 
- 
Family history of prostate cancer 
- 
History of hereditary prostate cancer  
- 
ECOG performance status  
- 
ASA classification  
- 
Comorbidities 
- 
Charlson Comorbidity index (CCI) 
- 
Marital status  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 30 
- 
Smoking 
- 
EPIC-26 domain scores [0-100] at baseline 
 
Physical diagnostic parameters:  
- 
Digital rectal exam outcome and side  
 
Biopsy parameters:  
- 
Date of biopsy  
- 
Route of biopsy (transperineal or transrectal)  
- 
Random and/or target biopsy  
- 
If target what method (cognitive fusion, MRI/TRUS fusion, in-bore MRI guided) 
- 
Number of random biopsies  
- 
Number of positive biopsies and location  
- 
Number of target biopsies  
- 
Number of positive biopsies  
- 
Gleason score 
- 
ISUP grade  
 
Risk group: 
- 
EAU risk group classification  
 
Serum tests:  
- 
PSA 
- 
Hemoglobin  
- 
Creatinine and eGFR 
- 
Free Testosterone  
- 
Total Testosterone  
- 
Sex Hormone Binding Globulin, LH, FSH, prolactin 
- 
Lipid spectrum (Total Cholesterol, HDL-C, TC-HDL ratio, LDL-C, Triglycerides) 
- 
Glucose 
- 
Liver function tests (ASAT, ALAT, gGT, AF) 
 
MRI prostate:  
- 
Date of MRI 
- 
Hospital of acquisition 
- 
Number of lesions 
- 
PIRADS score per lesion 
- 
Extracapsular extension (ECE) 
- 
Prostate volume 
- 
Suspicion of metastatic lymph nodes  
- 
Suspicion of bone or visceral metastases  
 
Other imaging modalities to asses metastatic status. For example: PSMA PET-CT, Bone scintigraphy, 
CT-scan.  
- 
Date of acquisition  
- 
Imaging parameters like contrast fluid or agents used 
- 
Metastatic lymph nodes  
- 
Bone or visceral metastases  
 
 
Radical prostatectomy: 
- 
Date of surgery 
- 
Surgeon 
- 
Surgery time in minutes 
- 
Estimated blood loss in mL 
- 
PLND performed  
- 
Nervesparing procedure (no/unilateral/bilateral) 
 
Pathology: 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 31 
- 
Tumor type  
- 
Tumor side 
- 
Gleason score 
- 
pT stage 
- 
Positive surgical margin (if yes, location and size in mm) 
- 
In case of PLND:  
o 
Number of regional lymph nodes dissected 
o 
Number of regional of metastatic lymph nodes 
o 
Number of extra-regional lymph nodes dissected 
o 
Number of extra-regional metastatic lymph nodes 
o 
N stage 
 
 
Treatment/follow-up items:  
• 
Laboratory test results 
• 
EPIC-26 domain scores and subquestions  
• 
MACE  
• 
PSA values at each follow-up moment 
• 
Occurrence of biochemical recurrence   
• 
Use of additional medication for penile rehabilitation.  
• 
Continuation of testosterone therapy after the treatment phase on patients request.  
 
 
8.2 
Randomization, blinding and treatment allocation 
Patients will be randomized to TRT:placebo in a 1:1 ratio. Randomization will be done centrally and 
computer generated with stratification per hospital in random block of 2, 4 and 6.  
Patients will be blinded for treatment; investigators will not be blinded. In case of serious adverse 
events, the participant can be unblinded at any time after consultation with the investigator or the 
physician. After the collection of the last assessment of functional outcomes (24 months) patients will 
receive an email with information about the intervention they have had (TRT/placebo).  
 
8.3 
Study procedures 
Before inclusion: 
• 
Patients diagnosed with prostate cancer who have chosen for RP, will be informed about the 
study by their treating urologist, (research) physician, physician assistant or nurse practitioner. 
Patients will be informed in person during on the outpatient clinic or by phone.  
• 
Patients who are interested receive additional study information (including Informed Consent 
Form) for the prescreening phase.  
• 
After signed informed consent, a blood sample will be drawn and patients will be invited to 
complete the baseline PROMS online.  
 
After RP: 
• 
Within 6 weeks after RP patients will have another blood sample drawn for the screening 
phase 
• 
Eligibility for inclusion will be checked using an eCRF.   
• 
If patients are eligible for inclusion, they will be asked to sign another informed consent form. 
Included patients in will be centrally randomized for TRT/placebo.  
 
After randomization: 
The researcher/research nurse will prepare the study medication according to randomization 
outcome and the guideline provided. A second person will check if the right medication is 
prepared. Patients will be given written and spoken instructions about the application of 
TRT/placebo.  
 
Except for the administration of TRT or placebo, patients will not undergo any other invasive 
procedures for study purposes.  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 32 
 
Participation in this study could potentially be a contra-indication for inclusion in other study (such as 
studies evaluating oncological or functional follow-up after RP).  
 
8.4 
Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent medical 
reasons. 
8.4.1 
Specific criteria for withdrawal 
Withdrawal criteria for study drug: 
• 
Detectable PSA at any time point during follow-up 
• 
No compliance with therapy 
• 
Clinical sign of local recurrence or metastatic disease 
• 
Any AE that leads to substantial changes in risk-benefit consideration  
• 
Delay of drug administration of more than 28 days.  
• 
Death 
• 
New medical condition that does not allow continuation of study drug compliance  
• 
Protocol deviation, including non-compliance with dosing regimen and retroactive failure 
to fulfill study entry criteria  
• 
Lost to follow-up (defined as no contact after 3 documented attempts by telephone 
followed by 1 attempt via certified letter)  
• 
Subject request  
• 
Investigator request  
 
8.5 
Replacement of individual subjects after withdrawal 
Patients that withdraw will not be replaced with new patients. Patients will not change groups after 
original assignment. 
 
8.6 
Follow-up of subjects withdrawn from treatment 
Patients that withdraw from treatment will be followed as usual.  
 
8.7 
Premature termination of the study 
After inclusion of 70 patients an interim analysis will be done to evaluate the safety of TRT. If a 
significant higher BCR rate in the TRT group is found, the study will be terminated. If a significant 
higher rate of cardiovascular events in the TRT group is found the study will be terminated. 
The final decision is with the sponsor.  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 33 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if there 
is sufficient ground that continuation of the study will jeopardize subject health or safety. The 
sponsor will notify the accredited METC without undue delay of a temporary halt including the 
reason for such an action. The study will be suspended pending a further positive decision by the 
accredited METC. The investigator will take care that all subjects are kept informed.  
9.2 AEs, SAEs and SUSARs 
Information on all AEs should be recorded at each contact on the AE-module of the CRF. Grading 
will be done according to the NCI-CTCAE version 5.0. AEs will be graded mild (grade 1), moderate 
(grade 2), severe (grade 3), life-threatening (grade 4) or death (grade 5). All AEs will be 
documented at every visit.  
9.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to the investigational product. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. 
Patients will be asked about the occurrence of AEs during every doctor visit. In case of an AE, 
dependent on the symptoms of the patient, he will be contacted by the investigator and if 
necessary, admitted to the hospital. The condition of the patient will be evaluated by the physician.  
 
 
9.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
• 
results in death; 
• 
is life threatening (at the time of the event); 
• 
requires hospitalization or prolongation of existing inpatients’ hospitalization; 
• 
results in persistent or significant disability or incapacity; 
• 
is a congenital anomaly or birth defect; or 
• 
any other important medical event that did not result in any of the outcomes listed above 
due to medical or surgical intervention but could have been based upon appropriate 
judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events.  
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in death 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 34 
or are life threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 days after 
the sponsor has first knowledge of the serious adverse events. 
 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product related to 
any dose administered. 
 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 9.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an undesirable 
reaction to the medicinal product under investigation, regardless of the administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity of the adverse 
reaction are not in agreement with the product information as recorded in: 
• 
Summary of Product Characteristics (SPC) for an authorized medicinal product; 
• 
Investigator’s Brochure for an unauthorized medicinal product. 
The sponsor will report expedited the following SUSARs through the web portal ToetsingOnline to the 
METC   
• SUSARs that have arisen in the clinical trial that was assessed by the METC; 
• SUSARs that have arisen in other clinical trials of the same sponsor and with the same medicinal 
product, and that could have consequences for the safety of the subjects involved in the clinical 
trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted once 
every half year to the METC. This line-listing provides an overview of all SUSARs from the study 
medicine, accompanied by a brief report highlighting the main points of concern.  
The expedited reporting of SUSARs through the web portal Eudravigilance or ToetsingOnline is 
sufficient as notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other Member States, 
according to the requirements of the Member States.  
 
The expedited reporting will occur not later than 15 days after the sponsor has first knowledge of the 
adverse reactions. For fatal or life-threatening cases, the term will be maximal 7 days for a 
preliminary report with another 8 days for completion of the report. 
 
9.3 
Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout 
the clinical trial, a safety report to the accredited METC, competent authority, and competent 
authorities of the concerned Member States. 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 35 
This safety report consists of: 
• 
a list of all suspected (unexpected or expected) serious adverse reactions, along with an 
aggregated summary table of all reported serious adverse reactions, ordered by organ system, 
per study; 
• 
a report concerning the safety of the subjects, consisting of a complete safety analysis and an 
evaluation of the balance between the efficacy and the harmfulness of the medicine under 
investigation. 
 
9.4 
Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol  
 
9.5 
Data Safety Monitoring Board (DSMB)  
A DSMB will be established prior to start of the trial. Prior to the start of the trial the DSMB will 
define criteria to terminate the trial prematurely. 
An interim analysis will be performed after the inclusion of 70 patients. The interim analysis will be 
done by a safety and monitoring board (DSMB) for safety and relevance.  
The advice(s) of the DSMB will only be sent to the sponsor of the study. Should the sponsor decide 
not to fully implement the advice of the DSMB, the sponsor will send the advice to the reviewing 
METC, including a note to substantiate why (part of) the advice of the DSMB will not be followed. 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 36 
10. STATISTICAL ANALYSIS 
The collected data will include nominal, categorical, ordinal and continuous variables. Continuous 
measures will be summarized using their means and standard deviations; ordinal data will be 
presented with the median and range; categorical data by portions (percentages). 
10.1 
Primary study parameter(s) 
The primary outcome parameter is sexual functioning score at 12 months after RP.  
At prescreening (T0) we will collect questionnaire-based information on sexual functioning (PROMS).  
A baseline analysis will be done to identify equal distribution of patients between groups. Baseline 
parameters such as age, BMI, Charlson Comorbidity Index, marital status, initial PSA, ISUP score, 
clinical t-stage and EAU risk group will be evaluated with a student’s t-test (for continuous variables) or 
chi-square test (categorical variables) for equal distribution among groups.  
For the analyses, we will conduct a linear regression analysis in which we use sexual functioning at 
T12 as outcome variable. Sexual functioning at baseline (T0) will be included as a determinant in order 
to decrease the effect of intraindividual variability and increase power. The effect of testosterone 
replacement therapy will be estimated by the coefficient (along with its 95% confidence interval) of the 
dichotomous variable indicating intervention versus control group. Any important prognostic 
characteristic for sexual functioning that will appear not to be equally distributed in both treatment 
groups after randomization will also be included in the model. 
 
10.2 
Secondary study parameter(s)  
The same procedure as described in paragraph 10.1 will be performed for the secondary study 
outcomes.  
Five years following RP, a final oncological analysis will be done to assess the biochemical recurrence 
rate (BCR) in the TRT and placebo group. This will be done by using the data from the Dutch Cancer 
Registry (Nederlandse Kanker Registratie, NKR). From this registry we will conduct the PSA level and 
in case of BCR, the date of BCR. To assess the rate of BCR, a Kaplan-Meier analysis with log-rank 
test will be done. Secondly a Cox regression analysis will be done to assess if multiple variables 
influence the BCR rate.  
10.3 
Other study parameters 
To gain insight in the prevalence of testosterone deficiency and on the effect of RP on the T level we 
will compare the T level of all patients in all groups before the RP and within 6 weeks following RP.  
 
10.4 
Interim analysis  
After inclusion of 70 patients an interim analysis will be done to evaluate the safety of TRT. If a 
significant higher BCR rate in the TRT group is found, the study will be terminated. If a significant 
higher rate of cardiovascular events in the TRT group is found the study will be terminated. 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 37 
11. ETHICAL CONSIDERATIONS 
11.1 
Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (version 8, 19 
October 2013), in accordance with the Medical Research Involving Human Subjects Act (WMO), the 
personal data protection act (Wet Bescherming Persoonsgegevens), and the Medical Treatment 
Agreement Act (WGBO). 
 
11.2 
Recruitment and consent 
Patients will be approached for study participation by their treating urologist. Eligible patients will be 
informed about the study by an investigator. After being informed, patients will be given at least one 
week to consider their participation. All subjects must sign and personally date an approved informed 
consent form after receiving detailed written and verbal information about the reason, the nature and 
the possible risks associated with the administration of the study agent. This will be done according to 
the guidelines provided in the Declaration of Helsinki, ICH E6 Guideline for GCP, and requirements of 
Title 21 CFR 50.20 through 50.27.   
 
The subject must be made aware and agree that personal information may be scrutinized during audit 
by competent authorities and properly authorized persons. However, personal information will be 
treated as strictly confidential and will not be publicly available.   
 
11.3 
Objection by minors or incapacitated subjects (if applicable) 
Not applicable. 
11.4 
Benefits and risks assessment, group relatedness 
The number of visits and blood drawings are equal to standard of care follow-up after RP, with the 
exception of one extra blood sample at inclusion and six weeks after RP. We ask patients to remain 
with the study hospital for 24 months after RP for follow-up and to complete online questionnaires for 
the given visits.  
The patients who receive TRT can experience local and systemic side-effects. Local side-effects can 
express themselves as itching, rash and/or irritation at the site of application. Systemic side-effects are 
gain of weight, hot flashes, acne and a change in red blood count level.  
TRT might improve sexual functioning, urinary continence, hormonal functioning, quality of life and 
BCR-free survival, but this is not certain and is subject of research in this study.  
 
11.5 
Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the WMO. 
The sponsor (also) has an insurance which is in accordance with the legal requirements in the 
Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects through 
injury or death caused by the study. 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 38 
The insurance applies to the damage that becomes apparent during the study or within 4 years after 
the end of the study. 
 
11.6 
Incentives  
Patients will not be compensated for participating in this study. Damage to subjects through injury or 
death, caused by the study or negligence of local study investigators, is not accountable to the 
principle investigator. The participating centers will provide appropriate insurance which is in 
accordance with the legal requirements.  

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 39 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 
Handling and storage of data and documents 
Data will be collected using an electronic Case Report Form (eCRF).  
Research nurses and local investigators in each of the participating centers will do data monitoring. 
Participants will be given a computer-generated numeric code. Data handling will be done 
anonymously, with the patient code only available to the local investigator and the research nurse 
working in the local center. A validated data management system will be used for storing all data.  
 
12.2 
Monitoring and Quality Assurance  
We classify this trial as a low risk study ‘laag-risico onderzoek’, with a negligible risk ‘verwaarloosbaar 
risico’ in terms of the risk classification table provided, because the  
intervention is already registered. Monitoring of the trial will be done by the Research Support Office of 
the main study site.  
The first monitor visit will take place before inclusion of the first study participant. During this visit the 
presence and completeness of the relevant Study Files will be checked. Additionally, the quality and 
competence will be evaluated of the personnel that will perform the informed consent and who will 
administer the research medication. After  
inclusion of 10 participants at the participating site, the site will be monitored with a check of the 
completeness of 3 informed consent forms and the accuracy of the eligibility criteria. If there are errors 
in this, more intensive monitoring will take place. 
Thereafter, monitoring will be performed centrally by checking the completeness of follow-up data from 
participants with the mobile application. At the closing visit, the presence and completeness of the 
relevant Study Files will be checked.  
 
12.3 
Amendments  
A ‘substantial amendment’ is defined as an amendment to the terms of the METC application, or to the 
protocol or any other supporting documentation, that is likely to affect to a significant degree: 
• 
the safety or physical or mental integrity of the subjects of the trial; 
• 
the scientific value of the trial; 
• 
the conduct or management of the trial; or 
• 
the quality or safety of any intervention used in the trial. 
 
All substantial amendments will be notified to the METC and to the competent authority. 
Non-substantial amendments will not be notified to the accredited METC and the competent authority, 
but will be recorded and filed by the sponsor.  
 
 
12.4 
Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited METC 
once a year. Information will be provided on the date of inclusion of the first subject, numbers of 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 40 
subjects included and numbers of subjects that have completed the trial, serious adverse events/ 
serious adverse reactions, other problems, and amendments.  
 
12.5 
Temporary halt and (prematurely) end of study report 
The sponsor will notify the accredited METC and the competent authority of the end of the study within 
a period of 90 days. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the reason of 
such an action. 
In case the study is ended prematurely, the sponsor will notify the accredited METC and the 
competent authority within 15 days, including the reasons for the premature termination. Within one 
year after the end of the study, the investigator/sponsor will submit a final study report with the results 
of the study, including any publications/abstracts of the study, to the accredited METC and the 
Competent Authority.  
 
12.6 
Public disclosure and publication policy 
The results will be prepared for publication in a peer-reviewed journal. 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 41 
13. STRUCTURED RISK ANALYSIS  
 
13.1 
Potential issues of concern 
 
See 13.2  
 
13.2 
Synthesis 
Considering that TRT is a well-established treatment for men with late-onset hypogonadism, 
we deem a structured risk-analysis is not necessary.  
 
 
 
 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 42 
14. REFERENCES 
 
1.  
NKR Cijfers - IKNL. https://iknl.nl/nkr-
cijfers?fs%7Cepidemiologie_id=6&fs%7Ctumor_id=315&fs%7Cregio_id=155&fs%7Cperiode_i
d=78%2C79%2C80%2C81%2C82%2C83%2C84%2C85%2C86%2C87%2C88%2C89%2C90
%2C91%2C92%2C93%2C94%2C95%2C96%2C97%2C98%2C99%2C100%2C101%2C102%
2C103%2C104%2C105%2C106%2C108%2C110&fs%7Cgeslacht_id=15&fs%7Cleeftijdsgroep
_id=67%2C36%2C37%2C38%2C39%2C40%2C41&fs%7Cjaren_na_diagnose_id=16&fs%7Ce
enheid_id=2&cs%7Ctype=line&cs%7CxAxis=periode_id&cs%7Cseries=leeftijdsgroep_id&ts%7
CrowDimensions=periode_id&ts%7CcolumnDimensions=leeftijdsgroep_id&lang%7Clanguage
=nl. Accessed March 19, 2020. 
2.  
Carlsson S, Jaderling F, Wallerstedt A, et al. Oncological and functional outcomes 1 year after 
radical prostatectomy for very-low-risk prostate cancer: results from the prospective LAPPRO 
trial. BJU Int. 2016;118(2):205-212. doi:10.1111/bju.13444 
3.  
Kyrdalen AE, Dahl AA, Hernes E, Smastuen MC, Fossa SD. A national study of adverse 
effects and global quality of life among candidates for curative treatment for prostate cancer. 
BJU Int. 2013;111(2):221-232. doi:10.1111/j.1464-410X.2012.11198.x 
4.  
Fridriksson JO, Folkvaljon Y, Nilsson P, et al. Long-term adverse effects after curative 
radiotherapy and radical prostatectomy:  population-based nationwide register study. Scand J 
Urol. 2016;50(5):338-345. doi:10.1080/21681805.2016.1194460 
5.  
Schepens MHJ, Des Plantes CMPZ, Somford DM, et al. Hoe vaak incontinentie na radicale 
prostatectomie? Ned Tijdschr Geneeskd. 2018;162(15):1-6. 
6.  
Eindrapportage 2019. ProZIB. 2019. 
7.  
Einstein DJ, Patil D, Chipman J, et al. Expanded Prostate Cancer Index Composite-26 (EPIC-
26) Online: Validation of an Internet-Based Instrument for Assessment of Health-Related 
Quality of Life After Treatment for Localized Prostate Cancer. Urology. 2019;127:53-60. 
doi:10.1016/j.urology.2019.02.004 
8.  
Freedland SJ, Humphreys EB, Mangold LA, et al. Death in patients with recurrent prostate 
cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their 
associated contributions to all-cause mortality. J Clin Oncol. 2007;25(13):1765-1771. 
doi:10.1200/JCO.2006.08.0572 
9.  
Van den Broeck T, van den Bergh RCN, Arfi N, et al. Prognostic Value of Biochemical 
Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic 
Review. Eur Urol. 2019;75(6):967-987. doi:10.1016/j.eururo.2018.10.011 
10.  
Kaufman JM, Vermeulen A. The decline of androgen levels in elderly men and its clinical and 
therapeutic implications. Endocr Rev. 2005;26(6):833-876. doi:10.1210/er.2004-0013 
11.  
Dohle GR, Arver S, Bettocchie C, Kliesch S PM. Male hypogonadism. European Association of 
Urology; 2018. EAU Guidel. 2018. 
12.  
Araujo AB, O’Donnell AB, Brambilla DJ, et al. Prevalence and incidence of androgen deficiency 
in middle-aged and older men: Estimates from the Massachusetts male aging study. J Clin 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 43 
Endocrinol Metab. 2004;89(12):5920-5926. doi:10.1210/jc.2003-031719 
13.  
Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptomatic androgen deficiency in 
men. J Clin Endocrinol Metab. 2007;92(11):4241-4247. doi:10.1210/jc.2007-1245 
14.  
Salonia A, Bettocchi C, Carvalho G, et al. European Association of Urology Guidelines. 2020 
Edition. In: Vol presented. European Association of Urology Guidelines Office; 2020. 
https://uroweb.org/guideline/sexual-and-reproductive-health-2/. 
15.  
Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N 
Engl J Med. 2016;374(7):611-624. doi:10.1056/NEJMoa1506119 
16.  
Corona G, Rastrelli G, Morgentaler A, Sforza A, Mannucci E, Maggi M. Meta-analysis of 
Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile 
Function Scores. Eur Urol. 2017;72(6):1000-1011. doi:10.1016/j.eururo.2017.03.032 
17.  
Hansson N, Moll F, Schultheiss D, Krischel M. Remembering Charles B. Huggins’ Nobel Prize 
for Hormonal Treatment of Prostatic Cancer at its 50th Anniversary. Eur Urol. 2016;69(6):971-
972. doi:10.1016/j.eururo.2016.01.030 
18.  
Denmeade SR, Isaacs JT. Bipolar AndrogenTherapy : The Rationale for Rapid Cycling of 
Supraphysiologic Androgen / Ablation in Men With Castration Resistant Prostate Cancer. 
2010;1607(July):1600-1607. doi:10.1002/pros.21196 
19.  
Isaacs JT, Brennen WN, Denmeade SR. Serial bipolar androgen therapy ( sBAT ) using cyclic 
supraphysiologic testosterone ( STP ) to treat metastatic castration-resistant prostate cancer ( 
mCRPC ). 2019;7(Suppl 8):8-11. doi:10.21037/atm.2019.10.32 
20.  
Li T, Sun X, Chen L. Free testosterone value before radical prostatectomy is related to 
oncologic outcomes and post-operative erectile function. BMC Cancer. 2019;19(1). 
doi:10.1186/s12885-018-5148-1 
21.  
Kardoust Parizi M, Abufaraj M, Fajkovic H, et al. Oncological safety of testosterone 
replacement therapy in prostate cancer survivors after definitive local therapy: A systematic 
literature review and meta-analysis. Urol Oncol Semin Orig Investig. 2019;37(10):637-646. 
doi:10.1016/j.urolonc.2019.06.007 
22.  
Ahlering TE, Huynh LM, Towe M, et al. Testosterone replacement therapy reduces biochemical 
recurrence post-radical prostatectomy. BJU Int. March 2020. doi:10.1111/bju.15042 
23.  
Skolarus TA, Dunn RL, Sanda MG, et al. Minimally Important Difference for the Expanded 
Prostate Cancer Index Composite Short Form * Acknowledgement: The PROSTQA 
Consortium includes contributions in cohort design, patient accrual and follow-up from the 
following investigators. Urology. 2015;85(1):101-106. doi:10.1016/j.urology.2014.08.044 
24.  
EPIC | Urology | Michigan Medicine | University of Michigan. 
https://medicine.umich.edu/dept/urology/research/epic. Accessed April 23, 2020. 
25.  
Healthcare B. Androgel SmPC. :1-9. 
26.  
Rastrelli G, Maggi M, Corona G. Pharmacological management of late-onset hypogonadism. 
Expert Rev Clin Pharmacol. 2018;11(4):439-458. doi:10.1080/17512433.2018.1445969 
27.  
Kaufman JM, Miller MG, Garwin JL, Fitzpatrick S, Mcwhirter C, Brennan JJ. Efficacy and 
Safety Study of 1.62% Testosterone Gel for the Treatment of Hypogonadal Men. J Sex Med. 

NL74362.091.20  
ENFORCE trial 
 
Version number: 2.6, date 8-12-2020 
 
 44 
2011;8(7):2079-2089. doi:10.1111/j.1743-6109.2011.02265.x 
28.  
Sanda MG, Wei JT, Litwin MS, Dunn RL. Scoring Instructions for the Expanded Prostate 
Cancer Index Composite Short Form (EPIC-26)* Questions Regarding the SAS Macro Should 
Be Addressed To.; 2002. http://roadrunner.cancer.med.umich.edu/epic/. Accessed October 7, 
2020.