Radium-223 Alpha Emitter Agent in Non-intervention Safety Study in mCRPC popUlation for Long-teRm Evaluation
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: Bayer

 
Document Type: 
Study Protocol 
Official Title: 
REASSURE - Radium-223 alpha Emitter Agent in nonintervention 
Safety Study in mCRPC popUlation for longteRm Evaluation 
NCT Number: 
NCT02141438 
Document Date: 
20 Aug 2018 
 

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Post Authorization Safety Study (PASS) Information 
Title 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for long-
teRm Evaluation  
Protocol version and date 
Version 5.0, 20 Aug 2018 
IMPACT study number 
16913 
Study type / Study phase 
Observational, Phase IV  
 PASS 
 
 non-PASS 
Joint PASS:  
 YES 
 NO 
EU PAS register number 
EUPAS7187 
Active substance 
Therapeutic Radiopharmaceuticals (V10XX03), radium 
(223Ra) dichloride 
Medicinal product 
Xofigo® 
Product reference 
EU/1/13/873/001; NDA 203971 
Procedure number 
N/A 
Study Initiator and Funder 
Bayer AG, Germany; Bayer Healthcare Pharmaceuticals 
Inc., USA 
Effective January 01, 2017 Bayer Pharma AG has 
transferred its assets to Bayer AG, an affiliated company 
within the Bayer Group. Thereby, Bayer AG assumed all 
rights and obligations of Bayer Pharma AG, including the 
role as initiator and funder of this study. No study 
procedures have changed. 
Research question and objectives 
This observational, prospective, single arm cohort study is 
designed to assess the incidence of second primary 
malignancies among patients with metastatic Castration 
Resistant Prostate Cancer (mCRPC) receiving Radium-223 
in routine clinical practice. In addition, safety, pain, and 
overall survival will be assessed. 
Country(-ies) of study 
Argentina, Austria, Belgium, Canada, Colombia, Czech 
Republic, Denmark, France, Germany, Greece, Israel, Italy, 
Luxembourg, Mexico, Netherlands, Portugal, Spain, 
Sweden, United Kingdom, United States 
Author 
 
Bayer Consumer Care AG 
, Switzerland 
 
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Marketing authorization holder  
Marketing authorization holder(s) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee 1 
51373 Leverkusen 
Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ, 
USA 
MAH contact person 
 
, Bayer HealthCare 
Pharmaceuticals Inc. 
, USA  
 
The study will be conducted in compliance with the protocol  
and any applicable regulatory requirements. 
 
Throughout this document, symbols indicating proprietary names (®, TM) may not be 
displayed. Hence, the appearance of product names without these symbols does not imply that 
these names are not protected. 
 
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1. 
Table of contents 
 
1. 
Table of contents ............................................................................................................... 3 
2. 
List of abbreviations ......................................................................................................... 6 
3. 
Responsible parties ............................................................................................................ 9 
3.1 
Initiator /MAH ................................................................................................................. 9 
3.2 
Collaborators / Committees ........................................................................................... 10 
4. 
Abstract ............................................................................................................................ 11 
5. 
Amendments and updates .............................................................................................. 16 
6. 
Milestones ......................................................................................................................... 17 
7. 
Introduction: Background and Rationale ..................................................................... 17 
8. 
Research questions and objectives ................................................................................. 21 
8.1 
Primary objective(s) ....................................................................................................... 21 
8.2 
Secondary objective(s) ................................................................................................... 22 
9. 
Research methods ............................................................................................................ 22 
9.1 
Study design ................................................................................................................... 22 
9.1.1 
Primary Endpoint(s) ................................................................................................... 23 
9.1.2 
Secondary Endpoint(s) ............................................................................................... 23 
9.1.3 
Strengths of the study design ...................................................................................... 23 
9.2 
Setting ............................................................................................................................ 23 
9.2.1 
Eligibility .................................................................................................................... 23 
9.2.2 
Inclusion criteria ......................................................................................................... 23 
9.2.3 
Exclusion criteria ........................................................................................................ 24 
9.2.4 
Withdrawal ................................................................................................................. 24 
9.2.5 
Replacement ............................................................................................................... 24 
9.2.6 
Representativeness...................................................................................................... 24 
9.2.7 
Visits ........................................................................................................................... 24 
9.3 
Variables ........................................................................................................................ 25 
9.3.1 
Variables to determine the primary endpoint(s) ......................................................... 26 
9.3.2 
Variables to determine the secondary endpoint(s) ..................................................... 27 
9.3.3 
Demography ............................................................................................................... 27 
9.3.4 
Prostate cancer history ................................................................................................ 28 
9.3.5 
Co-morbidities (medical history, concomitant diseases) ............................................ 28 
9.3.6 
Prior and concomitant medication .............................................................................. 28 
9.3.7 
Exposure / treatment ................................................................................................... 29 
9.3.8 
Assessment of therapy ................................................................................................ 29 
9.3.9 
Visits ........................................................................................................................... 29 
9.3.9.1 
Baseline ................................................................................................................... 29 
9.3.9.2 
Treatment phase ...................................................................................................... 30 
9.3.9.3 
Follow-up visit(s) .................................................................................................... 30 

 
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9.3.10 Laboratory parameters ................................................................................................ 30 
9.3.11 Progression ................................................................................................................. 31 
9.4 
Data sources ................................................................................................................... 31 
9.4.1 
REASSURE data sources ........................................................................................... 31 
9.4.2 
External reference secondary data sources ................................................................. 31 
9.5 
Study Size ...................................................................................................................... 32 
9.6 
Data management .......................................................................................................... 32 
9.6.1 
Dataflow ..................................................................................................................... 33 
9.6.2 
Database freeze/lock ................................................................................................... 33 
9.7 
Data analysis .................................................................................................................. 33 
9.7.1 
Statistical considerations ............................................................................................ 33 
9.7.2 
Analysis of demography, disease details, prior and concomitant medication and 
other baseline data ...................................................................................................... 34 
9.7.3 
Analysis of treatment data .......................................................................................... 34 
9.7.4 
Analysis of primary outcome(s) ................................................................................. 34 
9.7.5 
Analysis of secondary outcome(s) .............................................................................. 35 
9.7.5.1 
Overall survival (OS) .............................................................................................. 35 
9.7.5.2 
Pain assessment ....................................................................................................... 35 
9.7.5.3 
Bone fractures and bone associated events ............................................................. 35 
9.7.6 
Comparison with external reference secondary data sources ..................................... 35 
9.7.7 
Analysis of safety data ................................................................................................ 36 
9.7.8 
Analysis of other data ................................................................................................. 36 
9.7.9 
Bias, confounding, and effect-modifying factors ....................................................... 36 
9.7.10 Interim Analysis ......................................................................................................... 36 
9.7.11 Loss of follow-up ....................................................................................................... 37 
9.8 
Quality control ............................................................................................................... 37 
9.8.1 
Data quality ................................................................................................................ 37 
9.8.2 
Quality review ............................................................................................................ 38 
9.8.3 
Storage of records and archiving ................................................................................ 38 
9.8.4 
Certification/qualification of external parties ............................................................. 38 
9.9 
Limitations of the research methods .............................................................................. 38 
9.10 Other aspects .................................................................................................................. 39 
10. Protection of human subjects ......................................................................................... 39 
10.1 Ethical conduct of the study ........................................................................................... 39 
10.2 Regulatory authority approvals/authorizations .............................................................. 39 
10.3 Independent ethics committee (IEC) or institutional review board (IRB) ..................... 39 
10.4 Patient information and consent .................................................................................... 39 
10.5 Patient insurance ............................................................................................................ 40 
10.6 Confidentiality ............................................................................................................... 40 
11. Management and reporting of adverse events/adverse reactions ............................... 40 
11.1 Definitions ..................................................................................................................... 40 
11.2 Collection ....................................................................................................................... 42 
11.3 Management and reporting ............................................................................................ 43 
11.4 Evaluation ...................................................................................................................... 44 
12. Plans for disseminating and communicating study results ......................................... 44 

 
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13. List of references ............................................................................................................. 45 
Annex 1. List of stand-alone documents............................................................................... 48 
Annex 2. ENCePP checklist for study protocols .................................................................. 49 
Annex 3. Signature pages ....................................................................................................... 55 
Annex 4. Description of Amendments .................................................................................. 66 
 
 
Table of tables 
Table 1: Milestones .................................................................................................................. 17 
Table 2: Tabulated overview on variables collected during the study ..................................... 25 
Table 3: Incidence and corresponding 95% confidence limits ................................................ 32 
Table 4: List of stand-alone documents ................................................................................... 48 
Table 5: Description of Amendments ...................................................................................... 66 

 
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2. 
List of abbreviations 
 
AE 
Adverse Event 
ADT 
Androgen Deprivation Therapy 
ALAT 
Alanine Transaminase 
ALP 
Alkaline Phosphatase 
ALSYMPCA 
ALpharadin in SYMptomatic Prostate CAncer 
AML 
Acute Myeloid Leukemia 
ANC 
Absolute Neutrophil Count 
ASAT 
Aspartate Transaminase 
BIPS 
Bremen Institute for Prevention Research and Social Medicine 
BMI 
Body Mass Index 
BPI-SF 
Brief Pain Inventory Short Form 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRPC 
Castration Resistant Prostate Cancer 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMP 
Data Management Plan 
EAIR 
Exposure-adjusted incidence rate 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EFPIA 
European Federation of Pharmaceutical Industries and Associations 
EMA 
European Medicine Agency 
ENCePP 
European Network of Centers in Pharmacoepidemiology and 
Pharmacovigilance 
EU 
European Union 
FACT-P 
Functional Assessment of Cancer Therapy-Prostate 
FDA 
Food and Drug Administration 
GAMP 
Good Automated Manufacturing Practice 
GCP 
Good Clinical Practice 

 
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GePaRD 
The German Pharmacoepidemiological Research Database  
GGT 
Gamma-glutamyl Transpeptidase 
GPP 
Good Publication Practice 
GSL 
Global Safety Lead 
GVP 
Good Pharmacovigilance Practice 
HEOR 
Health Economics and Outcomes Research 
HR 
Hazard Ratio 
HRPC 
Hormone-Refractory Prostate Cancer 
ICD 
International Classification of Disease 
ICD-9 
International Classification of Disease, Ninth Revision 
ICD-10 
International Classification of Disease, Tenth Revision 
ICH 
International Conference of Harmonization 
ICH-GCP 
International Conference of Harmonization - Good Clinical Practice 
IEC 
Independent Ethics Committee 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
KM 
Kaplan-Meier 
LCL 
Lower Confidence Limit 
LDH 
Lactate Dehydrogenase 
M 
Month 
MAH 
Marketing Authorization Holder 
mCRPC 
Metastatic Castration Resistant Prostate Cancer 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRP 
Medical Review Plan  
N/A 
Not Applicable 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse 
Events 
NIS 
Non-Interventional Study 
OS 
Overall Survival 
PSA 
Prostate-specific Antigen 
PASS 
Post-Authorization Safety Study 
PSUR 
Periodic Safety Update Report 

 
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QoL 
Quality of life 
QPPV 
Qualified Person Responsible For Pharmacovigilance 
QRP 
Quality Review Plan 
REASSURE 
 
Radium-223 alpha Emitter Agent in non-intervention Safety Study in 
mCRPC popUlation for long-teRm Evaluation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Southern California 
SD 
Standard Deviation 
SEER 
Surveillance, Epidemiology and End Results 
SSE 
Symptomatic Skeletal Events 
SOPs 
Standard Operation Procedures 
SPM 
Second Primary Malignancy 
STROBE 
Strengthening the Reporting of Observational Studies in Epidemiology 
THIN 
The Health Improvement Network 
TTP 
Time To Progression 
UK 
United Kingdom 
UCL 
Upper Confidence Limit 
US 
United States 
USA 
United States of America 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 

 
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3. 
Responsible parties 
3.1 
Initiator /MAH 
Role: 
 
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Function: 
 
Name: 
  
 
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3.2 
Collaborators / Committees 
Contact details of physicians and other site personnel for each country and site participating in 
the study is kept in a central study tracking database and is available upon request.  
Information on the Steering Committee Members is kept as stand-alone document and is 
available upon request. 
Administrative changes of responsible persons and / or the composition of the committees 
will be documented by updating the respective lists, but do not require formal protocol 
amendments. 
 
 
 

 
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4. 
Abstract 
Title 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for long-teRm 
Evaluation 
Protocol version and date 
Version 5.0, 20 Aug 2018 
IMPACT study number  
16913 
Study type / Study phase 
Observational, Phase IV 
 PASS 
 
 non-PASS 
Joint PASS:  
 YES 
 NO 
Author 
 
Bayer Consumer Care AG  
, Switzerland 
Rationale and background 
Prostate cancer is the most common non-cutaneous malignancy 
in men worldwide. Once prostate cancer becomes metastatic, 
the survival of the patient depends on the extent of the disease 
and the site of metastases. The most common site of metastases 
for advanced prostate cancer is the skeletal system which is 
involved in more than 90% of the castration-resistant prostate 
cancer (CRPC) patients. 
The development of bone metastases is a serious threat to the 
patients’ quality of life and survival, with survival being 
impacted by the number of metastases. Approximately 50% of 
patients with bone-metastatic prostate cancer die of prostate 
cancer within 30 months, and 80% within 5 years. Patients with 
castration resistant prostate cancer usually suffer from very 
painful bone metastases with severe impact on their quality of 
life (QoL).  
There is also little or limited information on the timing of 
progression and management of progression in the clinical 
setting for this patient population. Time to progression has been 
and continues to be of interest as a potential surrogate marker in 
other solid tumors. This study provides an opportunity to collect 
and review these data in the clinical setting. 
The purpose of this observational study called REASSURE is to 
evaluate the short and long term safety profile of Radium-223, 
which selectively targets bone metastases with high-energy, 
short-range alpha-particles. REASSURE will assess the safety 
and tolerability of Radium-223 and the risk of developing 
second primary cancers among castration resistant prostate 
cancer patients receiving Radium-223 in the routine clinical 
practice setting. In addition, overall survival, pain-related data, 
disease progression data and data on all bone fractures and bone 
associated events will be collected. 
At the request of regulatory authorities, this study was 
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implemented in order to contribute information on the safety of 
treatment with Radium-223 in patients with castration resistant 
prostate cancer with bone metastases. 
Research question and 
objectives 
The primary objectives of this study are: 
• 
To assess the incidence of developing second primary 
malignancies in metastatic castration-resistant prostate 
cancer (mCRPC) patients treated with Radium-223 in 
the routine clinical practice setting.  
• 
To assess the incidence of treatment-emergent serious 
adverse events (SAEs) (collected up to 30 days after 
last administration), drug -related adverse events (AEs) 
(collected up to 30 days after last administration), and 
incidence of drug-related SAEs (up to 7 years after the 
last administration). 
• 
To assess bone marrow suppression.  
The secondary objectives of this study are: 
• 
To determine the Overall Survival (OS) in mCRPC 
patients treated with Radium-223 in the routine clinical 
setting. 
• 
To evaluate pain over time using the “Brief pain 
inventory short form” (BPI-SF) questionnaire. 
• 
To assess the incidence of bone fractures and bone 
associated events (e.g. osteoporosis). 
Study design 
This is an observational, prospective, single arm cohort study. 
The study will be conducted in routine clinical practice settings. 
It is planned to enroll 1,334 patients with CRPC with bone 
metastases. The decision to treat with Radium-223 will be 
agreed upon between the physician and the patient 
independently and prior to providing the patient study 
information. Treatment with Radium-223 should follow the 
approved local product information.  
The study will be initiated in the US, Canada, the EU and Latin 
America according to health authority approval timelines. 
Enrollment should start in 2014 and the recruitment is expected 
to last until the end of 2017. The observation period for each 
patient enrolled in this study will be the time from the start of 
therapy with Radium-223 to death, withdrawal of consent, lost 
to follow-up, or end of this study (maximum of 7 years after last 
administration) for each individual patient, whichever comes 
first. 
Appropriate external secondary data source (s) will be 
identified through the conduct of observational cohort study 
(ies), independent from the REASSURE study, to serve as 
reference group(s) for the evaluation of second primary 

 
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malignancies identified in mCRPC patients. The occurrence of 
second primary malignancies identified in mCRPC patients 
treated with Radium-223 and enrolled in the REASSURE study 
will be compared with corresponding information on patients in 
the external reference group(s).  
Population 
The study population will consist of CRPC patients with bone 
metastasis treated with Radium-223. 
Variables 
The following variables will be evaluated:  
• 
Second primary malignancies (reported as SAE) 
• 
Treatment-emergent SAEs (data will be  
collected up to 30 days after last administration) 
• 
Drug-related SAEs (data will be collected up to 7 years 
after last administration)  
• 
Drug related treatment-emergent adverse events (data 
will be collected for treatment period up to 30 days 
after last administration) 
• 
Bone marrow suppression 
• 
Overall survival, defined as the time interval from the 
start of Radium-223 therapy to death due to any cause 
• 
Worst pain score based the BPI-SF assessments 
• 
Pain interference score based the BPI-SF assessments 
• 
Progression, defined as the first progression from the 
start of Radium-223 therapy 
• 
Treatment post progression 
• 
Bone fractures and bone associated events (reported as 
AEs). 
Data sources 
Treating physician or designated medical person, medical 
records, routine measurements (e.g. tumor assessment), 
Radium-223 administering physician (if applicable), other 
physicians, patient questionnaires. 
For the external reference group(s), appropriate secondary data 
source(s) will be evaluated and identified. 
Study size 
For this study, data will be collected to assess the incidence of 
developing second primary malignancies among mCRPC 
patients receiving Radium-223 in the routine clinical practice 
setting. 
It is expected that approximately 1,334 patients will be enrolled 
into the study which accounts for 10% loss to follow-up from 
1,200 patients). Based on the current data from the Phase III 
study ALSYMPCA and SEER data, the incidence proportion of 

 
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second primary malignancy is approximately in the range of 
1.1% to 6.9%. The follow-up periods for the patients varied 
from approximately 3 years (ALSYMPCA) to > 10 years for 
SEER data. 
With 1,200 patients, if the observed incidence proportion is 
between 1.1% and 6.9%, the width of a 95% confidence interval 
(CI) for the rate of second primary malignancy (based on the 
exact binomial distribution) will be approximately 0.0131 (i.e. 
approximately 1.3%) to 0.0296 (i.e. approximately 3%).   
Data analysis 
Demographic data, baseline cancer characteristics, concomitant 
diseases, concomitant medication, and BPI-SF of the included 
patients will be described with summary statistics such as mean, 
SD, minimum 25 and 75 percentiles, median, maximum for 
continuous variables, and category counts and frequencies 
(percentages) for categorical variables.  
Development of second primary malignancy will be 
summarized using the incidence proportion (i.e. number of 
patients with event divided by the number of patients at risk) 
and in addition, the exposure-adjusted incidence rate (EAIR), 
which is defined as the number of patients with a specific event 
divided by the total person-time of observation or at risk, will 
be summarized. The corresponding exact 95% CIs will be given 
as well. 
Descriptive summaries of Kaplan-Meier (KM) estimates and 
KM curves will be presented for overall survival. Descriptive 
summaries only will be provided for progression (first 
progression after initial treatment with Radium-223). 
Adverse events will be summarized using Medical Dictionary 
for Regulatory Activities (MedDRA) and the National Cancer 
Institute – Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) coding system. The incidence proportion and 
EAIR will be estimated along with the corresponding exact 
95% CI. 
Due to the long follow-up period, two interim analyses are 
planned for this study. 
For the comparison with external reference groups, incidence of 
second primary malignancies in mCRPC patients treated with 
Radium-223 from the REASSURE study will be compared with 
corresponding information on patients with mCRPC identified 
in the external secondary data sources.   

 
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Milestones 
Start of data collection (FPFV): 
20 Aug 2014 
(actual) 
End of recruitment (LPFV):  
31 Dec 2017 
(actual) 
Planned end of data collection (LPLV) *: 
 Dec 2024 
Planned final report of study results**: 
Jun 2025 
* max. 7 years after LP last treatment or after LP documented End of 
Observation, whatever comes first  
** 6 months after LPLV  
 
 
 

 
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5. 
Amendments and updates 
 
Amendment 
Number 
Reason for Amendment 
New version 
number 
Effective Date 
AM01 
To include collection of data to allow 
assessment of time to progression and 
treatment post progression in the study 
setting. 
To update the protocol with timeline and 
administrative changes 
v 4.0 
18 January 2016 
AM02 
The ongoing randomized phase III study 
ERA-223 examines Radium-223 dichloride 
versus placebo in combination with 
abiraterone plus prednisone in prostate 
cancer patients. The ERA-223 study was 
unblinded based on the Independent Data 
Monitoring Committee (IDMC) 
recommendation following an ad hoc 
independent analysis where more treatment 
emergent fractures, symptomatic skeletal 
event free survival (SSE-FS), and total death 
events were observed in the active treatment 
arm compared to the placebo arm. The 
European Medicines Agency’s (EMA) 
Pharmacovigilance Risk Assessment 
Committee (PRAC) has reviewed 
preliminary data from the ERA-223 study 
and has taken action by introducing a 
contraindication as a temporary measure to 
protect patients’ safety while an in-depth 
review of the benefit and risks of Radium-
223 dichloride is ongoing. 
Based on this situation and to comply with 
the request of the clinical trial facilitation 
group (CTFG), the protocol amendment has 
been prepared with updates summary as: 
• Radium-223 dichloride should not be given 
concurrently with abiraterone plus 
prednisone/prednisolone. 
• Assessment of the incidence of bone 
fractures and bone associated events (e.g., 
osteoporosis) should be performed; 
• The option of starting a BHA should be 
considered, taking into consideration 
applicable guidelines. 
Other changes:Global LPFV was changed to  
v 5.0 
07 Jun 2018 

 
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31 Dec 2017 to allow for continued 
enrollment in Latin America (regulatory 
obligation).  
Adoption to most current template. 
Administrative changes were implemented 
and inconsistencies corrected. 
 
6. 
Milestones 
Table 1 presents planned milestones for the project. These milestones are based on a timely 
review and approval of the project. Administrative changes to milestones due to delays in 
study preparation and enrollment do not require amendments to the protocol. 
Table 1: Milestones 
Milestone 
Planned date 
Start of data collection (FPFV) 
20 Aug 2014 (actual)  
End of recruitment (LPFV) 
31 Dec 2017 (actual) 
End of data collection (LPLV)* 
Dec 2024 
Interim report 1 
Sep 2017 (actual) 
Interim report 2 
Sep 2019  
Registration in the EU PAS register 
17 Aug 2014 (actual) 
Final report of study results** 
Jun 2025 
* The observation period ends after the last patient alive has been followed up for 7 years after treatment or has 
died, has withdrawn consent, or was lost to follow-up. 
 
** 6 months after LPLV  
 
7. 
Introduction: Background and Rationale 
Prostate cancer is the most common non-cutaneous malignancy in men worldwide. In 2008, 
worldwide, an estimated total of 899,000 men (EU: 323,000; US: 186,000) had prostate 
cancer; worldwide, 258,000 died from the disease (EU: 71,000; US: 28,000) [1]. The crude 
incidence rate is estimated around 135 cases for every 100,000 men. Incidence rates increase 
sharply beyond the age of 50 years, peaking in the age category of ≥ 75 years of age. For men 
aged 55-59 years, the incidence rate is 161 per 100,000 men; 10 years later, at age 65-69 
years, the rate more than triples to 538 per 100,000, and by 75-79 years the rate is almost 
5 times higher at 781 per 100,000 [2]. Based on our growing and aging population, it is 
expected that by the year 2030, the burden of prostate cancer will increase to approximately 
1.7 million new cases and 499,000 new deaths worldwide [3]. 
Prostate cancer is unique amongst solid tumors in that the greatest threat to a patient’s 
survival and quality of life is posed by bone metastases rather than visceral involvement. 

 
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Indeed, nearly all treatments are directed toward eradicating or limiting osseous metastases or 
palliating their side effects [4]. Cellular invasion and migration, cell matrix adhesion or cell-
to-cell adhesions, interaction with endothelial cells, regulation of growth factors, and 
stimulation of osteoclasts and osteoblasts are thought to contribute to development of skeletal 
metastasis [5]. Once prostate cancer becomes metastatic, the survival of the patient depends 
on the extent of the disease and the site of metastases. The most common site of metastases 
for advanced prostate cancer is the skeletal system which is involved in more than 90% of the 
castration-resistant prostate cancer (CRPC) patients [6] [7]. 
Prostate cancer cells are stimulated by androgens, in particular testosterone. Conventional 
androgen deprivation therapy (ADT) in patients with bone metastases aims to reach castration 
levels of testosterone (i.e. ≤ 50 ng/mL or 1.7 nmoL/L), which can be initially effective in 
controlling the metastases in the bone. However, the majority of patients soon become 
castration resistant, i.e. progression occur even at castration levels of testosterone [8]. At this 
stage, the disease can interchangeably be referred to as either CRPC or the older term 
hormone-refractory prostate cancer (HRPC) [9]. The commonly accepted term “CRPC” is 
used throughout this document. Early stages of CRPC with bone metastases are associated 
with substantial pain and with rising levels of prostate-specific antigen (PSA) as seen in 35% 
and 90% of patients, respectively. The extent of PSA control after initial ADT affects 
prognosis: After 7 months of ADT, patients with PSA < 0.2 ng/ml (undetectable) have a 
better prognosis than patients with PSA ≥ 4 ng/ml [10]. 
In normal bone tissue, homeostasis is carried out by the balanced interplay between 
osteoclasts and osteoblasts which are cell types specialized in bone decomposition and bone 
formation, respectively. In the presence of malignant neoplasms and following hematological 
dissemination of tumor cells into the bone, bone metastases develop as a result of a pathologic 
interaction between tumor cells on one hand and osteoblasts as well as osteoclasts on the 
other hand [11]. 
The development of bone metastases is a serious threat to the patients’ quality of life and 
survival, with survival being impacted by the number of metastases. The associated 
complications present a substantial disease and economic burden [12]. Untreated patients face 
severe morbidity, including bone pain, bone fractures, compression of the spinal cord, and 
hematological consequences of bone marrow involvement such as anemia. As presence of 
bone metastases represents a major clinical problem for patients with mCRPC, specific 
treatment options for this condition are needed. Control of bone metastases is expected to lead 
to improved symptoms and quality of life as well as prolonged overall survival.  
There is also little or limited information on the timing of progression and management of 
progression in the clinical setting for this patient population, based on a review of the 
literature and a search of the www.clinicaltrials.gov data base (only 39 studies reported, with 
few completed and those being of a small sample size). Approximately 50% of patients with 
bone-metastatic prostate cancer die of prostate cancer within 30 months, and 80% within 
5 years [13]. Time to progression has been and continues to be of interest as a potential 
surrogate marker in other solid tumors [14] [15] [16]. 
The active moiety of Xofigo, a bone-targeted radiopharmaceutical, is the isotope Radium-223 
(as Radium-223 dichloride) that mimics calcium and selectively targets bone, specifically 

 
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areas of bone metastases, with high-energy, short-range alpha-particles. Xofigo is indicated 
for the treatment of castration-resistant prostate cancer patients with bone metastases [17]. 
A Phase III, double-blind, randomized, BC1-06, ALSYMPCA (Alpharadin in Symptomatic 
Prostate Cancer) trial was started in 2008 [18]. A total of 921 patients with CRPC and 
symptomatic bone metastases who were receiving best standard of care and were post-
docetaxel or unfit for or declined docetaxel were randomized (2:1) to receive 6 injections of 
Radium-223 (50 kBq/kg intravenous [IV]) or matching placebo every 4 weeks. The primary 
endpoint was overall survival. Main secondary efficacy endpoints were time to first skeletal-
related event, time to total alkaline-phosphatase (ALP), and total ALP response. Based on 
data of an interim analysis (n=809), the study was unblinded in July 2011, since Radium-223 
significantly improved OS compared to placebo (the median OS was 14.0 vs. 11.2 months, 
respectively; hazard ratio [HR] = 0.695; p=0.00185). Symptomatic skeletal events (SSE) were 
lower in the Radium-223 arm, and time to first SSE was significantly delayed (the median 
time to SSE was 13.6 months, versus 8.4 months, respectively; HR= 0.610; p= 0.00046). A 
low incidence of myelosuppression was observed, with grade 3/4 events of neutropenia 
(1.8%) and thrombocytopenia (6.2%). Adverse events of any grade were described in 88% of 
the patients who received Radium-223; versus 94% in the placebo arm (Grade 3/4 adverse 
events were described for 51% and 59%, respectively). The updated analysis (performed in 
June 2012; n=921) also showed that Radium-223 significantly improved OS compared to 
placebo (median OS 14.9 vs. 11.3 months, respectively; p=0.00007; HR=0.695). 
Quality of life (QoL) results from the ALSYMPCA study showed that Radium-223 better 
preserved QoL versus placebo (Functional Assessment of Cancer Therapy-Prostate [FACT-P] 
total score; p=0.006) [19]. Post hoc analyses of pain parameters and pain-related QoL 
revealed that in addition to prolonging survival, Radium-223 reduced pain and opioids use in 
patients with CRPC and bone metastases. Radium-223 significantly prolonged median time to 
external beam radiation therapy for bone pain, significantly prolonged time to opioid use, and 
decreased pain measured by patient-reported pain-related QoL score [20]. 
The ALSYMPCA pivotal Phase III study was conducted in a controlled patient population 
according to strict inclusion/exclusion criteria. A total of 173 study centers in 19 countries 
(Australia, Belgium, Brazil, Canada, Czech Republic, France, Germany, Hong Kong, Israel, 
Italy, Netherlands, Norway, Poland, Singapore, Slovakia, Spain, Sweden, United Kingdom, 
United States of America [USA]) were initiated to participate in the study, of which 136 
centers enrolled, i.e. randomized, subjects into the study. However, in the post-approval 
clinical practice setting, patients receiving Radium-223 are usually more heterogeneous with 
various co-morbid conditions.  
As of the updated analysis for safety (cut-off 10 October 2014), 479 patients (77.5%) in the 
Radium-223 group, 224 patients (74.4%) in the placebo group, and 15 patients (62.5%) in the 
crossover group died during the 3-year follow-up period [17].  
Overall, treatment-emergent SAEs were experienced by fewer patients (47.2%) in the 
Radium-223 group than patients in the placebo group (61.1%) or the crossover group 
(62.5%); total number of events was 685, 393, and 21 for the Radium-223 group, the placebo 
group, and the crossover group, respectively. The most common (≥ 5% in either group) 
treatment emergent SAEs were consistent with the disease itself such as malignant neoplasm 
progression (10.8%, Radium-223; 12.6%, placebo; 8.3%, crossover); bone pain (10.2%, 

 
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Radium-223; 16.6%, placebo; 4.2%, crossover); anemia (8.2%, Radium-223; 8.3%, placebo; 
4.2%, crossover); and spinal cord compression (3.5%, Radium-223; 5.3%, placebo; 4.2%, 
crossover). All other treatment-emergent SAEs occurred in < 5% of patients. No significant 
differences in individual treatment-emergent SAEs were reported for patients between the 
treatment groups.  
Since efficacy of Radium-223 solution for injection is achieved by distribution of Radium-
223 to bone with high metabolic activity such as bone metastases, and localized internal 
radiation, the possibility of long-term radiation effects to adjacent bone marrow and normal 
bone tissue was specifically evaluated during the follow-up period.  
Post-treatment follow-up of adverse events was performed in ALSYMPCA. Only AEs 
considered treatment related by the investigator were reported in the period from 12 weeks 
after last injection in the ALSYMPCA study. In total, 27 patients in the Radium-223 group, 
8 patients in the placebo group, and 2 patients in the crossover group reported related post-
treatment AEs. Anemia was reported by 11 patients in the Radium-223 group and 5 patients 
in the placebo group. Thrombocytopenia was reported by 3 patients in the Radium-223 group, 
and by none in the placebo group. Neutropenia was reported for 2 patients in the Radium-223 
group, no patient in the placebo group, and 1 patient in the crossover group. Leukopenia was 
reported for 2 patients in the Radium-223 group. Neutropenic sepsis and pancytopenia was 
reported by 1 patient in the crossover group. Aplastic anemia was reported by 1 subject in the 
Radium-223 dichloride group (1/27, 3.7%). Cardiopulmonary failure was reported by 1 
patient (0.3%, 1/301) in the placebo group, and no patient in the Radium-223 dichloride group 
or the crossover group. Multi-organ failure was reported by 1 patient in the Radium-223 
dichloride group [17].  
Long-term toxicity was assessed in ALSYMPCA. From Follow-up Visit 1 and onwards, 
specific diseases were assessed including acute myelogenous leukemia, myelodysplastic 
syndrome, aplastic anemia, primary bone cancer, or primary cancer in other organs. The 
following cases were reported as post-treatment follow-up AEs: a case of bladder cancer 
(Radium-223 patient at Follow-up Visit 1); squamous cell carcinoma of the left hand (placebo 
patient at Follow-up Visit 2); skin cancer (placebo patient at Follow-up Visits 7 and 8); 
squamous cell carcinoma of the skin (crossover patient at Follow-up Visit 1); adenocarcinoma 
rectum and adenocarcinoma sigmoideum (placebo patient at Follow-up Visit 4); lymph node 
metastases not originating from prostate cancer (Radium-223 patient at Follow-up Visit 6); 
and meningioma (crossover patient at Follow-up Visits 2). Aplastic anemia (Radium-223 
patient at Follow-up Visits 5 and 6) was also reported as Post-treatment follow-up AE/SAE. 
All events were regarded as not related to study drug by the investigator [17]. 
 
In summary, the safety and tolerability of Radium-223 did not show new or unexpected 
changes in the safety profile in ALSYMPCA [17]. 
Data from the Surveillance Epidemiology and End Results (SEER) Program cancer registry 
(1973-1993) [21] indicated that of a total of 51,584 men with prostate cancer who had 
received radiotherapy, 3549, i.e. 6.9% developed a second malignancy. Most (3171) had solid 
tumors. Skin cancers were not included in the analysis. The follow up period for these 
patients was up to more than 10 years (between 1973 and 1993).  

 
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The proposed 7 year follow-up of the present Radium-223 study is based on the finding from 
the "Spiess study" that follows the health of 899 persons who received multiple injections of 
another short-lived alpha-particle emitter Radium-224 mainly between 1945 and 1955 for the 
treatment of tuberculosis, ankylosing spondylitis, and some other diseases. In December 
2007, 124 persons were still alive. The most striking health effect, observed shortly after 
(224) Radium-223 injections, was a temporal wave of 57 malignant bone tumors. During the 
two most recent decades of observation, a significant excess of non-skeletal malignant 
diseases has become evident. Up to the end of December 2007, the total number of observed 
malignant non-skeletal diseases was 270 (248 specified cases of non-skeletal solid cancers 
and 22 other malignant diseases, among these 16 malignant neoplasms of lymphatic and 
hematopoietic tissue, six without specification of site) compared to 192 expected cases. The 
peak of development of secondary tumors was observed between 7 and 8 years [22]. 
In response to the Food and Drug Administration (FDA) and European Medicine Agency 
(EMA) post-marketing requirements, the Marketing Authorization Holder (MAH) will further 
assess the safety of Radium-223 through the conduct of an international, prospective, 
observational single arm cohort study to study the occurrence of second primary malignancies 
in patients treated with Radium-223: The REASSURE study (Radium-223 alpha Emitter 
Agent in non-intervention Safety Study in mCRPC population for long-teRm Evaluation. 
Due to the nature of the disease, stage of the prostate cancer, and the uniqueness of the 
treatment with Radium-223, it would be challenging to identify an active comparison group 
within the REASSURE study. As an optimal alternative, incidence rates on second primary 
malignancies in mCRPC patients treated with Radium-223 and enrolled in the REASSURE 
study could be indirectly compared with the corresponding reference information on second 
primary malignancies in mCRPC patients from external secondary data source(s), such as 
population based data in the US and/or EU. A feasibility evaluation of specific appropriate 
external secondary data sources was conducted by the MAH. Indirect comparison of 
REASSURE data with the external secondary data source(s) will be performed following the 
completion of the REASSURE study and in accordance with timelines of its study report. 
8. 
Research questions and objectives 
This observational study is conducted to evaluate the short and long term safety profile of 
Radium-223 and assess the incidence of developing second primary malignancies among 
prostate cancer patients receiving Radium-223 in the routine clinical practice setting. 
8.1 
Primary objective(s) 
The primary objectives of this study are: 
• To assess the incidence of all second primary malignancies (including myelodysplatic 
syndrome [MDS]/acute myeloid leukemia [AML] and osteosarcoma) in mCRPC 
patients treated with Radium-223 in the routine clinical practice setting.  
• To assess the incidence of treatment-emergent serious adverse events (SAEs) 
(collected up to 30 days after last administration), drug-related adverse events (AEs) 
(collected up to 30 days after last administration), and drug-related SAEs (up to 7 
years after the last administration of Radium-223). 

 
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• To assess bone marrow suppression. 
8.2 
Secondary objective(s) 
The secondary objectives of this study are: 
• To determine the Overall Survival (OS) in patients treated with Radium-223. 
• To evaluate pain over time using the “Brief pain inventory short form” (BPI-SF) 
questionnaire [23]. 
• To assess the incidence of bone fractures and bone associated events (e.g. 
osteoporosis). 
9. 
Research methods 
9.1 
Study design 
This study is a global, prospective, observational, multi-center, single arm cohort study. The 
study will be conducted in routine clinical practice settings. Site selection is done by the 
Bayer country medical departments. Sites are selected based only on the experience of the 
oncologist with the indication and the treatment with Radium-223. It is planned to enroll 
1,334 patients with CRPC with bone metastases for whom a decision has been made by the 
treating physician and the patient to treat with Radium-223. Treatment with Radium-223 
should follow the approved local product information according to local health authority 
approved label.  
The study will be initiated in the US, Canada, EU and Latin America (Argentina, Austria, 
Belgium, Canada, Colombia, Czech Republic, Denmark, France, Germany, Greece, Israel, 
Italy, Luxembourg, Mexico, Netherlands, Portugal, Spain, Sweden, United Kingdom, United 
States) according to health authority approval labels. The observation period for each patient 
enrolled in this study is the time from the start of therapy with Radium-223 to death, 
withdrawal of consent, lost to follow-up, or end of this study (maximum of 7 years after last 
administration of Radium-223), whichever comes first in time. To monitor the development 
of second primary malignancies and potential short and long term toxicities, second primary 
malignancies and Radium-223-related SAEs will be collected for each patient until end of 
study. 
In this observational study, the decision on the duration and dosage of treatment is agreed 
upon between the patient and the physician. However, it is highly recommended that the 
treating physician follows the local product information. The medication is used within the 
routine clinical practice setting. Commercially available product will be used to treat the 
patients. Radium-223 dichloride should not be given concurrently with abiraterone plus 
prednisone/prednisolone. The option of starting a bone health agent (BHA) including 
bisphosphonates or denosumab should be considered, taking into consideration applicable 
guidelines. 
Second primary malignancies incidence data from external secondary data sources will be 
generated to establish the reference group(s). 

 
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9.1.1 
Primary Endpoint(s) 
• The incidence of developing second primary malignancies  
• AEs / SAEs 
• Incidence of treatment-emergent SAEs (up to 30 days after last administration). 
• Incidence of drug-related treatment-emergent AEs (up to 30 days after last 
administration).  
• Incidence of drug-related SAEs (up to 7 years after last administration). 
• Bone marrow suppression. 
For details, please go to Section 10.3.1 
9.1.2 
Secondary Endpoint(s)  
• The OS in mCRPC patients treated with Radium-223 in the routine clinical setting. 
• The worst pain score and pain interference score over time as determined by patient 
responses on the BPI-SF questionnaire. 
• Bone fractures and bone associated events (e.g. osteoporosis), regardless of 
investigator assessment of causality, based on AEs. 
9.1.3 
Strengths of the study design 
This is an international, prospective, observational, cohort study of CRPC patients with bone 
metastasis who will receive Radium-223 in routine clinical practice settings. This study will 
include patients from a more diversified and less selected patient population than in clinical 
trial setting, using fewer eligibility criteria to be as representative to the general CRPC 
patients with bone metastasis as possible. 
9.2 
Setting  
The study will be conducted by Bayer AG with support of a Contract Research Organization 
(CRO). The study will be conducted according to local health authority approved label. 
9.2.1 
Eligibility 
The study population will consist of CRPC patients with bone metastasis who will be treated 
with Radium-223.  
9.2.2 
Inclusion criteria 
• The treatment decision to Radium-223 needs to be made independent from and 
before patient enrollment in the study.  
• Patients with histologically or cytologically confirmed castration resistant 
adenocarcinoma of the prostate with bone metastases. 
• Signed informed consent. 

 
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9.2.3 
Exclusion criteria 
• Patients previously treated with Radium-223 for any reason. 
• Patients currently treated in clinical trials including other Radium-223 studies. 
• Patients are planned for the systemic concomitant use of other 
radiopharmaceuticals for treatment of prostate cancer or for other use. 
Inclusion and exclusion criteria should follow the locally approved Radium-223 product 
information. 
9.2.4 
Withdrawal 
 In this observational study, withdrawal from the study is independent of the underlying 
therapy and will not affect the patient’s medical care. Each patient may withdraw from the 
study at any time and without giving a reason. If a patient wants to terminate the study 
participation, no further data will be collected. However, the patient will be asked whether he 
agrees that the data collected so far can be used. In case the patient does not agree, his data 
will be deleted from the study database and will not be used for any study-related analysis. In 
case a patient would like to withdraw the consent given earlier, he should inform his doctor 
and the site should document the withdrawal and the extent of withdrawal in the eCRF as well 
as in the patient’s medical records. 
9.2.5 
Replacement 
Patients will not be replaced after drop out. 
9.2.6 
Representativeness 
No further selection than outlined in Sections 10.2.1-10.2.3 should be made and patients 
should be enrolled consecutively in order to avoid any selection bias and thus to increase the 
likelihood of representativeness. With respect to site selection, this study could have potential 
limited representativeness (at convenience sample) as Bayer would be looking for sites with 
Radium-223 availability (nuclear-medicine licensed facility) and experience with prostate 
cancer management and treatment. 
9.2.7 
Visits  
Information on the patients, outcomes, and other variables is recorded using Electronic Data 
Capture (EDC) by the treating physician (medical oncologist, urologist) or designated medical 
person at different time points. In certain circumstances, dosing and other related variables are 
recorded using EDC by the Radium-223 administering physician (nuclear medicine physician 
or any other physician licensed in the administration of radioisotopes). After the patient and 
treating physician have agreed on a treatment decision, the patient is informed about the study 
and has to sign an informed consent in order to participate in this study. Baseline information 
is recorded with the status before the first Radium-223 administration during patient visit. For 
each treatment cycle, information from patient medical records is documented and entered 
into EDC system by the physician or designated medical person. Paper patient questionnaires 
will be collected at each treatment cycle and will entered into the database by the CRO. After 
end of treatment, the patient information will be gathered in regular intervals (approximately 

 
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3 and 6 months, 12 months and thereafter yearly for a maximum of 7 years after last 
administration of Radium-223 according to local clinical practice) from patient’s record or 
during follow-up visits by the recruiting physician or designated person within treatment 
team. The visit frequency should be driven by the local standard of care at the local site. 
9.3 
Variables 
At baseline, patients’ demographic variables and information about disease characteristics 
will be collected from the treating physician (including date of diagnosis, prior treatment, 
tumor staging information, co-morbidities, prior medication, and concomitant medication). 
Treatment information and potential outcomes (second primary malignancy, other safety 
information, OS, and progression (defined as first progression after initial treatment with 
Radium-223) are recorded by the treating physician (medical oncologist, urologist) or 
Radium-223 administering physician or designated medical person in an EDC system. Pain 
measurements are recorded starting before the first injection of Radium-223 until 6 months 
after last injection of Radium-223. 
The follow-up will take place at approximately 3 months (M), 6M, 12M, 24M, 36M, 48M, 
60M, 72M, and 84M to collect information regarding the outcomes of interest (second 
primary malignancy, other safety information, OS, and progression). The visit frequency 
should be driven by the local standard of care at the local site. 
 
Table 2: Tabulated overview on variables collected during the study 
 
Baseline 
Treatment 
(until 30 days 
post last dose)  
6 Months FU 
post last dose 
Long-term FU 
Demography 
X 
 
 
 
Vital Signs 
X 
 
 
 
Prostate cancer history 
(classification, risk factors, 
ECOG, procedures) 
X 
 
 
 
Medical history/concomitant 
disease 
X 
 
 
 
Medication (prior, 
concomitant, subsequent) 
X 
X 
X a 
X a 
Anti-cancer  therapyb (prior, 
concomitant, subsequent)  
X 
X 
X 
X 
Exposure Treatment 
(Radium-223) 
 
X 
 
 
Adverse Eventsc 
 
X 
X  
X  
Laboratory parameters 
X 
X 
Xd 
Xd 
Progressione 
 
X 
X 
X 
Pain measurements (BPI-SF) 
X 
X 
X 
 
a 
Medications taken for treating of drug related SAEs/second primary malignancies.  
 
Therapeutic, prevention measures, and treatment modalities for bone marrow suppression will be 
collected up to 6 months after the last dose administration. 
b 
Anti-cancer therapy includes antihormonals, chemotherapy, radiotherapy, immunotherapy, bone 
health agents (e.g.bisphosphonates / denosumab) and/or re-treatment with Radium-223. See 

 
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Section 10.3.6.  
c     All SAEs and drug-related AEs are collected during treatment and up to 30 days after the last 
administration of Radium-223. 
 
Drug related Serious Adverse Events (SAEs) are collected up to 7 years after the last 
administration of Radium-223.  
 
All SAEs of second primary malignancies are collected up to 7 years after the last administration 
of Radium-223. 
 
AEs of bone fractures and bone associated events are collected up to 7 years after the last 
administration of Radium-223.  
       All post treatment grade 3/4 hematological toxicities are collected up to 6 months after the last 
administration of Radium-223.  
 
For patients receiving subsequent chemotherapy, all AEs/SAEs of febrile neutropenia and 
hemorrhage will be recorded up to 6 months after the last administration of chemotherapy. 
d 
For patients with a platelet count or WBC less than the lower limit of normal at 6 months post last 
dose of Radium- 223 being followed until resolution at a frequency based on local clinical practice. 
e 
Only the first progression post treatment needs to be collected. 
 
 
9.3.1 
Variables to determine the primary endpoint(s)  
• Second primary malignancies (reported as SAE): 
Second primary malignancies are defined as new malignancy unrelated to prostate cancer 
or progression of prostate cancer. All second primary malignancies will be collected 
irrespectively of their relationship to Radium-223. Patients will be followed up until 
death, withdrawal of consent, lost to follow-up, or end of the study, whichever occurs 
first. All types of malignancies including MDS/AML and osteosarcoma (which have 
been reported with the use of radiation) and all other malignancies (including skin 
cancers) will be documented. Detailed information will be collected as an SAE as 
follows:  
- 
description of the event (including location and type); 
- 
start date; 
- 
stop date; 
- 
treatment prior to the event (particularly any cancer related treatment and 
radiotherapy); 
- 
relationship to Radium-223; 
- 
toxicity grade; 
- 
outcome. 
• Treatment-emergent SAEs (data will be collected up to 30 days after last administration). 
• Drug related treatment-emergent adverse events (data will be collected up to 30 days after 
last administration).  
• Drug-related SAEs (data will be collected up to 7 years after last administration)  
• Bone marrow suppression, the following will be assessed: 

 
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o Therapeutic or prevention measures, treatment modalities (e.g., blood 
transfusion/erythropoietin/colony growth stimulating factors) (up to 6 months after 
last administration of Radium-223). 
o All post treatment grade 3/4 hematological toxicities (up to 6 months after last 
administration of Radium-223 as AEs/SAEs): 
- 
description of the event; 
- 
start date; 
- 
stop date;  
- 
therapeutic or prevention measures, treatment modalities;  
- 
toxicity grade; 
- 
outcome;  
- 
relationship to Radium-223. 
o Patients with a platelet count or white blood cell count (WBC) less than the lower 
limit of normal at 6 months post last dose of Radium- 223 are being followed until 
resolution at a frequency based on local clinical practice. 
o Patients who receive subsequent cytotoxic chemotherapy will be followed for the 
development of febrile neutropenia and hemorrhage up to 6 months after the last 
administration of chemotherapy at a frequency based on local clinical practice. 
9.3.2 
Variables to determine the secondary endpoint(s)  
• Overall Survival (OS):  
Overall survival is defined as the time interval from the start of Radium-223 therapy to death 
due to any cause. Patients whose death is not confirmed at the time of data-cut will be 
censored at the last date known to be alive. Date and cause of death will be collected. 
• Pain 
Pain severity will be measured using the worst pain score from the BPI-SF questionnaire.  
Pain interference will be measured using the pain interference score form the BPI-SF 
questionnaire. The BPI-SF questionnaire will be administered prior to each injection of 
Radium-223. The BPI-SF questionnaire will also be used at each follow-up visit until 6 
months after the last injection of Radium-223. Completion of the BPI-SF questionnaire by the 
patient is voluntary. 
• Bone fractures and bone associated events 
Incidence of bone fractures and bone associated events (e.g. osteoporosis), regardless of 
investigator assessment of causality, reported as AEs. 
9.3.3 
Demography 
For demographic assessment, the following data will be recorded:  
• Year of birth 

 
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• Race (only where legally permitted) 
• Ethnicity (only where legally permitted)  
• Basic patient characteristics 
• Weight 
• Height 
• Body Mass Index (BMI) 
• Vital signs 
9.3.4 
Prostate cancer history 
Findings meeting the criteria listed below are considered to be relevant to the study indication 
and have to be documented: 
• Risk factors for cancer 
• Tumor Classification 
• Number of metastases and extent of disease and/or related procedures/surgeries 
• Baseline Eastern Cooperative Oncology Group (ECOG) performance status 
9.3.5 
Co-morbidities (medical history, concomitant diseases)  
Co-morbidities are any medical findings, whether or not they pertain to the study indication, 
that was present before start of therapy with Radium-223, independent whether or not they are 
still present. They are to be documented in the Medical History/ Concomitant Diseases 
section of the CRF. The patient’s medical history from the last 10 years prior to the start of 
the study (defined as Baseline visit) will be collected. 
For any co-morbidity, the diagnosis, the start and the stop date/ongoing have to be 
documented in the CRF. 
9.3.6 
Prior and concomitant medication  
All medications taken before study start (initiated and stopped before study start [defined as 
Baseline visit]) are termed prior medications.  
All medications taken in addition to the study drug for any indication (either initiated before 
study start [Baseline] or during the study) are termed concomitant medications.  
All medications after the last dose of Radium-223 are termed subsequent medications. 
Medications taken for drug-related SAEs up to 7 years post last dose of Radium-223, for 
Grade 3/4 hematologic toxicities up to 6 months post last dose of Radium-223, and for febrile 
neutropenia and hemorrhage up to 6 months post last dose of subsequent chemotherapy will 
also be collected. 
Therapeutic and prevention measures for bone marrow suppression (blood 
transfusion/erythropoietin/colony growth stimulating factors) are to include: trade name or 

 
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International Nonproprietary Name (INN), start date, stop date/ongoing, dose, unit, frequency, 
and indication.  
Information to be collected for co-medication at baseline includes: trade name or INN, start 
date, stop date/on-going, dose, unit, frequency, and indication. Information to be collected for 
concomitant and subsequent medication includes: trade name or INN, start date, stop 
date/ongoing, dose, unit, frequency,  and indication. Information on prior treatments for the 
prostate cancer is part of the baseline information collection. Additionally, all co-medication 
taken at baseline and during the study will be recorded. Relevant prostate cancer therapy 
variables will be collected in the categories stated below: 
• Prior, concomitant, and subsequent cancer related treatment including antihormonals 
(e.g. LHRH analogues, antiandrogens, abiraterone, enzalutamide), chemotherapy 
(e.g.docetaxel, cabazitaxel), radiotherapy, immunotherapy (incl. sipuleucel-T), bone 
health agents (bisphosphonates, denosumab) and/or re-treatment with Radium-223. 
• Therapeutic radiopharmaceuticals  
Additionally, the level of analgesic pain management will be assessed at each treatment visit, 
starting before the first injection of Radium-223, at each follow-up visit until 6 months after 
the last injection of Radium-223 based on concomitant medication data collected at these 
visits.   
9.3.7 
Exposure / treatment 
Information on Radium-223 to be documented at each Radium-223 administration: 
• Dose 
• Unit 
• Dates (of each injection) 
• Reasons for any significant delay/interruption/discontinuation 
9.3.8 
Assessment of therapy 
Not applicable (N/A) 
9.3.9 
Visits 
• Date of visit/contact  
9.3.9.1 
Baseline  
 
After the patient and treating physician have agreed on a treatment decision, the patient is 
informed about the study and has to sign an informed consent in order to participate in this 
study. 
At baseline, medical history, cancer history, demography, disease characteristics, vital signs, 
prior and concomitant medication, prior diagnostic and therapeutic procedures are 
documented. Following local routine medical practice, laboratory parameters will be 
documented. 

 
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Level of analgesic pain management will be assessed, starting before the first injection of 
Radium-223, based on concomitant medication data collected at these visits. 
9.3.9.2 
Treatment phase  
The dates of the administrations, the dose of Radium-223, changes in concomitant 
medications, and anti-cancer therapy will be collected. 
Data on progression will be collected. Changes in anti-cancer therapy will be documented. 
Safety data will be collected as specified in Section 10.3.1 and Section 10.3.2. 
Pain measurements will be documented at each treatment visit using the BPI-SF 
questionnaire.  
Level of analgesic pain management will be assessed at each treatment visit, based on 
concomitant medication data collected at these visits. 
Paper patient questionnaires (BFI-SF) will be collected at each treatment cycle and will be 
entered into the database by the CRO. 
The recruiting or treating physician or designated medical person or Radium-223 
administering physician will be contacted by the designated CRO with reminders to follow-up 
if the patient received at least one treatment cycle.  
9.3.9.3 
Follow-up visit(s) 
The follow-up will take place at approximately 3M, 6M, 12M, 24M, 36M, 48M, 60M, 72M, 
and 84M from the last administration of Radium-223 to collect information regarding the 
outcomes of interest (e.g., second primary malignancy, other information on safety, and OS). 
Safety data will be collected as specified in Section 10.3.1 and Section 10.3.2. 
Data on progression will be collected. Changes in anti-cancer therapy will be documented. 
Pain measurement will be assessed up to and including the 6M follow-up visit. Level of 
analgesic pain management will be assessed at each follow-up visit until 6 months after the 
last injection of Radium-223 based on concomitant medication data collected at these visits.  
After end of treatment, the patient information will be gathered in regular intervals 
(approximately 3 and 6 months, 12 months and thereafter yearly for a maximum of 7 years 
after last administration of Radium-223 according to local clinical practice) from patient’s 
record or during follow-up visits by the recruiting physician or designated person within 
treatment team. The visit frequency should be driven by the local standard of care at the local 
site. 
The designated CRO will remind physicians/sites when collection of follow-up information is 
due with email documentation reminder.  
9.3.10 
Laboratory parameters 
Following local routine medical practice, laboratory parameters will be documented, e.g. 
sodium, potassium, chloride, calcium, phosphate, magnesium, aspartate transaminase 
(ASAT,) alanine transaminase (ALAT), lactate dehydrogenase (LDH), gamma-
glutamyltranspeptidase (GGT), creatinine, urea, bilirubin, albumin, ALP, PSA, protein, 

 
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hematocrit, hemoglobin, platelet counts, red and white blood cell counts, and differential 
white blood cell count. Laboratory abnormalities considered to be clinically significant and 
drug-related should be also documented on the AE page. 
Hematologic evaluation of patients should be performed at baseline and prior to every dose of 
Radium-223 based on the approved local product information: before the first administration 
of Radium-223, the absolute neutrophil count (ANC) should be ≥ 1.5 x 109/L, the platelet 
count ≥ 100 x 109/L, and hemoglobin ≥ 10 g/dL. Before subsequent administrations of 
Radium-223, the ANC should be ≥ 1 x 109/L and the platelet count ≥ 50 x 109/L. 
For patients with a platelet count or WBC less than the lower limit of normal at 6 months post 
last dose of Radium- 223 are to be followed until resolution at a frequency based on local 
clinical practice. 
9.3.11 
Progression 
Progression is defined as first progression after initial treatment with Radium-223. The type 
of progression (as assessed by the physician) will be collected. This may include symptomatic 
skeletal events (SSEs), prostate specific antigen level (PSA), radiological imaging, or other 
unequivocal clinical progression.   
Progression defined as SSE includes any of the following:  the use of EBRT to relieve skeletal 
symptoms, new pathological bone fractures (vertebral or non-vertebral), occurrence of spinal 
cord compression, or tumor-related orthopedic surgical intervention. 
Progression defined as increase of PSA level and/or radiological progression is solely based 
on physician’s assessment. 
Progression does not include second primary malignancies, tumor-related death, or death 
from any cause. 
9.4 
Data sources 
9.4.1 
REASSURE data sources 
Treating physicians (medical oncologist, urologist) or designated medical person will collect 
historic and on study data from the medical records, routine measurements (e.g. tumor 
assessment), and other treating physicians. Radium-223 administering physicians in certain 
circumstances may also collect from similar sources dosing data and other related data. 
Patients will be asked to answer patient questionnaires. 
9.4.2 
External reference secondary data sources 
A feasibility assessment was performed for the selection of potential data source(s) to 
generate reference incidence data on second primary malignancies in mCRPC patients. Three 
population-based studies on the background rates of second primary malignancies were 
conducted in Germany, Sweden and in the US. 
In the US, several electronic healthcare databases including commercially available claims 
databases and electronic medical record databases are being evaluated. The Kaiser 
Permanente electronic healthcare record database has been identified as a potential 

 
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appropriate data source to serve as the reference group. Other US data sources are also under 
evaluation. 
In Europe, an evaluation of data sources including The Health Improvement Network (THIN) 
in UK, The German Pharmacoepidemiological Research Database (GePaRD) via the Bremen 
Institute for Prevention Research and Social Medicine (BIPS) in Germany, and the Swedish 
National Registers is also ongoing.  
9.5 
Study Size 
The sample size estimation for the proposed observational study is challenging because the 
probability of developing second primary malignancies varies for different cancer types 
among prostate cancer survivors. For this study, accordingly, data will be collected on all 
second primary malignancies and their potential relationship to Radium-223 will be 
evaluated.  
Approximately 1,334 patients will be enrolled into the study (which accounts for 10% loss to 
follow-up for 1,200 patients). Based on the current data from the Phase III study 
ALSYMPCA and SEER data [21], the incidence proportion of second primary malignancy is 
approximately in the range of 1.1% to 6.9%.  
Table 3 shows the width of a 95% confidence interval (CI) for the rate of second primary 
malignancy (based on the exact binomial distribution) for different observed incidence 
proportion with 1,200 patients: 
Table 3: Incidence and corresponding 95% confidence limits 
Incidence (%) 
UCL 
LCL 
Width (%) 
1.0 
0.52 
1.74 
1.22 
1.1 
0.64 
1.95 
1.31 
5.0 
3.84 
6.39 
2.55 
6.9 
5.55 
8.50 
2.96 
10.0 
8.36 
11.84 
3.48 
LCL=lower confidence limit; UCL=upper confidence limit 
With 1,200 patients, if the observed incidence proportion is between 1.1% and 6.9%, the 
width of a 95% CI for the rate of second primary malignancy (based on the exact binomial 
distribution) will be approximately 0.0131 (i.e. approximately 1.3%) to 0.0296 (i.e. 
approximately 3%). The sample size calculation is based on an estimated 10% for the loss to 
follow up. The sample size could be increased if loss to follow up rate proves to be higher 
than expected. 
9.6 
Data management  
A CRO will be selected and assigned for EDC system development. All CRFs will be part of 
the EDC system, which allows documentation of all outcome variables and covariates by all 
participating sites in a standardized way. Information on the EDC system is available upon 
request.  
Patient questionnaires will be collected via paper forms which will be entered into the study 
database.  

 
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Each patient is identified by a unique central patient identification code. This code is only 
used for study purposes. The patient code consists of a combination of a country code, site 
number, and patient number. For the duration of the study and afterwards, only the study team 
is able to identify the patient based on the patient identification code. 
The Study Database (SDB) contains all (pseudonymous) study data. The development of this 
application and the development and setup is done by applying Good Automated 
Manufacturing Practice (GAMP) standards, fulfilling the FDA 21 CFR Part 11 and EU 
EudraLex V4 Annex 11 regulations. A set of Standard Operation Procedures (SOPs) and 
guidelines are used during the study lifecycle project for supporting all study phases from 
specification, development, study start, deployment and change management and up to study 
termination.  
Detailed information on checks for completeness, accuracy, plausibility and validity are given 
in the Data Management Plan (DMP). The same plan will specify measures for handling of 
missing data and permissible clarifications. The DMP is available upon request.  
9.6.1 
Dataflow  
Participating physicians or designated medical person will use the EDC system to enter the 
data. Patient questionnaires will be collected via paper forms, which will be entered into the 
study database. Quality control of entered data will include range, coding, missing, and date 
checks as well as cross-reference (consistency) checks between variables. Accuracy of data 
transcription from source (medical records) to the EDC would be done by source data 
verification. 
9.6.2 
Database freeze/lock  
For each interim analysis and for the final analysis, the database is frozen at a predefined time 
point. The database will be ‘cleaned’ in approximately 4 weeks of the database freeze. After 
the final freeze, no additional incoming data is entered in the database – this database will 
represent the final data source for all analyses. Duplicate copies are made of each database, so 
that all calculations can be repeated if necessary. 
For information on quality control, refer to Section 10.8.  
9.7 
Data analysis 
9.7.1 
Statistical considerations 
Statistical analyses will be primarily explorative and descriptive. All statistical issues 
including calculated variables and proposed format and content of tables will be detailed in 
the Statistical Analysis Plan (SAP). Wherever reasonable, evaluation will be stratified by 
subgroups (i.e. age, other baseline characteristics). 
Patients who receive at least one dose of Radium-223 will be considered valid for safety and 
included in the full analysis set. 
Summary statistics such as mean, standard deviation (SD), minimum, 25 and 75 percentiles, 
median, and maximum will be calculated for continuous variables. Frequencies (percentages) 
will be calculated for categorical variables. 

 
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9.7.2 
Analysis of demography, disease details, prior and concomitant 
medication and other baseline data 
Demography and baseline characteristics will be described with summary statistics. 
Concomitant medication will be coded using World Health Organization (WHO)'s drug 
dictionary. 
9.7.3 
Analysis of treatment data 
Summary statistics will be provided for the treatment duration, starting dose and average 
dose, the number of patients with dose modification (interruption, delay, and discontinuation), 
number of dose modifications, and reasons for dose modifications. 
9.7.4 
Analysis of primary outcome(s) 
Second primary malignancies (reported as SAE) 
Development of second primary malignancies will be summarized using incidence 
proportion, i.e. number of patients with event divided by the number of patients at risk. In 
addition, the EAIR, which is defined as the number of patients with the specific event divided 
by the total person-time of observation or at risk, will be summarized. For patients developing 
a second primary malignancy, the exposure time will be truncated at the time when the second 
primary malignancy is reported. For both the incidence proportion and EAIR, the 
corresponding exact 95% CI will be provided. 
The annualized incidences rate to be presented with median time to follow up.  
In addition, descriptive summaries of KM estimates (including number of failed, number 
censored, 25th and 75th percentiles with respective 95% CI, and median with 95% CI) and 
KM curves will be presented for time to development of second primary malignancy. Patients 
who start other radiopharmaceuticals or enroll into other trials will be censored when they 
start other radiopharmaceuticals or enroll into other trials. 
AEs / SAEs 
These following events will be summarized using the MedDRA and the CTCAE 
(Version 4.03) coding system.  
Adverse events will be categorized and summarized according to relation, seriousness, 
CTCAE grade, discontinuation of therapy, action taken, and outcome. The incidence 
proportion and EAIR will be summarized, along with the exact 95% CI. 
• Incidence of treatment-emergent SAEs (up to 30 days after last administration). 
• Incidence of drug-related treatment-emergent adverse events (up to 30 days after 
last administration). 
• Incidence of drug-related SAEs (up to 7 years after last administration). 
Bone marrow suppression 
The following will be provided: 
• Proportion of patients who take therapeutic or prevention measures, treatment 
modalities (e.g., blood transfusion/erythropoietin/colony growth stimulating factors).   

 
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• Incidence of post treatment grade 3/4 hematological toxicities. 
This will be summarized by CTCAE category and the worst grade. The incidence 
proportion will be provided, along with the exact 95% CI. 
Information for therapeutic or prevention measures, treatment modalities will also be 
summarized. 
• Incidence of abnormal platelet count or WBC. 
This will be summarized by period (up to 30 days after last administration, and after 
30 days after last administration to 6 months after last administration) and the worst 
grade. 
Incidence of febrile neutropenia and hemorrhage for patients who receive subsequent 
cytotoxic chemotherapy. Further details will be described in the SAP. 
9.7.5 
Analysis of secondary outcome(s) 
9.7.5.1 
Overall survival (OS) 
Descriptive summaries of KM estimates and KM curves will be presented for OS. Patients 
alive at the end of the study will be censored at the last date known to be alive.  
Further details will be described in the SAP. 
9.7.5.2 
Pain assessment 
For the BPI-SF pain assessments, summary statistic, including means and change from 
baseline, for the pain severity and pain intensity and the items that make up these indices will 
be provided for each assessment time point. In addition, an analysis of covariance model will 
be used to assess changes in pain severity, as measured by the worst pain score on the BPI-
SF, at each post-baseline assessment time point. The baseline worst pain score will be used as 
a covariate in each analysis of covariance model. 
Further details will be described in the SAP. 
9.7.5.3 
Bone fractures and bone associated events 
For bone fractures and bone associated events, the incidence proportion and EAIR will be 
summarized, along with the exact 95% CI. 
Fracures will be identified based on MedDRA coding system.  
9.7.6 
Comparison with external reference secondary data sources 
Incidence of second primary malignancies in mCRPC patients treated with Radium-223 in the 
REASSURE study will be compared with corresponding information on patients with 
mCRPC identified in external secondary data sources. 
Site specific incidences on cancer diagnosis will be analyzed by comparing the observed 
number of cases for second primary malignancies in the REASSURE cohort with 
corresponding expected number based on cancer incidence rated derived from the external 
reference secondary data source(s). The expected numbers will be ascertained by individually 

 
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computed person-years at risk for the entire REASSURE cohort. The time recorded will start 
at date of first injection of Radium-223 and will end at the time of second primary malignancy 
occurrence, the date of death or the end of study follow up (data collection is estimated to be 
completed at December, 2023), whichever comes first. Age (by 5-year age groups) will be 
accounted for in the analysis. The ratio of the observed and expected number of cases by 
means of Standardized Morbidity Ratio will be used as the measure of the increased or 
decreased incidence rates, accompanied by an exact 95% CI assuming the observed number 
of second primary malignancy cases.   
The indirect comparison of REASSURE data with the external secondary data source(s) will 
be performed following the completion of the REASSURE study and in accordance with 
timelines of its study report.  
9.7.7 
Analysis of safety data 
Safety variables are indicated as primary or secondary outcomes.  
Analyses of further variables will be detailed in the SAP, as appropriate. 
9.7.8 
Analysis of other data 
Descriptive summaries of KM estimates and KM curves will be presented for time to 
progression (TTP) (Section 10.3.11 for definition of progression). Time to progression is 
defined as the time interval from the day of the first dose to the date of first progression. 
Second primary malignancies and death will not be counted in the analysis for progression. 
Patients who do not have a progression at the end of the study will be censored at the date of 
their last evaluable assessment. 
Further details will be described in the SAP. 
9.7.9 
Bias, confounding, and effect-modifying factors  
In this observational study, careful attention should be paid to describing the patient 
population, and caution should be applied to the interpretation of results, especially when 
making comparisons to previous studies, and/or making comparisons across subgroups, as 
there may be confounding factors, measured or unmeasured. 
In addition, as a result of the relatively long follow-up time and challenges to evaluation and 
documentation of the occurrence of a second primary malignancies some patients may not 
have complete follow-up and/or the time to development of the second primary malignancies 
may not be completely known. Therefore, careful attention should be applied to the 
interpretation of the summary measures to be estimated, including incidence proportion and 
EAIR. 
9.7.10 
Interim Analysis 
It is estimated that it will take approximately 1.5 years for completion of enrollment. Two 
interim analyses will be planned based on the milestones for this study. 

 
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9.7.11 
Loss of follow-up  
A patient is considered “lost to follow-up” if during the course of the study no further follow-
up data can be retrieved and/or if at the time of End of Observation no further data collection 
is possible. 
A low “lost to follow-up rate” will be essential for the validity of the study, especially in this 
patient population with a chronic disease and fragile overall survival chances.  
In order to minimize loss to follow-up, a multi-faceted follow-up process will be established. 
The aim is to keep the total loss to follow-up at the end of the study as low as possible.  
The designated CRO will remind physicians/sites when collection of follow-up information is 
due with email documentation reminder. The local conduct responsible is in the loop for the 
reminder, and will follow-up and coordinate with the sites afterwards. Site personnel should 
apply due diligence – within the applicable standard patient care procedures – to contact 
patients to ascertain the reason for lost-to-follow-up.  
In case the site personnel obtains knowledge that the patient is lost to follow-up due to 
transfer to another hospital, a hospice or has died, site personnel should apply due diligence to 
retrieve information required for the End of Observation documentation (e.g. second primary 
malignancies) or date of death, if applicable. Although a patient is not obliged to give his/her 
reason(s) for withdrawing prematurely from a trial, the treating physician should make a 
reasonable effort to ascertain the reason(s), while fully respecting the patient's rights. This 
excerpt expresses the need for physicians associated with this study to make a first-hand effort 
to contact patients who are lost-to-follow-up [24]. 
 
9.8 
Quality control 
9.8.1 
Data quality 
Before study start at the sites, all physicians participating in the study will be sufficiently 
trained by Bayer or the designated CRO on the background and objectives of the study and 
ethical as well as regulatory obligations. Treating physicians and Radium-223 administering 
physician (if applicable) will have the chance to discuss and develop a common 
understanding of the study protocol and the CRF. 
A CRO will be assigned for EDC system development, quality assurance, verification of the 
data collection, data analysis, and data transfer to Bayer.  
Prior to submission of the electronic CRF, all pages should be filled out completely. A check 
for plausibility will be performed while data is being entered. Missing or implausible data will 
be queried directly online. Data from the CRF must be verifiable against source documents. 
Data from patient questionnaires will be entered in the study database. Checks for multiple 
documented patients will be done. All details of the above analyses will be described in detail 
in the data management plan.  
Adverse events and SAEs will be handled in the same way as the other data reported in the 
CRF. However, in addition, the SAEs will be entered into the safety database for coding, 
medical assessment, and for reporting to authorities according to national regulatory 

 
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requirements. Coding of AEs, medical history, and signs and symptoms will be performed 
according to MedDRA and coding of concomitant medications, prior anti-cancer therapy, and 
further therapy will be performed according to WHO-Drug dictionary.  
Detailed information on checks for completeness, accuracy, plausibility and validity are given 
in the DMP. The same plan will specify measures for handling of missing data and 
permissible clarifications. The DMP is available upon request.  
Medical Review of the data will be performed according to the Medical Review Plan (MRP). 
The purpose of the Medical Review is to verify the data from a medical perspective for 
plausibility, consistency, and completeness and to identify potential issues that could affect 
the robustness of the collected study data or the progress of the study. Detailed information on 
the Medical review will be described in the MRP, which is available upon request. 
A final database will be declared when all data have been entered, the data entry verified, the 
data validated, and a final SAE reconciliation has taken place.  
National and international data protection laws as well as regulations on observational studies 
will be followed. Electronic records used for patient documentation will be validated 
according to 21 Code of Federal Regulations (CFR) Part 11 (FDA) [25]. The documentation 
is available upon request. 
9.8.2 
Quality review 
Quality review will be done in two steps: in the first step the site’s training status will be 
assessed via standardized telephone interviews. In the second step, source data verification 
will be conducted. The purpose is to review the documented data for completeness and 
plausibility, adherence to the OS protocol and verification with source documents. 
Detailed measures for quality reviews will be described in the Quality Review Plan (QRP). 
The QRP is available upon request (see Table 4, Annex 1).  
9.8.3 
Storage of records and archiving 
The initiator of the study will make sure that all relevant documents of this PASS, including 
CRFs and other patient records, will be stored after end or discontinuation of the study at least 
for 15 years. Other instructions for storage of medical records will remain unaffected.  
9.8.4 
Certification/qualification of external parties 
N/A 
9.9 
Limitations of the research methods 
This prospective observational cohort study provides an opportunity to collect data of real-life 
safety and effectiveness information that can be analyzed and disseminated in a timely 
manner. However, this study is a single arm cohort study without an active comparison 
group. The results generated from this study will need to be compared with those derived 
from the reference group(s). Although the reference group(s) can provide information for 
understanding the results observed in REASSURE, it has its own weakness as these data are 
generally not collected using the same way and the same or similar information may not be 
available.   

 
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In addition, this study could experience a higher than expected loss of follow-up because of 
the long follows up period. However, due to the advanced stage of the mCRPC and the 
average age of the treated population, the probability of 7 years survival is very low. 
9.10 
Other aspects 
N/A 
10. 
Protection of human subjects 
10.1 
Ethical conduct of the study 
This study is an observational study where Radium-223 is prescribed in the usual manner in 
accordance with the terms of the marketing authorization. There is no assignment of a patient 
to a particular therapeutic strategy. The treatment decision falls within current practice and the 
prescription of the medicines is clearly separated from the decision to include the patient in 
the study. No additional diagnostic or monitoring process is required for participation or 
during the study. Epidemiological methods will be used for the analysis of the collected data. 
10.2 
Regulatory authority approvals/authorizations 
The study will be carried out within an approved indication in accordance with guidelines and 
regulations of EMA, FDA, and applicable local law(s) and regulation(s) (e.g. Regulation (EU) 
No 520/2012 [26]). Recommendations given by other organizations will be followed as well 
(e.g. European Federation of Pharmaceutical Industries and Associations [EFPIA] [27], 
European Network of Centers in Pharmacoepidemiology and Pharmacovigilance [ENCePP] 
[28]). International Conference of Harmonisation - Good Clinical Practice [ICH-GCP] 
guidelines will be followed whenever possible [29]. 
In addition, the guidelines on good pharmacovigilance practices (GVP module VI [30] and 
since the study qualifies as a PASS, GVP module VIII [31], [32]) will be followed. 
 
10.3 
Independent ethics committee (IEC) or institutional review board (IRB) 
In all countries where reference to an IEC/IRB is required, documented approval from 
appropriate IECs/IRBs will be obtained for all participating centers prior to study start. When 
necessary, an extension, amendment or renewal of the IEC/IRB approval must be obtained 
and also forwarded to the study initiator and funder. The IEC/IRB must supply to the study 
initiator and funder, upon request, a list of the IEC/IRB members involved in the vote and a 
statement to confirm that the IEC/IRB is organized and operates according to applicable laws 
and regulations. 
10.4 
Patient information and consent 
Before documentation of any data, informed consent is obtained by the patient in writing. In 
countries where required by law or regulation, the IECs/IRB written approval/favorable 
opinion of the written informed consent form and any other written information to be 
provided to patients must be obtained prior to the beginning of the observation. 

 
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10.5 
Patient insurance 
In this study, data on routine treatment of patients in daily practice are documented and 
analyzed with the help of epidemiological methods. Treatment including diagnosis and 
monitoring of therapy follows exclusively routine daily practice. Current medical daily 
practice is observed, and for the patient no risks beyond regular therapy exist – there is no 
additional hazard arising from study participation and the study has no interventional 
character. As no study related risks exist, there is no need to protect the patient additionally by 
a patient insurance. The general regulations of medical law and the professional indemnity 
insurance of the enrolling and treating physicians and Radium-223 administering physicians 
and, respectively, the institutions involved provide sufficient protection for both patient and 
physician. 
10.6 
Confidentiality 
Bayer as well as the designated CRO ensure adherence to applicable data privacy protection 
regulation. Data are transferred to Bayer in encoded form only. The entire documentation 
made available to Bayer does not contain any data which, on its own account or in 
conjunction with other freely available data, can be used to re-identify natural persons. The 
designated CRO is obligated to ensure that no documents contain such data. Study findings 
stored on a computer will be stored in accordance with local data protection laws.  
All records identifying the patient will be kept confidential and will not be made publicly 
available. Patient names will not be supplied to the initiator. If the patient name appears on 
any document, it must be obliterated before a copy of the document is supplied to the initiator. 
Study findings stored on a computer will be stored in accordance with local data protection 
laws.  
The investigator will maintain a list to enable patients’ records to be identified in case of 
queries. In case of a report of a serious adverse event (SAE), the responsible 
pharmacovigilance person may ask for additional clarification. In that case, the company is 
not allowed to directly contact the patient. All additional information will be provided by the 
investigator. 
11. 
Management and reporting of adverse events/adverse reactions 
11.1 
Definitions 
The observation period / reporting of adverse events for a patient in this study starts with 
screening. 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
medicinal product and which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (e.g. an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to this medicinal product [29]. 
The term also covers laboratory findings or results of other diagnostic procedures that are 
considered to be clinically relevant (e.g. that require unscheduled diagnostic procedures or 
treatments or result in withdrawal from the study). 

 
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The AE may be: 
• A new illness 
• Worsening of a sign or symptom of the condition under treatment or of a concomitant 
illness 
• An effect of the study medication 
• Any combination of one or more of these factors 
• An effect related to lack of drug effect 
• An effect related to medication errors  
• Medication error, overdose, drug abuse, drug misuse or drug dependency itself event, 
as well as any resulting event  
• An effect related to off-label use or occupational exposure 
• An effect related to pre-existing condition improved (unexpected therapeutic benefits 
are observed) 
• Drug exposure via mother / father (exposure during conception, pregnancy, childbirth 
and breastfeeding). 
As mentioned above, no causal relationship with a study medication is implied by the use of 
the term “adverse event”. 
Hospitalizations will not be regarded as adverse events, if they: 
• were planned before inclusion in the study 
• are ambulant (hospitalization shorter than 12 hours) 
• are part of the normal treatment or monitoring of the studied disease, i.e. they were not 
due to a worsening of the disease. 
A drug related AE is any AE judged by the treating physician or Radium-223 administering 
physician (if applicable) as having a reasonable suspected causal relationship to Radium-223. 
It is defined as a response to a medicinal product, which is noxious and unintended. 
An AE is serious if it: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization (see 
exceptions below) 
• Results in persistent or significant disability or incapacity 
• Results in a congenital anomaly or birth defect in an offspring 
• Is medically important. 

 
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Death is usually the outcome of an underlying clinical event that causes it. Hence, it is the 
cause of death that should be regarded as the SAE. The one exception to this rule is ‘sudden 
death’ where no cause has been established. In this instance, ‘sudden death’ should be 
regarded as the AE and ‘fatal’ as its reason for being ‘serious’. 
Life-threatening: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the event. It does not refer to an AE which 
hypothetically might have caused death if it were more severe. 
Hospitalization: Any AE leading to hospitalization or prolongation of hospitalization will be 
automatically considered as Serious, UNLESS at least one of the following exceptions is met: 
• The admission results in a hospital stay of less than 12 hours, or 
• The admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the 
start of the study), or 
• The admission is not associated with an adverse event (i.e. social hospitalization for 
purposes of respite care). 
However it should be noted that invasive treatment during any hospitalization may fulfill the 
criteria of ‘medically important’ and as such may be reportable as a SAE dependent on 
clinical judgment. In addition where local regulatory authorities specifically require a more 
stringent definition, the local regulation takes precedent. 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
Congenital anomaly (birth defect), i.e. any congenital anomaly observed in an infant, or later 
in a child, should be regarded as a SAE when: 
• The father was exposed to a medicinal product prior to conception 
• Other medically important serious event: Any adverse event may be considered 
serious because it may jeopardize the patient and may require intervention to prevent 
another serious condition.  
Medically important events either refer to or might be indicative of a serious disease state. 
Such reports warrant special attention because of their possible association with serious 
disease state and may lead to more decisive action than reports on other terms. 
Progression of the underlying disease itself does not qualify as an AE. However, if 
progression of the underlying disease leads to signs and symptoms that fulfill the criteria of 
seriousness, these should be documented as SAEs. In this case progression of the underlying 
disease should be mentioned in the comment section of the AE report form. 
11.2 
Collection 
Starting with the first administration of Radium-223, all drug-related non-serious Adverse 
Events (AE) must be documented on the AE Report Form or on the CRF and forwarded to 
Bayer within 7 calendar days of awareness. All serious AEs (SAE) must be documented and 
forwarded immediately (within 1 business day of awareness). 

 
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For each AE/SAE, the recruiting physician must assess and document the seriousness, 
duration, causal relationship to study drug, action taken and outcome of the event. 
The documentation of treatment related AE/SAE ends with the completion of the treatment 
phase (including 30 days after last administration of Radium-223) of the patient.   
All post treatment grade 3/4 hematological toxicities are collected up to 6 months after the 
last administration of Radium-223. 
As long as the patient has not received any Radium-223, AEs /SAEs do not need to be 
documented as the patient is considered ineligible. 
After the treatment period, all SAEs judged as being drug-related by the treating physician or 
Radium-223 administering physician (if applicable) have to be documented until 7 years from 
last treatment or until death, withdrawal of consent, or lost to follow-up, whichever occurs 
earlier. However, all occurrences of leukemia, myelodysplastic syndrome, aplastic anemia, 
primary bone cancer or any other second primary malignancy must be reported as SAEs at 
any time, and regardless of the causality assessment. All bone fractures and bone associated 
events such as osteoporosis need to be reported as either AE(s) or SAEs if the criteria of SAE 
were met, regardless of the investigator’s causality assessment. 
If a pregnancy occurs in a female partner of a study patient during the study, although it is not 
a serious adverse event itself, it should be documented and forwarded to Bayer within the 
same time limits as a serious adverse event. The result of a pregnancy will be followed-up 
according to applicable Bayer SOPs. 
For any serious drug-related AE occurring after study end, the standard procedures that are in 
place for spontaneous reporting have to be followed on behalf of the treating physician or 
Radium-223 administering physician (if applicable).  
Patients with a platelet count or white blood cell count (WBC) less than the lower limit of 
normal at 6 months post last dose of Radium- 223 are being followed until resolution at a 
frequency based on local clinical practice. Patients who receive subsequent cytotoxic 
chemotherapy will be followed for the development of febrile neutropenia and hemorrhage up 
to 6 months after the last administration of chemotherapy at a frequency based on local 
clinical practice. 
11.3 
Management and reporting 
Drug-related non-serious Adverse Events (AE) occurring under treatment with Radium-223 
that qualify for expedited reporting will be submitted to the relevant authorities according to 
EU PV legislation (Regulation (EU) No 1235/2010 and Directive 2010/84/EU, Module VI) 
and according to national regulations by Bayer; however, all treating physicians or Radium-
223 administering physicians (if applicable) must obey local legal requirements. 
Serious AEs 
All SAEs will be forwarded immediately (within 24 hours of awareness) to the 
pharmacovigilance country person at Bayer being responsible for SAE processing. The 
outcome of all reported SAEs (resolution, death etc.) will be followed up and documented 
until study end. Where required, the designated CRO might be contacted directly by the 
pharmacovigilance country person in charge to provide further information.  

 
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Submission to the relevant authorities according to national regulations will be done by Bayer 
for SAEs occurring under Radium-223 treatment; however, all treating physicians or Radium-
223 administering physicians (if applicable) must obey local legal requirements. 
For SAEs that occurred while administering non-Bayer drugs, the designated CRO has to 
account for and comply with the reporting system of the product’s Marketing Authorization 
Holder within the frame of local laws and regulations as well as other locally applicable laws 
and regulations. 
11.4 
Evaluation 
Whenever new important safety information is received, e.g. case reports from a physician, 
the reports are processed and entered into the GPV safety database.  
12. 
Plans for disseminating and communicating study results  
This study will be registered at “www.clinicaltrials.gov" and in the EU PAS register at 
“http://www.encepp.eu/encepp_studies/indexRegister.shtml”. Results will be disclosed in a 
publicly available database within the standard timelines. 
For this mandated PASS, progress reports will be submitted with each Periodic Safety Update 
Report (PSUR) or in the agreed frequency and content to the competent authorities. Interim 
reports will be written depending on analysis performed by the designated CRO.  
The results of this study are intended to be published in a peer-reviewed journal and as 
abstracts/presentations at national and international congresses. Current guidelines and 
recommendation on good publication practice will be followed (e.g. Good Publication 
Practice [GPP] Guidelines [33], Strengthening the Reporting of Observational Studies in 
Epidemiology [STROBE] [34]). No individual treating physician or Radium-223 
administering physician (if applicable) may publish on the results of this study, or their own 
patients, without prior approval from Bayer.  
 
 

 
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13. 
List of references 
 
[1]  "GLOBOCAN. http://globocan.iarc.fr/factsheets/cancers/prostate.asp".  
[2]  "http://info.cancerresearchuk.org/cancerstats/types/prostate/incidence/uk-
prostatecancerincidence-statistics," [Online].  
[3]  Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM, "GLOBOCAN 2008 
v2.0 Cancer Incidence and Mortality Worldwide: IARC CancerBase No 10. [Internet]. 
Lyon, France: International Agency for Research on Cancer, 2010," [Online]. Available: 
http://globocan.iarc.fr. [Accessed November 2013]. 
[4]  Morris MJ and Scher HI, "Clinical approaches to osseous metastases in prostate cancer.," 
The Oncologist, vol. 8, pp. 161-173, 2003.  
[5]  Pandit-Taskar N, Batraki M and Divgi CR, "Radiopharmaceutical Therapy for Palliation 
of Bone Pain from Osseous Metastases.," J Nucl Med, vol. 45, pp. 1358-1365, 2004.  
[6]  Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L and Rider W, 
"Treatment of metastatic prostatic cancer with low dose prednisone: evaluation of pain 
and quality of life as pragmatic indices of response.," J. Clin Oncol, vol. 7, p. 590, 1989.  
[7]  Petrylak DP, Tangen CM, Hussein MH, Lara PN Jr, Jones JA and Taplin ME et al., 
"Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced 
refractory prostate cancer.," N Engl J Med., vol. 351(15), pp. 1513-1520, 2004.  
[8]  Saad F, "Therapeutic approach to castration-resistant prostate cancer," European 
Urological Review., vol. 3(2), pp. 15-17, 2008.  
[9]  Kasper S and Cookson MS, "Mechanisms leading to the development of hormone 
resistant prostate cancer.," Urol Clin North Am., vol. 33, p. 201–210, 2006.  
[10] Hussain M, Goldman B, Tangen C, Higano CS, Petrylak DP and Wilding G et al, 
"lProstate-specific antigen progression predicts overall survival in patients with 
metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup 
Study 0162) and 9919.," J Clin Oncol., 2009.  
[11] Rodan GA, "The development and function of skeleton and bone metastasis," Cancer, 
pp. 726-732, 2003.  
[12] Shulman KL and Kohles J, "Economic burden of metastatic bone disease in the US.," 
Cancer, no. 109, pp. 2334-42, 2007.  
[13] Soloway MS, Hardeman SW, Hickey D, Raymond J, Todd B and Soloway S et al, 
"Stratification of Patients With Metastatic Prostate Cancer Based on Extent of Disease on 
Initial Bone Scan.," Cancer, no. 61:, pp. 195-202, 1988.  
[14] Buyse M, Burzykowski T, Carroll K, Sargent DJ, Miller LL and Elfring GL et al, 
"Progression-free survival is a surrogate for survival in advanced colorectal cancer," J 
Clin Oncol., vol. 25 (33), pp. 5218-5224, 2007.  
[15] Korn RL and Crowley JJ, "Overview: Progression-free survival as and endpoint in 
clinical trials with solid tumors.," Clin Cancer Res., pp. 2607-2612, 2013.  
[16] Begg CB, "Justifying the choice of endpoints for clinical trials.," J Natl Cancer Inst, pp. 
1594-1595, 2013.  
[17] Investigator's Brochure: BAY 88-8223, Version 5.0 ed., 2015.  

 
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[18] Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM and Fossa SD et al, "Alpha 
emitter radium-223 and survival in metastatic prostate cancer," N Engl J Med, vol. 369 
(3), pp. 213-223, 2013.  
[19] Parker C, Coleman RE, Nilsson S, Vogelzang N, Llyod A, Staudacher K, Cislo P, Van 
Gool R and Sartor O, "Quality of life (QOL), updated survival, and safety of radium-223 
dichloride in patients with castration-resiistant prosate cancer (CPRC) with bone 
metastases frm the phase 3 double-blind randomized, multinatinal study 
(ALSYMPCA)(Poster 898PD)," in ESMO, Vienna, Austria, 2012.  
[20] Nilsson S, Sartor O, Bruland O, Fang F, Aksnes AK, Cislo P and Parker C, "Pain 
Analyses From the Phase 3 Randomized ALSYMPCA Study With Radium-223 
Dichloride in Castration-Resistant Prostate Cancer (CPRC) Patients with Bone 
Metastases. (Abstract 5038)," in ASCO Annual Meeting, Chicago, 2013.  
[21] Brenner DJ, Curtis RE, Hall EJ and Ron E, "Second Malignacies in Prostate Carcinoma 
Patients after Radiotherapy Compared with Surgery.," Cancer, vol. 2, no. 88, pp. 398-
406, 2000.  
[22] W. L. S. H. Nekolla EA, "Incidence of malignant diseases in humans injected with 
radium-224.," Radiat Res., vol. 174(3), no. doi: 10.1667/RR1955.1., pp. 377-86, 2010 
Sep.  
[23] C. S. Cleeland, "The Brief Pain Inventory User Guide," M. D. Anderson Cancer Center, 
2009. [Online]. Available: https://www.mdanderson.org/research/departments-labs-
institutes/departments-divisions/symptom-research/symptom-assessment-tools.html. 
[Accessed 25 04 2018]. 
[24] "Section 4.3.4 of the ICH E-6 Good Clinical Practice: Consolidated Guidance. 2009".  
[25] "Code of Federal Regulations. Title 21, Volume 1. 21CFR 11: Electronic records; 
electronic signatures. 62 FR 13464, Mar. 20, 1997. Revised 01.04.2012.".  
[26] "Commission implementing regulation (EU) No 520/2012 of 19 June 2012 on the 
performance of pharmacovigilance activities provided for in Regulation (EC) No 
726/2004 of the European Parliament and of the Council and Directive 2001/83/EC of 
the European".  
[27] "EFPIA Code on the Promotion of Prescription-Only Medicines to, and Interactions 
with, Healthcare Professionals, EFPIA, October 2007.".  
[28] "ENCePP guide on methodological standards in pharmacoepidemiology. European 
Medicines Agency. EMA/95098/2010. 05.11.2010.".  
[29] "ICH Harmonized Tripartite Guideline: Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting (E2D), November 2003.".  
[30] EMA, "GPV Module VI - Management and reporting of adverse reactions to medicinal 
products (Rev 1)," Guideline on good pharmacovigilance practices 
(EMA/8731138/2011_Rev1), 08 Sep 2014.  
[31] EMA, "GPV Module VIII - Post-authorisation safety studies (Rev 1)," Guideline on good 
pharmacovigilance practices (EMA/813938/2011_Rev1), 19 Apr 2013.  
[32] EMA, "GPV Module VIII Addendum 1 - Member States' requirements for transmission 
of information on non-interventional post-authorisation safety studies (Rev 1)," 
Guideline on good pharmacovigilance practices (EMA/395730/2012_Rev 1), 19 Apr 

 
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2013.  
[33] Graf C, Battisti WP, Bridges D, Bruce-Winkler V, Conaty JM and Elison JM et al, 
"International Society for Medical Publication Professionals. Research Methods & 
Reporting. Good publication practice for communicating company sponsored medical 
research: the GPP2 guidelines," BMJ, vol. 339, p. b4330, 2009.  
[34] von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC and Vandenbroucke JP et al, 
"STROBE-Initiative. The Strengthening the Reporting of Observational Studies in 
Epidemiology (STROBE) statement: guidelines for reporting of observational studies.," J 
Clin Epidemiol, vol. 61 (4), pp. 344-349, 2008.  
 
 
 
 
 
 

 
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Annex 1. List of stand-alone documents 
Table 4: List of stand-alone documents 
Number 
Document reference number 
Date 
Title 
1 
16913_List of active physicians_final 
living document 
available from 
NIS Base system 
List of all 
active 
physicians  
2 
16913_REASSURE_CRF_V10.0_20180322 
22 Mar 2018 
CRF  
3 
16913_REASSURE_DMP_V1.0_signed 
14 Aug 2014 
Data 
Management 
Plan 
4 
16913_REASSURE_SAP IA1 V1.0 
8 Nov 2016 
Statistical 
Analysis Plan 
5 
16913_REASSURE_QRP_V 3.0_20170731 
31 Jul 2017 
Quality 
Review Plan 
6 
16913_REASSURE_Medical Review Plan 
V3.0_final 
18 Jan 2018 
Medical 
Review Plan 
7 
Reassure SC members 
 
List of 
Steering 
Committee 
Members 
 

 
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Annex 2. ENCePP checklist for study protocols 
ENCePP Checklist for Study Protocols (Revision 3); adopted by the ENCePP Steering Group 
on 01/07/2016. 
 
Section 1: Milestones 
Yes 
No 
N/A 
Section 
Number 
1.1 
Does the protocol specify timelines for  
 
 
 
 
1.1.1 Start of data collection1 
 
 
 
6 
1.1.2 End of data collection2 
 
 
 
6 
1.1.3 Study progress report(s) 
 
 
 
-- 
1.1.4 Interim progress report(s) 
 
 
 
6 
1.1.5 Registration in the EU PAS register 
 
 
 
6 
1.1.6 Final report of study results. 
 
 
 
6 
Comments: 
 
 
Section 2: Research question 
Yes 
No 
N/
A 
Section 
Number 
2.1 
Does the formulation of the research question 
and objectives clearly explain:  
 
 
 
7 
2.1.1 Why the study is conducted? (e.g. to address 
an important public health concern, a risk identified in the 
risk management plan, an emerging safety issue) 
 
 
 
7 
2.1.2 The objective(s) of the study? 
 
 
 
8 
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised) 
 
 
 
7 
2.1.4 Which hypothesis(-es) is (are) to be 
tested? 
 
 
 
-- 
2.1.5 If applicable, that there is no a priori 
hypothesis? 
 
 
 
-- 
 
Comments: 
 
 
                                                 
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts. 
2 Date from which the analytical dataset is completely available. 

 
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Section 3: Study design 
Yes 
No 
N/
A 
Section 
Number 
3.1 
Is the study design described? (e.g. cohort, case-
control, cross-sectional, new or alternative design)  
 
 
 
7 
3.2 
Does the protocol specify whether the study is 
based on primary, secondary or combined data 
collection? 
 
 
 
7, 9.1 
3.3 
Does the protocol specify measures of 
occurrence? (e.g. incidence rate, absolute risk) 
 
 
 
9.1, 9.3, 
9.7 
3.4 
Does the protocol specify measure(s) of 
association? (e.g. relative risk, odds ratio, excess risk, 
incidence rate ratio, hazard ratio, number needed to harm 
(NNH) per year) 
 
 
 
-- 
3.5 
Does the protocol describe the approach for the 
collection and reporting of adverse 
events/adverse reactions? (e.g. adverse events that 
will not be collected in case of primary data collection) 
 
 
 
11.2 
Comments: 
 
 
Section 4: Source and study populations 
Yes 
No 
N/A 
Section 
Number 
4.1 
Is the source population described? 
 
 
 
9.2. 
4.2 
Is the planned study population defined in terms 
of: 
 
 
 
 
4.2.1 Study time period? 
 
 
 
7 
4.2.2 Age and sex? 
 
 
 
9.2 
4.2.3 Country of origin? 
 
 
 
9.1 
4.2.4 Disease/indication? 
 
 
 
7, 9.2 
4.2.5 Duration of follow-up? 
 
 
 
9.1 
4.3 
Does the protocol define how the study 
population will be sampled from the source 
population? (e.g. event or inclusion/exclusion criteria) 
 
 
 
9.2 
Comments: 
 
 
Section 5: Exposure definition and measurement 
Yes 
No 
N/
A 
Section 
Number 
5.1 
Does the protocol describe how the study 
exposure is defined and measured? (e.g. operational 
details for defining and categorising exposure, measurement 
of dose and duration of drug exposure) 
 
 
 
9.3 
5.2 
Does the protocol address the validity of the 
exposure measurement? (e.g. precision, accuracy, use 
of validation sub-study) 
 
 
 
-- 

 
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Section 5: Exposure definition and measurement 
Yes 
No 
N/
A 
Section 
Number 
5.3 
Is exposure classified according to time 
windows? (e.g. current user, former user, non-use) 
 
 
 
-- 
5.4 
Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug? 
 
 
 
-- 
Comments: 
 
 
Section 6: Outcome definition and measurement 
Yes 
No 
N/
A 
Section 
Number 
6.1 
Does the protocol specify the primary and 
secondary (if applicable) outcome(s) to be 
investigated? 
 
 
 
9.1.1, 
9.1.2, 
9.3 
6.2 
Does the protocol describe how the outcomes are 
defined and measured?  
 
 
 
9.3 
6.3 
Does the protocol address the validity of 
outcome measurement? (e.g. precision, accuracy, 
sensitivity, specificity, positive predictive value, prospective 
or retrospective ascertainment, use of validation sub-study) 
 
 
 
-- 
6.4 
Does the protocol describe specific endpoints 
relevant for Health Technology Assessment? 
(e.g. HRQoL, QALYs, DALYS, health care services utilisation, 
burden of disease, disease management) 
 
 
 
-- 
Comments: 
 
 
Section 7: Bias 
Yes 
No 
N/
A 
Section 
Number 
7.1 
Does the protocol describe how confounding will 
be addressed in the study? 
 
 
 
 
7.1.1. Does the protocol address confounding by 
indication if applicable? 
 
 
 
 
7.2 
Does the protocol address: 
 
 
 
 
7.2.1. Selection biases (e.g. healthy user bias) 
 
 
 
9.7.9 
7.2.2. Information biases (e.g. misclassification of 
exposure and endpoints, time-related bias) 
 
 
 
9.7.9 
7.3 
Does the protocol address the validity of the 
study covariates? 
 
 
 
 
Comments: 
Section 9.7.9 addresses bias in general 
 

 
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Section 8: Effect modification 
Yes 
No 
N/
A 
Section 
Number 
8.1 
Does the protocol address effect modifiers? 
(e.g. collection of data on known effect modifiers, sub-group 
analyses, anticipated direction of effect)  
 
 
 
 
Comments: 
 
 
Section 9: Data sources 
Yes 
No 
N/A 
Section 
Number 
9.1 
Does the protocol describe the data source(s) 
used in the study for the ascertainment of: 
 
 
 
 
9.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview) 
 
 
 
9.3, 9.4.1 
9.1.2 Outcomes? (e.g. clinical records, laboratory 
markers or values, claims data, self-report, patient 
interview including scales and questionnaires, vital 
statistics) 
 
 
 
9.3, 9.4.1 
9.1.3 Covariates? 
 
 
 
-- 
9.2 
Does the protocol describe the information 
available from the data source(s) on: 
 
 
 
 
9.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily 
dosage,  prescriber) 
 
 
 
9.4.1 
9.2.2 Outcomes? (e.g. date of occurrence, multiple 
event, severity measures related to event) 
 
 
 
9.4.1 
9.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, lifestyle) 
 
 
 
-- 
9.3 
Is a coding system described for:  
 
 
 
 
9.3.1 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC) Classification System) 
 
 
 
9.8.1 
9.3.2 Outcomes? (e.g. International Classification of 
Diseases (ICD)-10, Medical Dictionary for Regulatory 
Activities (MedDRA)) 
 
 
 
9.7.4, 
9.8.1 
9.3.3 Covariates? 
 
 
 
-- 
9.4 
Is a linkage method between data sources 
described? (e.g. based on a unique identifier or other)  
 
 
 
-- 
Comments: 
 
 
Section 10: Analysis plan 
Yes 
No 
N/
A 
Section 
Number 
10.1 Is the choice of statistical techniques described?  
 
 
 
9.7.1 
10.2 Are descriptive analyses included? 
 
 
 
9.7.1 
10.3 Are stratified analyses included? 
 
 
 
9.7.1 

 
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Section 10: Analysis plan 
Yes 
No 
N/
A 
Section 
Number 
10.4 Does the plan describe methods for adjusting for 
confounding? 
 
 
 
 
10.5 Does the plan describe methods for handling 
missing data? 
 
 
 
9.8.1 
10.6 Is sample size and/or statistical power 
estimated? 
 
 
 
9.5 
Comments: 
 
 
Section 11: Data management and quality 
control 
Yes 
No 
N/
A 
Section 
Number 
11.1 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving) 
 
 
 
9.8.3 
11.2 Are methods of quality assurance described? 
 
 
 
9.8 
11.3 Is there a system in place for independent 
review of study results?  
 
 
 
 
Comments: 
 
 
Section 12: Limitations 
Yes 
No 
N/
A 
Section  
Number 
12.1 Does the protocol discuss the impact on the 
study results of: 
 
 
 
 
12.1.1 Selection bias? 
 
 
 
 
12.1.2 Information bias? 
 
 
 
 
12.1.3 Residual/unmeasured confounding? 
(e.g. anticipated direction and magnitude of such biases, 
validation sub-study, use of validation and external data, 
analytical methods) 
 
 
 
9.5 
12.2 Does the protocol discuss study feasibility? 
(e.g. study size, anticipated exposure, duration of follow-up 
in a cohort study, patient recruitment) 
 
 
 
9.5 
Comments: 
 
 
Section 13: Ethical issues 
Yes 
No 
N/
A 
Section  
Number 
13.1 Have requirements of Ethics Committee/ 
Institutional Review Board been described? 
 
 
 
10.3 
13.2 Has any outcome of an ethical review procedure 
been addressed? 
 
 
 
10.3 

PPD
PPD
PPD

 
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Annex 3. Signature pages 
 
 

20Aug2018 
Title 
Protocol version and date 
IMP ACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
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REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase IV 
D non-PASS 
cg] PASS 
Joint PASS: 0 YES 
cg)NO 
EUPAS7187 
Therapeutic Radiopharmaceuticals (V 1 OXX03 ), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee 1; 51373 
Leverkusen; Ge1many 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned confirms that slhe agrees to conduct the study under the conditions 
described in this protocol. 
Date, Signature: 
t -AU-t,-
PPD
PPD
PPD
PPD

20 Aug 2018 
Title 
Protocol version and date 
IMP ACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
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REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase N 
D non-PASS 
Joint PASS: 
DYES 
EUPAS7187 
Therapeutic Radiopharmaceuticals (VI OXX03), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee I; 51373 
Leverkusen; Gennany 
USA: Bayer HealthCare Phmmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned confirms thats/he agrees to conduct the study under the conditions 
described in this protocol. 
. 
.0J -
- :NJ ( t 
Date, Signature: 
____ 
PPD
PPD
PPD

20 Aug 2018 
Title 
Protocol version and date 
IMPACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
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REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase IV 
D non-PASS 
Joint PASS: 0 YES 
EUPAS7187 
Therapeutic Radiopharmaceuticals (V l OXX03 ), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee l ; 51373 
Leverkusen; Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned confirms thats/he agrees to conduct the study under the conditions 
described in this protocol. 
Date, Signature: 
c,, ,g 
PPD
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20 Aug 2018 
Title 
Protocol version and date 
IMP ACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
16913 -REASSURE 
Version 5.0 
Page: 59 of72 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase IV 
D non-PASS 
[8J PASS 
Joint PASS: 
DYES 
EUPAS7187 
[8'.INO 
Therapeutic Radiopharmaceuticals (VlOXX03), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee 1; 51373 
Leverkusen; Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned confirms thats/he agrees to conduct the study under the conditions 
described in this protocol. 
nate, signature: 
2 7, 1 
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16913 - REASSURE 
20 Aug 2018 
Version 5.0 
Page: 60 of72 
Title 
Protocol version and date 
IMPACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase IV 
D non-PASS 
Joint PASS: 0 YES 
EUPAS7187 
Therapeutic Radiopharmaceuticals (VI OXX03), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee I; 51373 
Leverkusen; Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned confirms thats/he agrees to conduct the study under the conditions 
described in this protocol. 
Date, Signature: 
· 01{ l <-•IP 
PPD
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20 Aug2018 
Title 
Protocol version and date 
IMP ACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
16913 - REASSURE 
Version 5.0 
Page: 61 of 72 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase IV 
0 non-PASS 
rg) PASS 
Joint PASS: 0 YES 
i:gjNO 
EUPAS7187 
Therapeutic Radiopharmaceuticals (V 1 OXX03 ), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee 1; 51373 
Leverkusen; Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned confirms that slhe agrees to conduct the study under the conditions 
described in this protocol. 
Date, Signature: M 
l&{t 
PPD
PPD
PPD

20 Aug 2018 
Title 
Protocol version and date 
IMP ACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
16913 - REASSURE 
Version 5.0 
Page: 62 of 72 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in rnCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase IV 
D non-PASS 
k'.SI PASS 
Joint PASS: 
DYES 
EUPAS7187 
k:SI NO 
Therapeutic Radiopharmaceuticals (V10XX03), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee 1; 51373 
Leverkusen; Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned confirms thats/he agrees to conduct the study under the conditions 
described in this protocol. 
Date, signature: :20-A U ·o2o J,3 _
----
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20 Aug 2018 
Title 
Protocol version and date 
IMPACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
16913 - REASSURE 
Version 5.0 
Page: 63 of 72 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase IV 
D non-PASS 
PASS 
Joint PASS: 0 YES 
EUPAS7187 
Therapeutic Radiopharmaceuticals (V10XX03), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee 1; 51373 
Leverkusen; Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned corifirms thats/he agrees to conduct the study under the condUions 
described in this protocol. 
PPD
PPD
PPD

26 APR2018 
Title 
Protocol version and date 
IMP ACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
16913 - REASSURE 
Version 5.0 
Page: 64 of72 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 26 APR 2018 
16913 
Observational, Phase IV 
D non-PASS 
[gl PASS 
Joint PASS: 
DYES 
EUPAS7187 
[g]NO 
Therapeutic Radiopharmaceuticals (V10XX03), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee 1; 51373 
Leverkusen; Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
The undersigned confirms thats/he agrees to conduct the study under the conditions 
described in this protocol. 
PPD
PPD
PPD

20 Aug2018 
Title 
Protocol version and date 
IMP ACT study number 
Study type I Study phase 
EU PAS register number 
Active substance (medicinal 
product) 
Marketing authorization 
holder(s) 
Role 
Name 
16913 - REASSURE 
Version 5.0 
Page: 65 of72 
REASSURE - Radium-223 alpha Emitter Agent in non-
intervention Safety Study in mCRPC popUlation for 
long-teRm Evaluation 
5.0, 20 Aug 2018 
16913 
Observational, Phase IV 
D non-PASS 
Joint PASS: 
DYES 
EUPAS7187 
Therapeutic Radiopharmaceuticals (Vl OXX03 ), radium 
(223Ra) dichloride (Xofigo®) 
Ex-USA: Bayer AG, Kaiser-Wilhelm-Allee 1; 51373 
Leverkusen; Germany 
USA: Bayer HealthCare Pharmaceuticals Inc. Wayne, 
NJ, USA 
 
 
 
The undersigned coefzrms thats/he agrees to conduct the study under the conditions 
described in this protocol. 
Date, Signature: Olf-
.;io1g, 
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16913 - REASSURE 
20 Aug 2018 
Version 5.0 
 
Page:  66 of 72 
 
Annex 4. Description of Amendments 
 
Table 5: Description of Amendments 
AM01: 18 January 2016 
Protocol Section 
Description 
General 
General formatting, defining abbreviations and updating abbreviations list, 
correcting spelling, grammar, and terms for consistency was performed 
throughout. Changed terms from subject to patient, sponsor to initiator, 
and investigator to physician to comply with terminology convention for 
non-interventional studies. 
Header 
Changed logo and Bayer HealthCare to Bayer logo 
Title 
Corrected for consistency to include non-intervention throughout. 
Author 
Author changed from 
 to 
 
throughout 
Section 3: Responsible 
Parties 
Updated to indicate change of contacts: 
: from 
 to 
 
: from 
 to 
, 
and 
: from 
 to 
 
Section 4:  Abstract 
Added to Rationale and Background time to progression will be assessed 
and that the study was being conducted at the request of regulatory 
authorities.  Corrected for consistency with study design by removing 
“non-interventional” as the statement already includes observational. 
Added progression and treatment post progression to variables and data 
analysis. 
Section 6: Milestones  
Updated end of recruitment and added date of EU PAS registration. 
Section 7: Introduction:  
Background and 
Rationale 
Added missing reference for bone tissue homeostasis. Added text and 
reference for rationale of collecting timing of progression.  Updated 
ALSYMPCA data with text from updated Investigator’s Brochure.  
Section 9.3: Variables 
Added progression and definition of first progression. Added progression 
to Table 2 and corrected footnote a. 
Section 9.3.2: Variables 
to determine the 
secondary endpoint(s) 
Added that completion of BPI-SF questionnaire is voluntary. 
Section 9.3.5: Co-
Added clarification of study start. 
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AM01: 18 January 2016 
Protocol Section 
Description 
morbidities (medical 
history, concomitant 
diseases) 
Section 9.3.6: Prior and 
concomitant medications 
Added clarification of study start. 
Section 9.3.9.1: Baseline 
Reordered text for clarity and ensured all variables being assessed were 
captured and consistent with CRF and elsewhere in text. 
Section 9.3.9.2:  
Treatment Phase 
Added that data on progression and changes in anti-cancer therapy will be 
documented. Moved text for clarity and ensured all variables being 
assessed were captured and consistent with CRF and elsewhere in text. 
Section 9.3.9.3:  Follow-
up visit(s) 
Added that data on progression will be collected. Moved text for clarity 
and ensured all variables being assessed were captured and consistent with 
CRF and elsewhere in text. 
Section 9.3.11:  
Progression 
New section added to address time to progression and defining progression 
may be defined by the physician, including SSEs, PSA, RECIST 1.1, or 
other types of progression. Definition of progression by SSE and PSA 
added; use of PCWG 2 or 3 for other progression, specifically bone 
lesions. Defined what is not considered progression: second primary 
malignancies, tumor-related death, or death from any cause. 
Section 9.7.8:  Analysis 
of other data 
New section added to address time to progression, defining progression 
TTP as time interval from day of first dose to date of first progression, and 
how data will be analyzed (descriptive summaries of KM and KM curves). 
Second primary malignancies and death will not be counted in the analysis 
for progression. 
Section 9.7.11: Loss of 
follow-up 
Text deleted that was no longer applicable: 
“It is assumed that a loss-to follow-up rate of less than 10% for the US and 
less than 5% for Europe can be achieved.” 
“The designated CRO should be notified in case of the change of the 
treating physician and Radium-223 administering physician (if applicable) 
and all efforts to receive information of the new site/physician should be 
made.” 
Section 9.8.1 Data 
Quality 
Text added for Medical Review Plan to comply with updated protocol 
template. 
Section 11 Management 
and reporting of adverse 
events/adverse 
reactions’;  subsection 
Deleted “worsening of a sign or symptom of the condition under treatment 
or of a concomitant illness” as progression is not an adverse event in this 
study. Added text to this section to further clarify. 

 
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20 Aug 2018 
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AM01: 18 January 2016 
Protocol Section 
Description 
11.1: Definitions 
Section 11.2: Collection 
Text added reporting and recording requirements regarding pregnancy in a 
female partner of a study patient per applicable Bayer SOPs. 
Section 13: List of 
references 
New references added to support new text in introduction and rationale. 
Annex 1: List of stand-
alone documents 
Table 4: Amendment and Medical Review Plan added. 
Annex 3: Signature 
pages 
Title corrected; version and date updated; signatories updated as 
appropriate. 
Annex 4: Description of 
Amendments 
New annex added for amendment. 
 
 
AM02: 07 June 2018 
Protocol Section 
Description 
General 
Protocol was updated to reflect changes in timelines(actual), to adopt the 
most current template,  to add administrative changes and to remove 
inconsistencies. 
Enrollment was terminated in all countries except for Argentina, 
Colombia, and Mexico in Mar 2017. Global LPFV was changed to Q4 
2017 (31 Dec 2017) to allow for continued enrollment in Latin America 
only (regulatory obligation). 
Reporting of all bone fractures and bone associated events (e.g. 
osteoporosis) was added as either AE(s) or SAEs if the criteria of SAE 
were met, regardless of the investigator’s causality assessment, through 
the long-term follow-up. 
Additionally, the following was specified:  
Radium-223 dichloride should not be given concurrently with 
abiraterone plus prednisone/prednisolone. 
The option of starting a BHA should be considered, taking into 
consideration applicable guidelines. 
Title page 
Update of version and date, addition of EU PAS register number, study 
phase, change in name of study initiator, change in countries of study, 
change in author and MAH contact person 
Section 3: Responsible 
Updated to indicate change of contacts: 

 
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AM02: 07 June 2018 
Protocol Section 
Description 
Parties 
: from 
 to 
 
: from 
 to 
,  
: from 
 to 
 and 
 
: from 
 to 
 
: from 
 to 
 
: from 
 to 
 
: from 
 to 
 
and 
: from 
 
 to 
 
Section 4: Abstract 
Addition of study phase, update of version and date, change in author, 
addition of evaluation of bone fractures in the section on background and 
rationale, in the section on research question and objectives and in the 
section variables, change in countries of study and dates for study 
milestones (end of recruitment and data collection, final report of study 
results) 
Section 6: Milestones 
Change in dates for study milestones (end of recruitment and data 
collection, final report of study results) 
Section 8.1 Primary 
objective 
Correction of text by adding “serious” to “To assess the incidence of 
treatment-emergent serious adverse events (TESAEs)” 
Section 8.2 Secondary 
objectives 
Addition of “To assess the incidence of bone fractures and bone 
associated events (e.g. osteoporosis)” 
Section 9.1 
Addition of Latin America and country specifications (Argentina, 
Austria, Belgium, Canada, Colombia, Czech Republic, Denmark, 
France, Germany, Greece, Israel, Italy, Luxembourg, Mexico, 
Netherlands, Portugal, Spain, Sweden, United Kingdom, United States). 
Addition of “Radium-223 dichloride should not be given concurrently 
with abiraterone plus prednisone/prednisolone. The option of starting a 
bone health agent (BHA) including bisphosphonates or denosumab 
should be considered, taking into consideration applicable guidelines.” 
Section 9.1.2 Secondary 
Endpoints 
Addition of a secondary endpoint: 
• 
Bone fractures and bone associated events (e.g. osteoporosis), 
regardless of investigator assessment of causality, based on AEs. 
Section 9.2.4 
Update of the section according to current template and process. 
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AM02: 07 June 2018 
Protocol Section 
Description 
Withdrawal 
Section 9.3: Variables 
Update of footnotes to Table 2 to reflect collection of data for bone 
fracture and bone associated events 
Section 9.3.2: Variables 
to determine the 
secondary endpoint(s) 
Correction of description of censoring for overall survival to “Patients 
whose death is not confirmed at the time of data-cut will be censored at 
the last date known to be alive.” 
Addition of variable bone fracture and bone associated events 
Section 9.3.3: 
Demography 
“Sex” was deleted 
Section 9.3.6 Prior and 
concomitant medication 
Update of relevant prostate cancer therapy variables collected in the 
categories stated. 
Section 9.3.9.2 
Treatment phase 
Addition of reference to Section 9.3.2 
Section 9.3.9.3 Follow-
up visits 
Addition of reference to Section 9.3.2 
Addition of “email documentation reminder.” 
Section 9.3.11. 
Progression  
Updates of definitions 
Section 9.4.2 External 
reference secondary data 
sources  
Update of date on external sources 
Section 9.7.4 Analysis 
of primary outcome 
Deletion of definition of “number of patients at risk” 
Deletion of specification of sensitivity analysis. 
Deletion of “(up to 6 months after last administration of Radium-223 as 
AEs/SAEs)” concerning incidence of post treatment grade 3/4 
hematological toxicities. 
Section 9.7.5 Analysis 
of secondary data 
Addition of Section 9.7.5.3 Bone fractures and bone associated events 
“For bone fractures and bone associated events, the incidence proportion 
and EAIR will be summarized, along with the exact 95% CI. 
AEs will be summarized using the MedDRA and the CTCAE (Version 
4.03) coding system.  
AEs will be categorized and summarized according to relation, 
seriousness, CTCAE grade, discontinuation of therapy, action taken, and 
outcome.” 

 
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20 Aug 2018 
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AM02: 07 June 2018 
Protocol Section 
Description 
Section 9.7.6 
Comparison with 
external reference 
secondary data 
sources 
Deletion of “Upon the completion of the feasibility assessment for the 
selection of external secondary data source(s), separate individual study 
protocol(s) using external secondary data source(s) will be developed 
independently from the REASSURE protocol. This/these protocol(s) 
will include more details on the statistical analysis approach for 
comparison of data on second primary malignancies in mCRPC patients 
from the REASSURE study with the corresponding information from 
external secondary data sources. 
The proposed study(ies) will be performed and completed according the 
timelines that will be provided upon the completion of the feasibility 
assessment for the external secondary data source(s).” 
Section 9.7.7 Analysis 
of safety data 
Addition of “or secondary” 
Addition of “Analyses of further variables will be detailed in the SAP, as 
appropriate.“ 
Section 9.7.11 Loss to 
follow-up 
Updated text on loss to follow up 
Section 9.8.1 Data 
quality 
Deleted part of the text on monitoring 
Section 9.8.2 Quality 
review 
Updated text on quality review 
Section 10.2 Regulatory 
authority 
approvals/authorizations 
Updated based on new template and added text on GVP modules. 
Section 10.3 IEC and 
IRB 
Updated text on IEC/IRB approval 
Section 10.6 
Confidentiality 
Added text (on investigator maintaining patient records) from latest 
template 
Section 11.2 Collection 
Added text on the collection of AEs based on all bone fractures and bone 
associated events. 
Added text about “platelet count or white blood cell count (WBC) 
less”. 
Section 12 Plans for 
disseminating and 
communicating study 
results 
Addition of details on the EU PAS register and PSUR submission 

 
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AM02: 07 June 2018 
Protocol Section 
Description 
Annex 1: List of stand-
alone documents 
Table 4: Update of the documents, dates and document reference 
numbers. 
Annex 2: ENCePP 
checklist of study 
protocols 
Update of ENCePP checklist to revision 3, 01/07/2016 
Annex 3: Signature 
pages 
Title updated; version and date updated; EU PAS register number added, 
signatories updated as appropriate. 
Annex 4: Description of 
Amendments 
Annex for amendment updated with the specifications of Amendment 
02.