Conditions: Prostatic Neoplasms
Keywords: Phase III Radium-223 dichloride Abiraterone acetate Combination therapy Chemotherapy-naive Bone metastasis Castration-resistant prostate cancer (CRPC)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 806
Healthy volunteers: no

Brief summary:
To determine if the addition of radium-223 dichloride to standard treatment is able to prolong life and to delay events specific for prostate cancer which has spread to the bone, such as painful fractures or bone pain which needs to be treated with an X-ray machine.

Detailed description:
This study is a phase III multinational, multicenter,randomized, double blind, placebo controlled, study with a randomization allocation ratio of 1:1 (radium-223 dichloride plus abiraterone acetate plus prednisone/prednisolone: placebo plus abiraterone acetate plus prednisone/prednisolone). Until the final overall survival (OS) analysis, the study period consisted of screening / randomization, treatment, active follow-up with clinic visits, active follow-up without clinic visits, and longterm follow-up phases. Up until this point, subjects received study treatment (radium-223 dichloride or placebo in addition to abiraterone acetate plus prednisone / prednisolone for the first 6 cycles followed by abiraterone acetate plus prednisone / prednisolone thereafter) until an on-study SSE occurred (or other withdrawal criteria were met). After the final OS analysis (after implementation of Amendment 7), in order to reduce the burden to study subjects, evaluation of efficacy and exploratory endpoints will be discontinued, except for symptomatic skeletal event (SSE) and OS. Subjects who are discontinued from study treatment will initiate the long-term follow-up period; therefore, active follow-up periods will no longer be applicable. Subjects who are in active follow-up at the time of Amendment 7 is implemented should have the end of active follow-up completed (protocol driven decision) and should be directly transitioned into the extended safety follow-up study. Long term follow-up will continue until the subject dies, is lost to follow-up, withdraws informed consent, actively objects to collection of further data , or is transitioned to the extended safety follow-up study. Subjects will be followed for safety for up to 7 years, which eventually will be completed in this study or in the extended safety follow-up study.

Arms:
arm 1: Participants received 6 intravenous (IV) administrations of radium-223 dichloride 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update) body weight at intervals of 4 weeks, along with oral abiraterone acetate tablets 1000 milligrams (mg) every day plus prednisone/prednisolone 5 mg twice daily (abi/pred) for 6 cycles, followed by abi/pred until an on-study symptomatic skeletal event (SSE) occurred (or other withdrawal criteria were met) arm 2: Participants received 6 IV administrations of placebo matched to radium-223 dichloride at intervals of 4 weeks, along with abi/pred for 6 cycles, followed by abi/pred until an on-study SSE occurred (or other withdrawal criteria were met)

Interventions: intervention 1: Radium-223 dichloride (Xofigo, BAY88-8223) intervention 2: Matching placebo (normal saline) intervention 3: Abiraterone intervention 4: Prednisone/Prednisolone
Intervention descriptions: intervention 1: 50 kiloBecquerel per kilogram (kBq/kg) (55 kBq/kg after implementation of NIST update) body weight, intravenous injection (IV-slow bolus), every 4 weeks for 6 cycles intervention 2: Intravenous injection ( IV-slow bolus), every 4 weeks for 6 cycles intervention 3: 1000 mg once daily, oral, with best supportive care intervention 4: 5 mg twice daily, oral, with best supportive care

Protocol document:
Prot_002.pdf: 
 
Document Type: Study Protocol 
Official Title: 
A phase III randomized, double-blind, placebo-controlled trial of 
radium-223 dichloride in combination with abiraterone acetate 
and prednisone/prednisolone in the treatment of asymptomatic or 
mildly symptomatic chemotherapy-naïve subjects with bone 
predominant metastatic castration-resistant prostate cancer 
(CRPC) 
NCT Number: 
NCT02043678 
Document Date: 
08 FEB 2023 
 
 


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Cover Page of the Integrated Clinical Study Protocol 
A phase III randomized, double-blind, placebo-controlled trial of radium-223 dichloride 
in combination with abiraterone acetate and prednisone/prednisolone in the treatment 
of asymptomatic or mildly symptomatic chemotherapy-naïve subjects with bone 
predominant metastatic castration-resistant prostate cancer (CRPC) 
For this study, the protocol and subsequent protocol amendment were released as follows: 
• Original protocol, Version 1.0, dated 05 NOV 2013
• Amendment 1 (global amendment described in Section 13.1) forming integrated
protocol Version 2.0, dated 26 AUG 2014
• Amendment 2 (global amendment described in Section 13.2) forming integrated
protocol Version 3.0, dated 12 JUN 2015
• Amendment 3 (local for Brazil only), dated 10 JUN 2016
• Amendment 4 (global amendment described in Section 13.3) forming integrated
protocol Version 4.0, dated 13 SEP 2016
• Amendment 5 (local for Japan only), dated 21 SEP 2016
• Amendment 6 (global amendment described in Section 13.4) forming integrated
protocol Version 5.0, dated 03 APR 2018
• Amendment 7 (global amendment described in Section 13.6) forming integrated
protocol Version 6.0, dated 26 NOV 2019
• Amendment 8 (global amendment described in Section 13.6) forming integrated
protocol Version 7.0, dated 08 FEB 2023
This document integrates the original protocol and all global amendments. 


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Title page 
 
A phase III randomized, double-blind, placebo-controlled trial of radium-223 
dichloride in combination with abiraterone acetate and prednisone/prednisolone in the 
treatment of asymptomatic or mildly symptomatic chemotherapy-naïve subjects with 
bone predominant metastatic castration-resistant prostate cancer (CRPC) 
Short title:  Evaluation of Radium-223 dichloride in combination with Abiraterone in 
CRPC - ERA 223 
Test drug:  
BAY 88-8223 / Radium-223 dichloride and abiraterone and 
prednisone / prednisolone 
Study purpose: 
To compare the symptomatic skeletal event-free survival of subjects 
with asymptomatic or mildly symptomatic chemotherapy-naïve bone 
predominant metastatic castration-resistant prostate cancer treated with 
radium-223 dichloride or placebo, in combination with abiraterone and 
prednisone / prednisolone 
Clinical study phase: 
III 
Date: 
 08 FEB 2023 
EudraCT no.: 
2013-003438-33 
Version no.: 
7.0  
Study no.: 
BAY 88-8223 / 15396 
 
 
Sponsor: 
Bayer AG, D-51368 Leverkusen, Germany 
Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard,  
P.O. Box 915, Whippany, NJ 07981-0915, US  
Sponsor’s medical expert: 
 
  
Bayer AG  
Muellerstr. 178 
13342 Berlin, Germany  
  
The study will be conducted in compliance with the protocol, International Council on Harmonisation and 
Good Clinical Practice and any applicable regulatory requirements. 
Confidential 
The information provided in this document is strictly confidential and is intended solely for the guidance of the 
clinical investigation.  Reproduction or disclosure of this document - whether in part or in full - to parties not 
associated with the clinical investigation, or its use for any other purpose, without the prior written consent of 
the sponsor is not permitted. 
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. 
PPD
PPD
PPD


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Signature of the sponsor’s medically responsible person 
 
This document is electronically signed. The eSignature is archived in the trial master file 
(TMF) and can be provided upon request. 
 
The signatory agrees to the content of the final clinical study protocol as presented. 
 
Name: 
  
 
Role:   
 
 
Date: 
 
 
Signature: 
 
 
 
 
PPD
PPD


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Signature of principal investigator 
 
The signatory agrees to the content of the final clinical study protocol as presented. 
 
Name:  
Date: 
 
 
Signature:  
 
 
 
Signed copies of this signature page are stored in the sponsor’s study file and in the 
respective center’s Investigator Site file. 
 
 


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Synopsis 
Title 
A phase III randomized, double-blind, placebo-controlled trial of 
radium-223 dichloride in combination with abiraterone acetate and 
prednisone/prednisolone in the treatment of asymptomatic or mildly 
symptomatic chemotherapy-naïve subjects with bone predominant 
metastatic castration-resistant prostate cancer (CRPC) 
Short title 
Evaluation of Radium-223 dichloride in combination with 
Abiraterone in CRPC - ERA 223 
Clinical study phase 
Phase III 
Study objectives 
The primary objective is to compare, in subjects with asymptomatic 
or mildly symptomatic chemotherapy-naïve bone predominant 
metastatic castration-resistant prostate cancer (CRPC), the clinical 
benefit of radium-223 dichloride versus placebo in combination with 
abiraterone and prednisone / prednisolone, with the primary efficacy 
endpoint being: 
• Symptomatic skeletal event free survival (SSE-FS) 
The secondary objectives are to compare the radium-223 dichloride 
and placebo treatments to establish additional clinically relevant 
improvements in subjects with CRPC bone predominant metastasis 
using the variables below: 
• Overall survival (OS) 
• Time to opiate use for cancer pain 
• Time to pain progression 
• Time to cytotoxic chemotherapy 
• Radiological progression-free survival (rPFS) 
• Safety, acute and long-term, including new primary 
malignancies and hematopoietic reserve for tolerability of 
subsequent chemotherapy 
The study will also include the following exploratory endpoints: 
• Time to first on-study symptomatic skeletal event (SSE) 
• Percentage change in total alkaline phosphatase (ALP) from 
baseline 
• Time to ALP progression 
• Time to prostate specific antigen (PSA) progression 
• ALP response 
• PSA response 


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• Bone scan specific rPFS 
• Time to increase in physical symptoms of disease based on the 
functional assessment of cancer therapy / National 
Comprehensive Cancer Network prostate cancer symptom 
index 17 item questionnaire disease related symptoms - 
physical (FPSI-DRS-P) subscale score measured during the 
treatment period 
• Time to increase in physical symptoms of disease based on the 
FPSI-DRS-P subscale score measured during the period 
between start of treatment and end of active follow-up with 
clinic visits 
• Assessment of pharmacokinetics of abiraterone (see 
Section 7.4) 
• Resource utilization 
• Biomarker assessments 
An explorative objective is to evaluate the impact of baseline total 
body weight and ideal body weight on SSE-FS and adverse events 
(AEs). 
 
Note: Evaluation of efficacy and exploratory endpoints, except for 
SSE and OS, will be discontinued following the final OS analysis. 
Test drug 
BAY 88-8223, administered in combination with oral abiraterone 
acetate and prednisone / prednisolone 
Name of active 
ingredient 
Radium-223 dichloride 
Dose 
50 kBq/kg (55 kBq/kg after implementation of National Institute of 
Standards and Technology [NIST] update) body weight every 4 
weeks for 6 cycles 
Route of 
administration 
Intravenous (IV) injection (slow bolus)  


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Duration of 
treatment 
6 cycles  
Reference drug 
Matching placebo (normal saline), administered in combination with 
oral abiraterone acetate and prednisone / prednisolone 
Name of active 
ingredient 
Not applicable 
Dose 
Every 4 weeks for 6 cycles 
Route of 
administration 
IV injection (slow bolus) 
Duration of 
treatment 
6 cycles  
Background treatment All study subjects will receive treatment with oral abiraterone acetate 
(1000 mg once daily) and oral prednisone / prednisolone (5 mg twice 
daily), with best supportive care 
Indication 
Radium-223 dichloride in combination with abiraterone acetate and 
prednisone / prednisolone is indicated for the treatment of 
asymptomatic or mildly symptomatic chemotherapy-naïve subjects 
with bone predominant metastatic CRPC  
Diagnosis and main 
criteria for inclusion 
Subjects must meet the following criteria for inclusion in the study: 
1. Have provided written informed consent.  Subjects must be 
able to understand and be willing to sign the written informed 
consent form (ICF).  A signed, written ICF must be 
appropriately obtained prior to the conduct of the any 
trial-specific procedure. 
2. Histologically confirmed adenocarcinoma of the prostate.  
3. Male subjects of age ≥ 18 years.  The lower limit may be 
higher if legally required in the participating country. 
4. Prostate cancer progression documented by prostate specific 
antigen according to the Prostate Cancer Working Group 2 
criteria or radiological progression according to Response 
Evaluation Criteria in Solid Tumors, version 1.1. 
5. Two or more bone metastases on bone scan within 4 weeks 
prior to randomization with no lung, liver, other visceral, 
and / or brain metastasis. 
6. Asymptomatic or mildly symptomatic prostate cancer.  A 
worst pain score (WPS) of 0 on the Brief Pain 
Inventory-Short Form Question #3 (worst pain in last 


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24 hours) will be considered asymptomatic, and a WPS of 
1 to 3 will be considered mildly symptomatic.  This is to be 
assessed once during the screening period. 
7. Subjects who received combined androgen blockade with an 
anti-androgen must have shown PSA progression after 
discontinuing the anti-androgen prior to enrollment 
(≥ 4 weeks since last flutamide, ≥ 6 weeks since last 
bicalutamide or nilutamide).   
8. Maintenance of medical castration or surgical castration with 
testosterone less than 50 ng/dL (1.7 nmol/L).  If the subject is 
being treated with luteinizing-hormone-releasing hormone 
agonists or antagonists (subject who has not undergone 
orchiectomy), this therapy must have been initiated at least 4 
weeks prior to randomization and must be continued 
throughout the study. 
9. Eastern Cooperative Oncology Group Performance Status 0 
or 1 
10. Life expectancy ≥ 6 months 
11. Laboratory requirements: 
a. Absolute neutrophil count ≥ 1.5 x 109/L 
b. Platelet count ≥ 100 x 109/L 
c. Hemoglobin ≥ 9.0 g/dL (90 g/L; 5.6 mmol/L) 
d. Total bilirubin level ≤ 1.5 x institutional upper limit of 
the normal (except for subjects with documented 
Gilbert’s disease) 
e. Aspartate aminotransferase and alanine 
aminotransferase ≤ 2.5 x upper limit of the normal 
(ULN) 
f. Estimated glomerular filtration rate 
≥ 30 mL/min/1.73 m2 
g. International normalized ratio (INR) of prothrombin 
time (PT; PT-INR) and partial thromboplastin time 
(PTT) ≤ 1.5 x ULN.  Subjects treated with warfarin or 
heparin will be allowed to participate in the study if no 
underlying abnormality in coagulation parameters 
exists per prior history; weekly evaluation of 
PT-INR / PTT will be required until stability is 
achieved (as defined by local standard of care and 
based on prestudy PT-INR / PTT values) 
h. Serum albumin > 30 g/L 
i. Serum potassium ≥ 3.5 mmol/L 


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12. Able to swallow abiraterone and prednisone / prednisolone as 
whole tablets 
13. Subjects who have partners of childbearing potential must be 
willing to use a method of effective birth control during 
treatment and for 6 months following completion of treatment 
with radium-223 dichloride / placebo or 13 weeks of the last 
administration of abiraterone, whichever occurs later.  The 
contraception measures must be discussed with the subject.  
Suitable contraception could be, for example, an oral 
contraceptive combined with the use of condoms. 
Study design 
International, phase III, double-blind, randomized, 
placebo-controlled, parallel group study.  Randomization will be 
stratified by: 
• Geographical regions (Western Europe / North 
America / Australia versus Asia versus rest of world) 
• Concurrent use of denosumab or bisphosphonates or none 
• Total ALP < 90 U/L versus total ALP ≥ 90 U/L 
Methodology  
The study will comprise 4 periods: 
Screening period:  
All trial-related procedures and evaluations will only be performed 
after the subject has agreed to participate and has signed the ICF.  
The screening period will consist of multiple evaluations that will 
take place within 2 weeks (+ 7 days) prior to randomization to ensure 
that all eligibility criteria are met. 
Randomization:  
Once eligibility is confirmed, eligible subjects will be randomized 1:1 
to treatment with radium-223 dichloride plus abiraterone and 
prednisone / prednisolone (Arm A) or placebo (normal saline) plus 
abiraterone and prednisone / prednisolone (Arm B). 
Treatment period:  
Treatment consists of up to 6 cycles of radium-223 dichloride 
(Arm A) or placebo (Arm B) in combination with abiraterone plus 
prednisone / prednisolone followed by ongoing treatment for all 
subjects with abiraterone plus prednisone / prednisolone. 
• Up to 6 cycles of treatment in Arm A or Arm B:  Treatment 
consists of 6 IV administrations of radium-223 dichloride 
50 kBq/kg (55 kBq/kg after implementation of NIST update) 
body weight (Arm A) or placebo (Arm B) each separated by 
an interval of 4 weeks plus abiraterone acetate 1000 mg every 
day plus prednisone / prednisolone 5 mg twice daily. 


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• Ongoing treatment with abiraterone plus 
prednisone / prednisolone:  After the completion of treatment 
with radium-223 dichloride (Arm A) or placebo (Arm B), all 
randomized subjects will continue to receive abiraterone 
acetate 1000 mg every day plus prednisone / prednisolone 
5 mg twice daily until disease progression (or other 
withdrawal criteria are met). 
After the final OS analysis (Amendment 7): 
In order to reduce the burden to study subjects, evaluation of efficacy 
and exploratory endpoints will be discontinued, except for SSE and 
OS.  Discontinuation of abiraterone acetate plus 
prednisone/prednisolone will follow standard clinical practice; 
therefore, subjects who present disease progression defined as 
radiological progression (either by RECIST or bone progression by 
PCWG2), SSE, clinical progression (clinical deterioration or lack of 
clinical benefit, assessed by investigator) or initiation of a new anti-
cancer therapy, should be discontinued from study treatment.  After 
disease progression, abiraterone acetate will be considered standard 
of care (i.e., non-investigational medicinal product [non-IMP]) and 
will not be supplied as study medication. 
Subject management, unless defined otherwise in this protocol, will 
be in accordance with routine clinical practice, at the discretion of the 
investigator.  Subjects will be assessed every 4 weeks (± 7 days) for, 
safety and clinical progression, at each treatment visit and will be 
evaluated every 12 weeks (± 7 days) for radiological progression 
until disease progression occurs or subject is discontinued from study 
treatment, whichever occurs sooner. After discontinuation from study 
treatment, no additional radiological assessments will be required by 
protocol. 
The treatment period extends from the initiation of treatment until 
4 weeks after the last administration of abiraterone as IMP and 
prednisone / prednisolone.  Until then, subjects will be followed by a 
visit every 4 weeks ± 7 days.  Subjects with a platelet count or white 
blood cell count less than the lower limit of normal at 6 months will 
be followed additionally until resolution at a frequency based on local 
clinical practice. 
Active follow-up period with clinic visits and active follow-up 
period without clinic visits: 
After the final OS analysis (Amendment 7), subjects who are 
discontinued from study treatment will initiate the long-term follow-
up period; therefore, the active follow-up period will no longer be 
applicable. Subjects who are in active follow-up at the time 
Amendment 7 is implemented should have the end of active follow-
up completed (protocol driven decision) and should be directly 
transitioned into the extended safety follow-up study. 


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Long-term follow-up: 
After the final OS analysis (Amendment 7), subjects who are 
discontinued from study treatment will initiate the long-term follow-
up period in order to collect safety and OS information. The long-
term follow-up period will end when the subject has completed 
7 years of follow-up, dies, is lost to follow-up, withdraws informed 
consent, actively objects to collection of further data, or is 
transitioned to the extended safety follow-up study. During this 
period, subjects will be monitored via telephone call every 6 months 
for survival, treatment-related AEs and SAEs; and all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia; and primary 
bone cancer or any other new primary malignancy.  All bone 
fractures and bone associated events (e.g., osteoporosis) need to be 
reported as either AEs or SAEs if the criteria of SAE were met, 
regardless of the investigator’s causality assessment. In addition, 
subjects who receive cytotoxic chemotherapy will be followed up for 
the development of febrile neutropenia and hemorrhage during their 
chemotherapy treatment and for up to 6 months at a frequency based 
on local clinical practice. 
Once a separate extended safety follow-up protocol for the inclusion 
of subjects who received radium-223 dichloride / placebo in the 
course of Bayer sponsored clinical trials has been implemented, the 
study subjects who are in active follow-up or in long-term follow-up 
will be transitioned to a separate extended safety follow-up study  in 
order to complete 7 years of safety follow-up.  All efforts will be 
made to transition all subjects to the extended safety follow-up study.  
End of study (after implementation of Amendment 8): 
The end of the study (EOS) is defined as the date of the last subject 
last visit in the study. The EOS will occur at the time the last subject 
on study completes 7 years of follow-up unless the subject dies, 
withdraws consent or is lost to follow-up.  
Number of subjects 
800 in total (with 1:1 randomization) 
Primary variable 
SSE-FS 
Plan for statistical 
analysis 
The analysis of efficacy will be performed using the intent-to-treat 
population, defined as all subjects who are randomized.   
The overall 2-sided type I error rate for the analysis of primary 
efficacy endpoint, SSE-FS, is 0.05. 
Symptomatic skeletal event-free survival will be analyzed using a 
stratified log-rank test with the same stratification factors as for 
randomization.  The hazard ratio (HR; radium-223 
dichloride / placebo) will be computed together with the 2-sided 95% 
confidence interval (CI) using a stratified Cox regression model, with 


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the same stratification factors as strata in the model.  Kaplan-Meier 
estimates and plots for both treatment groups will be produced to 
accompany these analyses.  
Each of the secondary variables will be tested using an overall 
2-sided alpha of 0.025.   
The secondary efficacy time-to-event endpoints will be analyzed 
using a stratified log-rank test, with the factors from the 
randomization used for stratification.  An HR with a 95% CI from a 
stratified Cox proportional hazards model will also be provided.  
Kaplan-Meier plots will be produced to accompany these analyses. 
Data collected following the final OS analysis will be analyzed 
descriptively only. Analysis may be done through listings.  
Independent Data 
Monitoring Committee 
(IDMC) 
An IDMC will be established for this study to review accumulating 
efficacy and safety data at regular intervals throughout the study and 
monitor overall study conduct.  The IDMC will include experts in 
oncology, biostatistics, and safety who are not participating in this 
trial and do not have affiliation with the investigators or the sponsor 
or other significant conflicts of interest.  Their main objective will be 
to protect the interests of the subjects in the study and of those still to 
be entered.  They will do this by monitoring the study periodically for 
safety, study progress, and protocol compliance, as well as assessing 
the risk / benefit of the trial.   
Independent Data Monitoring Committee meetings will be held every 
6 months throughout the blinded trial phase.  Ad hoc meetings will 
take place if needed. 
Note: No longer applicable after primary analysis. 
 


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Table of contents 
Cover Page of the Integrated Clinical Study Protocol .................................................... 1 
Title page.............................................................................................................................. 2 
Signature of the sponsor’s medically responsible person ................................................ 3 
Signature of principal investigator .................................................................................... 4 
Synopsis ................................................................................................................................ 5 
Table of contents ............................................................................................................... 13 
Table of tables ................................................................................................................... 17 
Table of figures .................................................................................................................. 17 
List of abbreviations ......................................................................................................... 18 
Definitions of terms ........................................................................................................... 20 
1. 
Introduction ................................................................................................................ 21 
1.1 
Castrate resistant prostate cancer:  Disease and treatment ....................................... 21 
1.1.1 
Chemotherapies ..................................................................................................... 21 
1.1.2 
Secondary hormonal therapies .............................................................................. 22 
1.1.3 
Bone metastasis in castration-resistant prostate cancer ........................................ 23 
1.1.4 
Asymptomatic or mildly symptomatic patients with metastatic castration-resistant 
prostate cancer ....................................................................................................... 24 
1.2 
Study medications .................................................................................................... 24 
1.2.1 
Radium-223 dichloride .......................................................................................... 24 
1.2.1.1 
Drug development .............................................................................................. 24 
1.2.1.2 
Benefits and risks ............................................................................................... 25 
1.2.1.3 
Dosing rationale ................................................................................................. 26 
1.2.2 
Abiraterone acetate ................................................................................................ 26 
1.2.2.1 
Drug development .............................................................................................. 26 
1.2.2.2 
Abiraterone in chemotherapy-naïve castration-resistant prostate cancer .......... 27 
1.2.2.3 
Dosing rationale ................................................................................................. 28 
1.2.3 
Concurrent prednisone / prednisolone .................................................................. 29 
1.3 
Study rationale .......................................................................................................... 29 
1.4 
Primary efficacy endpoints ....................................................................................... 30 
2. 
Study objectives .......................................................................................................... 31 
3. 
Investigators and other study personnel .................................................................. 32 
3.1 
Independent Data Monitoring Committee ................................................................ 32 
3.2 
Independent radiological review .............................................................................. 33 
4. 
Study design................................................................................................................ 33 
4.1 
Design overview ....................................................................................................... 33 
4.1.1 
Study periods and duration .................................................................................... 33 
4.1.2 
Study endpoints ..................................................................................................... 36 
4.2 
Primary variables ...................................................................................................... 37 
4.3 
End of study .............................................................................................................. 37 
5. 
Study population ........................................................................................................ 37 


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5.1 
Eligibility .................................................................................................................. 37 
5.1.1 
Inclusion criteria .................................................................................................... 38 
5.1.2 
Exclusion criteria .................................................................................................. 39 
5.2 
Withdrawal of subjects from study ........................................................................... 41 
5.2.1 
Withdrawal ............................................................................................................ 41 
5.2.1.1 
Withdrawal from treatment period (collection of follow-up data) .................... 41 
5.2.1.2 
Withdrawal from treatment period and all follow-up ........................................ 42 
5.2.2 
Replacement .......................................................................................................... 42 
5.3 
Subject identification ................................................................................................ 42 
6. 
Treatments .................................................................................................................. 42 
6.1 
Treatments to be administered .................................................................................. 42 
6.2 
Identity of study treatment ........................................................................................ 43 
6.2.1 
Study medication supply and packaging ............................................................... 43 
6.2.1.1 
Radium-223 dichloride ...................................................................................... 43 
6.2.1.2 
Saline.................................................................................................................. 44 
6.2.1.3 
Abiraterone acetate ............................................................................................ 44 
6.2.1.4 
Prednisone / prednisolone .................................................................................. 44 
6.3 
Treatment assignment ............................................................................................... 44 
6.4 
Dosage and administration ....................................................................................... 45 
6.4.1 
Radium-223 dichloride dose calibration ............................................................... 46 
6.4.2 
Radium-223 dichloride dose ordering and handling ............................................. 46 
6.4.3 
Radium-223 dose calculation ................................................................................ 47 
6.4.4 
Study drug dose preparation .................................................................................. 48 
6.4.5 
Dose adjustments for study drug-related adverse events ...................................... 49 
6.4.6 
Dose adjustments, delays, and treatment discontinuations ................................... 49 
6.4.6.1 
Radium-223 dichloride / placebo ....................................................................... 49 
6.4.6.2 
Abiraterone ........................................................................................................ 50 
6.4.7 
Supportive care guidelines .................................................................................... 54 
6.5 
Blinding .................................................................................................................... 54 
6.6 
Drug logistics and accountability ............................................................................. 55 
6.7 
Treatment compliance .............................................................................................. 56 
6.8 
Post-study treatment therapy .................................................................................... 57 
6.9 
Prior and concomitant therapy .................................................................................. 57 
6.9.1 
Prohibited concomitant therapy ............................................................................ 57 
6.9.2 
Permitted concomitant therapy ............................................................................. 59 
7. 
Procedures and variables .......................................................................................... 59 
7.1 
Schedule of procedures ............................................................................................. 59 
7.1.1 
Tabulated overview ............................................................................................... 60 
7.1.2 
Timing of assessments .......................................................................................... 67 
7.1.2.1 
Screening period (Visit 1) .................................................................................. 67 
7.1.2.2 
Randomization ................................................................................................... 69 
7.1.2.3 
Treatment period ................................................................................................ 69 
7.1.2.4 
Active follow-up ................................................................................................ 75 
7.1.2.5 
Long-term follow-up .......................................................................................... 77 
7.1.2.6 
End of study ....................................................................................................... 79 
7.2 
Population characteristics ......................................................................................... 79 
7.2.1 
Demographic ......................................................................................................... 79 


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7.2.2 
Medical history ...................................................................................................... 79 
7.2.3 
Other baseline characteristics ................................................................................ 79 
7.3 
Efficacy ..................................................................................................................... 80 
7.3.1 
Efficacy variables .................................................................................................. 80 
7.3.2 
Definition of efficacy variables ............................................................................. 81 
7.3.2.1 
Primary endpoint ................................................................................................ 81 
7.3.2.2 
Secondary efficacy endpoints ............................................................................ 81 
7.3.2.3 
Exploratory efficacy endpoints .......................................................................... 83 
7.4 
Pharmacokinetics (selected sites only) ..................................................................... 86 
7.4.1 
Drug measurement ................................................................................................ 86 
7.4.2 
Pharmacokinetic evaluation .................................................................................. 86 
7.5 
Safety ........................................................................................................................ 87 
7.5.1 
Adverse events ...................................................................................................... 87 
7.5.1.1 
Definitions.......................................................................................................... 87 
7.5.1.2 
Classifications for adverse event assessment ..................................................... 89 
7.5.1.3 
Assessments and documentation of adverse events ........................................... 91 
7.5.1.4 
Reporting of serious adverse events ................................................................... 91 
7.5.1.5 
Expected adverse events and suspected unexpected adverse reactions ............. 93 
7.5.2 
Pregnancies ........................................................................................................... 93 
7.5.3 
Symptomatic skeletal events ................................................................................. 93 
7.6 
Other procedures and variables ................................................................................ 93 
7.6.1 
Self-reported health status ..................................................................................... 93 
7.6.2 
Resource utilization ............................................................................................... 94 
7.6.3 
Biomarker assessments ......................................................................................... 94 
7.6.3.1 
Urine, serum, and plasma based biomarker analysis ......................................... 95 
7.6.3.2 
Tumor based biomarker analysis ....................................................................... 95 
7.7 
Appropriateness of procedures / measurements ....................................................... 96 
8. 
Statistical methods and determination of sample size ............................................ 96 
8.1 
General considerations ............................................................................................. 96 
8.2 
Analysis sets ............................................................................................................. 96 
8.3 
Efficacy variables ..................................................................................................... 96 
8.4 
Statistical and analytical plans .................................................................................. 97 
8.4.1 
Primary efficacy analysis ...................................................................................... 97 
8.4.2 
Secondary efficacy analysis .................................................................................. 97 
8.4.3 
Safety analysis ....................................................................................................... 97 
8.4.4 
Pharmacokinetic data ............................................................................................ 97 
8.5 
Planned interim analyses .......................................................................................... 98 
8.6 
Determination of sample size ................................................................................... 98 
9. 
Data handling and quality assurance ....................................................................... 99 
9.1 
Data recording .......................................................................................................... 99 
9.2 
Monitoring ................................................................................................................ 99 
9.3 
Data processing ...................................................................................................... 100 
9.4 
Audit and inspection ............................................................................................... 100 
9.5 
Archiving ................................................................................................................ 100 
10. Premature termination of the study ....................................................................... 101 
11. Ethical and legal aspects .......................................................................................... 102 


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11.1 Ethical and legal conduct of the study .................................................................... 102 
11.2 Subject information and consent ............................................................................ 102 
11.3 Publication policy ................................................................................................... 103 
11.4 Compensation for health damage of subjects / insurance ...................................... 104 
11.5 Confidentiality ........................................................................................................ 104 
12. Reference list ............................................................................................................ 104 
13. Protocol amendments .............................................................................................. 109 
13.1 Amendment 1 ......................................................................................................... 109 
13.1.1 Overview of changes ........................................................................................... 111 
13.1.2 Changes to the protocol text ................................................................................ 126 
13.2 Amendment 2 ......................................................................................................... 126 
13.2.1 Overview of changes ........................................................................................... 126 
13.2.2 Changes to the protocol text ................................................................................ 129 
13.3 Amendment 4 ......................................................................................................... 129 
13.3.1 Overview of changes ........................................................................................... 130 
13.3.2 Changes to the protocol text ................................................................................ 133 
13.4 Amendment 6 ......................................................................................................... 133 
13.4.1 Overview of changes ........................................................................................... 133 
13.4.1.1 Modification 1 .................................................................................................. 134 
13.4.1.2 Modification 2 .................................................................................................. 134 
13.4.1.3 Modification 3 .................................................................................................. 135 
13.4.1.4 Modification 4 .................................................................................................. 135 
13.4.1.5 Minor clarifications .......................................................................................... 136 
13.4.2 Changes to the protocol text ................................................................................ 136 
13.5 Amendment 7 ......................................................................................................... 136 
13.5.1 Overview of changes ........................................................................................... 136 
13.5.2 Changes to the protocol text ................................................................................ 139 
13.6 Amendment 8 ......................................................................................................... 139 
13.6.1 Overview of changes ........................................................................................... 139 
13.6.2 Changes to the protocol text ................................................................................ 140 
14. Appendices ................................................................................................................ 141 
14.1 National Cancer Institute-Common Terminology Criteria, version 4.03 ............... 141 
14.2 Prostate Cancer Working Group 2 Criteria ............................................................ 141 
14.3 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ............................... 142 
14.4 Calculation for glomerular filtration rate ............................................................... 144 
14.5 New York Heart Association functional classification .......................................... 145 
14.6 ECOG performance status ...................................................................................... 146 
14.7 NCCN-FACT FPSI-17 ........................................................................................... 147 
14.8 EQ-5D ..................................................................................................................... 148 
14.9 BPI-SF .................................................................................................................... 151 
14.10 Resource utilization questionnaire ......................................................................... 153 
 


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Table of tables 
Table 6–1:  Management of hypokalemia ............................................................................... 51 
Table 7–1:  Schedule of assessments ....................................................................................... 61 
Table 14–1:  Overall time point response .............................................................................. 142 
Table 14–2:  Modified RECIST 1.1 criteria .......................................................................... 143 
 
 
Table of figures 
Figure 1–1:  The enzyme complexes inhibited by abiraterone ................................................ 27 
Figure 1–2:  Pro-drug abiraterone acetate is converted to abiraterone after absorption .......... 27 
 


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List of abbreviations 
 
AAWD 
Anti-androgen withdrawal 
abi+pred 
Abiraterone plus prednisone / prednisolone 
ACTH 
Adrenocorticotropic hormone 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALSYMPCA 
Alpharadin in Symptomatic Prostate Cancer 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Androgen receptor 
AST 
Aspartate aminotransferase 
BHA 
Bone health agent 
bid 
Twice daily (bis in die) 
BPI-SF 
Brief Pain Inventory-Short Form  
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
Cl2 
Dichloride 
CRO 
Contract research organization 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events; version 4.03 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DES 
Diethylstilbestrol 
DK 
Decay correction factor 
DNA  
Deoxyribonucleic acid 
EBRT 
External beam radiotherapy 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EOS 
End of study 
EOT 
End of treatment 
ePRO 
Electronic patient-reported outcome 
EQ-5D 
European Quality of Life-5 Dimensions 
EQ-VAS 
European Quality–Visual Analogue Scale 
ERA 223 
Evaluation of Radium-223 dichloride in combination with Abiraterone 
in CRPC 
EU 
European Union 
FDA 
Food and Drug Administration 
FFPE  
Formalin-fixed, paraffin-embedded 
FPSI-DRS-P 
NCCN-FACT FPSI-17 disease related symptoms - physical 
FU 
Follow-up 


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G-CSF 
Granulocyte-colony stimulating factor 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GM-CSF 
Granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICSR 
Individual case safety report 
ID 
Identification number 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee  
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IXRS 
Interactive voice / web response system 
K+ 
Potassium 
LDH 
Lactate dehydrogenase 
LET 
Linear energy transfer 
LHRH 
Luteinizing hormone-releasing hormone; also known as 
gonadotropin-releasing hormone (GnRH) 
LLOQ 
Lower limit of quantification 
LSLV 
Last subject last visit 
LT FU 
Long-term follow-up 
miRNA 
Micro-ribonucleic acid 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
MUGA 
Multi-gated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCCN-FACT 
FPSI-17 
Functional assessment of cancer therapy / National Comprehensive 
Cancer Network prostate cancer symptom index 17 item questionnaire 
NCI 
National Cancer Institute 
NF-κB 
Nuclear factor kappa-B 
NIST 
National Institute of Standards and Technology 
NYHA 
New York Heart Association 
OS 
Overall survival 
PCWG2 
Prostate Cancer Working Group 2 
PD 
Progressive disease 
PK 
Pharmacokinetics 
PLC 
Placebo 
PLT 
Platelet count 
po 
Oral (per os) 
PRD 
Patient ready dose 
PS 
Performance status 


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PSA 
Prostate specific antigen 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
q 
Every 
qd 
Every day (quaque die) 
Ra-223 
Radium-223 
RANKL 
Receptor activator of NF-κB ligand 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiological progression-free survival 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SPECT 
Single photon emission tomography 
SRE 
Skeletal-related event 
SSE 
Symptomatic skeletal event 
SSE-FS 
Symptomatic skeletal event-free survival 
SUSAR 
Suspected unexpected serious adverse reaction 
tx 
Treatment 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
W/O 
Without 
WPS 
Worst pain score 
 
Definitions of terms 
Radium-223 
dichloride  
The investigational product, a targeted alpha particle emitting 
radiopharmaceutical, is a ready-to-use solution for intravenous injection 
containing the drug substance radium-223 dichloride.  The active moiety 
is the alpha particle emitting nuclide radium-223, present as a divalent 
cation (223Ra2+). 
Dose  
Doses are given as kiloBecquerel (kBq) per kilogram body weight, with 
the corresponding dose given in millicurie (mCi) per kilogram in 
parenthesis.  The term “dose” is used to describe the quantity of 
radioactivity from radium-223 administered. 
Bone scan 
Whole body technetium-99m bone scan 
 


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1. 
Introduction 
1.1 
Castrate resistant prostate cancer:  Disease and treatment 
Prostate cancer has become an increasingly important health issue globally.  Prostate cancer 
is the fifth most common tumor type worldwide, with 679,060 men diagnosed each year,(1) 
and is one of the leading causes of cancer-related morbidity and death.(2) 
Prostate cancer is hormone sensitive at the time of initial diagnosis.  Although most patients 
with advanced metastatic disease initially respond to conventional androgen deprivation 
therapy (ADT) with medical (3) or surgical (4) castration, the median duration of disease 
control has been 13 to 22 months and overall survival (OS) 28 to 36 months.(5)  After 
progression to castration-resistant disease, close to 90% of those men already have bone 
metastases, and all their related undesirable effects, such as pain and deterioration of 
health-related quality of life (HRQoL).  Patients with metastatic castration-resistant prostate 
cancer (CRPC) have a very limited life expectancy and most often die of their prostate 
cancer. 
1.1.1 
Chemotherapies 
Several agents have been approved as palliative therapy for prostate cancer.  Estramustine 
was approved in the 1970s; however, in a randomized study where OS was compared, 
diethylstilbestrol (DES), a hormonal agent, was found to be superior to estramustine.(6)  In 
1996, mitoxantrone and prednisone were approved in the United States (US) for palliation of 
pain and improvement in HRQoL in a randomized study with prednisone as control.(7)  
Docetaxel was the first agent that has demonstrated a survival benefit in CRPC.  In the 
TAX-327 study, a 3-weekly docetaxel regimen had a median OS of 18.9 months 
(95% confidence interval [CI] 17.0 to 21.2) compared with the mitoxantrone control arm of 
16.5 months (95% CI, 14.4 to 18.6 months).  The hazard ratio (HR) for death was 0.76 
(95% CI, 0.62 to 0.94, p = 0.009) in the docetaxel regimen as compared with control.(8)  
Results from the Southwest Oncology Group Study 99-16 in 770 men (3-weekly 
docetaxel + estramustine + dexamethasone versus mitoxantrone + prednisone) demonstrated 
a median OS of 17.5 months versus 15.6 months, respectively, p = 0.02 and were consistent 
with the TAX-327 data.(8,9)  The results of these 2 studies established docetaxel as the new 
standard agent for first-line treatment of CRPC, and the toxicity of this agent was considered 
acceptable. 
Cabazitaxel, a novel member of the taxane class of anti-microtubule agents, demonstrated 
effectiveness in preclinical models that were resistant to paclitaxel and docetaxel.(10,11)  
Furthermore, cabazitaxel is able to cross the blood-brain barrier, a potential advantage in the 
treatment of some malignancies.(12)  In a phase III clinical trial that was launched with the 
aim of comparing cabazitaxel to mitoxantrone in docetaxel-refractory CRPC,(13) 
755 patients were treated with prednisone (10 mg daily) and randomized to receive either 
cabazitaxel (25 mg/m2) or mitoxantrone (12 mg/m2) every 3 weeks, with OS as the primary 
endpoint.  The median OS was 15.1 months in the cabazitaxel group and 12.7 months in the 
mitoxantrone group (HR = 0.70; p < 0.0001).  Cabazitaxel was associated with a higher 
incidence of adverse events (AEs) than mitoxantrone.  The most common toxicities 
associated with cabazitaxel were neutropenia, anemia, and diarrhea.  Of note, peripheral 
neuropathy was uncommon and typically mild or moderate in severity.  The results of this 


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phase III clinical trial led to the approval of cabazitaxel for the second-line treatment of 
CRPC in many countries. 
1.1.2 
Secondary hormonal therapies 
Secondary hormonal therapies in prostate cancer include anti-androgens, ketoconazole or 
abiraterone acetate, steroids, DES, or other estrogens based on the National Comprehensive 
Cancer Network (NCCN) guideline, version 3.(14) 
Ketoconazole inhibits several adrenal enzymes required for steroid biosynthesis.  Its efficacy 
in prostate cancer in terms of prostate specific antigen (PSA) response is comparable to that 
of aminoglutethimide.  Pilot studies in patients after failure of combined androgen blockade 
where ketoconazole was given simultaneously with anti-androgen withdrawal (AAWD) 
showed that 55% of patients achieved a 50% PSA decline.(15)  When administered after 
AAWD, 36% to 62.5% of patients had a 50% PSA decline.(16,17)  In a phase III study 
conducted by the Cancer and Leukemia Group B, the PSA response rate was 27% with a 
median duration of response of 9 months in the group of patients randomized to the 
combination arm of AAWD and ketoconazole plus hydrocortisone versus the AAWD alone 
arm.  Objective responses were observed in 2% of patients treated with AAWD alone 
compared to 20% in patients treated with AAWD / ketoconazole (p = 0.02).  The median time 
to PSA progression was 8.6 months in patients treated with simultaneous AAWD and 
ketoconazole while it was only 5.9 months with AAWD alone.  There was no difference in 
survival.(18)  However, ketoconazole inhibits cytochrome P450 (CYP) 3A4 with substantial 
risk of drug-drug interactions, such as warfarin and statins,(19) and it is often poorly tolerated 
by patients, with commonly occurring side effects including diarrhea, nausea, vomiting, and 
depression.(16-18)  Ketoconazole is not approved for the treatment of CRPC. 
Glucocorticoids appear to possess both hormonal and direct anti-tumor effects in prostate 
cancer.  Patients with CRPC may still have hormone-sensitive disease that is stimulated by 
weak androgens of adrenal origin, and these androgens are suppressed by prednisone through 
its negative feedback on secretion of adrenocorticotropic hormone (ACTH).  Tannock et al. 
have demonstrated that low-dose prednisone treatment (7.5 to 10 mg daily) led to a decrease 
in the concentration of serum testosterone in 7 of 9 patients where it was not initially 
suppressed below 2.0 nmol/mL, and caused a decrease in serum levels of androstenedione 
and dehydroepiandrosterone sulfate in more than 50% of patients.(20) These changes were 
associated with symptomatic and clinical improvement.  Glucocorticoids may also have 
direct inhibitory effects on prostate cancer cells through enhanced growth inhibitory 
transforming growth factor beta-1 signaling and suppression of the transcriptional activities 
of nuclear factor kappa-B (NF-κB).(21,22). 
Prednisone, dexamethasone, and hydrocortisone have been frequently administered as 
standard of care in advanced prostate cancer because of their modest anti-tumor activity and 
palliative effects on disease.  Two prospective phase III studies have documented the safety 
profile and palliative benefit of prednisone.  Prednisone 7.5 to 10 mg daily was examined 
among 81 patients in one arm of a phase III trial, with 22% of patients achieving a 50% PSA 
decline and a median time to progression of 4.0 months.(23)  Likewise, in a randomized 
study control arm where 201 patients were treated with prednisone 5 mg twice daily, a PSA 
decline of ≥ 50% was observed in 21% of patients.(24)  Significant improvements in pain, 
HRQoL, and fatigue were also reported.  Other glucocorticoids have similar activity in 
advanced prostate cancer. 


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Prostate cancer normally expresses estrogen receptors, and estrogenic compounds have been 
used for the treatment of CRPC.  The most commonly used estrogen is DES.(25-27) 
Although estrogens remain an option for the secondary hormonal treatment of CRPC, their 
use is limited by concerns regarding cardiovascular toxicity.(28) 
1.1.3 
Bone metastasis in castration-resistant prostate cancer 
The most common site of cancer spread in men with CRPC is bone.  Development of bone 
metastases is a major problem in prostate cancer and is a serious threat to a patient’s survival 
and HRQoL.  Untreated patients face severe morbidity, including bone pain, bone fracture, 
compression of the spinal cord, and hematological consequences of bone marrow 
involvement.  
Skeletal homeostasis is carried out by continuous destruction and rebuilding of skeletal 
tissue.  There are several potential explanations for the marked predisposition of prostate 
cancer to metastasize preferentially to bones.(29)  Both osteoblasts and osteoclasts appear to 
play a critical role in the interactions between prostate cancer cells and bone, and the receptor 
activator of NF-κB ligand (RANKL) is a key element in osteoclastogenesis, bone resorption, 
and chemo-attraction of tumor cells.(30)  The prominent role of bone metastases in the 
natural history of metastatic prostate cancer has prompted investigators to target this site of 
metastasis in hopes of palliating symptoms and prolonging survival through the use of 
androgen ablation, bisphosphonates, radiopharmaceuticals, focal radiation, chemotherapy, 
and targeted agents.(29) 
Unfortunately, therapeutic options at this stage of illness are still limited.  
Zoledronic acid, a bisphosphonate, has been shown to delay and reduce skeletal-related 
events (SREs) in patients with CRPC (31) by inhibiting osteoclast mediated bone resorption 
in this population; however, these results may not apply to other bisphosphonates (e.g., 
pamidronate results were not positive in the same setting).  None of these agents improved 
the overall or prostate cancer-specific survival of patients with CRPC. 
More recently, denosumab, a monoclonal antibody that binds RANKL, has been found to be 
more effective than zoledronic acid as measured by the time to first and subsequent on-study 
SREs in patients with CRPC.  The median time to the first on-study SRE was 20.7 months for 
the denosumab group compared with 17.1 months for the zoledronic acid group (HR = 0.82; 
95% CI, 0.71 to 0.95; p = 0.008 for superiority).(32)  Denosumab was approved for the 
treatment of patients with metastatic solid tumors in bone by the US Food and Drug 
Administration (FDA) and the European Commission in 2010. 
Bone-seeking radionuclides have been developed for palliation of bone pain from 
metastases.(33) Metastron (strontium-89) and Quadramet (samarium-153 EDTMP) (34) have 
been approved in several countries.  The bone-seeking nature of these agents results in direct 
delivery of beta radiation to the sites of disease.  Due to the long range of the beta particles 
from these radioisotopes, the major dose-limiting factor with this treatment modality is 
toxicity to the bone marrow cells, limiting the use of these agents to pain palliation only as 
they have not demonstrated an OS benefit.  This toxicity has seriously limited their clinical 
use. 


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1.1.4 
Asymptomatic or mildly symptomatic patients with metastatic 
castration-resistant prostate cancer 
Approximately 50% of patients with metastatic prostate cancer will have no noticeable 
symptoms related to the tumor.(35)  Cytotoxic chemotherapy (docetaxel or mitoxantrone) is 
ordinarily reserved for patients with symptomatic or rapidly progressive cancer.(36)  The 
American Society of Clinical Oncology / Cancer Care of Ontario and European Association 
of Urology guidelines for the cytotoxic treatment of CRPC (28,37) emphasize the need to 
individualize the timing of non-hormonal therapy for prostate cancer and consider routine 
docetaxel questionable in men who have metastatic disease but lack symptoms.  Similarly, 
the current European Society of Medical Oncology guidelines (38) for metastatic prostate 
cancer recommend that patients with castrate-resistant disease should receive second and 
possibly third-line hormonal therapies, while chemotherapy with docetaxel given every 
3 weeks should be considered for patients with CRPC who are symptomatic.(38) 
Patients with metastatic CRPC who are not good candidates for immediate chemotherapy 
may still benefit from alternate therapies since they develop symptomatic disease progression 
in a short period of time. 
Abiraterone acetate, a pro-drug of abiraterone and a selective inhibitor of androgen 
biosynthesis that potently blocks CYP17, has been approved for the treatment of metastatic 
CRPC in patients who have failed treatment with docetaxel.  Recently, this agent in 
combination with prednisone / prednisolone was shown to significantly delay disease 
progression, when compared to placebo in combination with prednisone / prednisolone 
(HR = 0.43; p-value = 0.0001).(39)  As a result, abiraterone plus prednisone / prednisolone 
was approved by the US FDA and the European Commission as treatment for patients with 
chemotherapy-naïve metastatic CRPC.  Despite this advance in treatment, skeletal events 
remain a therapeutic challenge; therefore, the combination of abiraterone and 
prednisone / prednisolone with bone-targeted therapies may further improve clinical benefit. 
1.2 
Study medications 
1.2.1 
Radium-223 dichloride 
1.2.1.1 
Drug development 
Radium-223 dichloride solution for injection is a novel alpha particle emitting 
radiopharmaceutical.  The bone-targeting property of radium-223 is similar to that of other 
earth alkaline elements, like calcium or strontium-89.  However, the radiation characteristics 
of an alpha particle emitting radionuclide appear to be more advantageous than of a 
beta-emitting radionuclide.  Radium-223, with a physical half-life of 11.4 days, emits high 
linear energy transfer (LET) alpha radiation, with a range limited to less than 
100 micrometers.  The high LET of alpha emitters (80 keV/micrometer) leads to a high 
frequency of double-strand deoxyribonucleic acid (DNA) breaks in adjacent cells, resulting in 
an anti-tumor effect on bone metastases.  The alpha particle range from radium-223 
dichloride is less than 100 micrometers (less than 10 cell diameters) which limits damage to 
the surrounding normal tissue. 
Biodistribution studies have shown that radium-223 is selectively concentrated in bone 
compared to soft tissues, and that radium-223 is retained in the bone matrix.(40,41) Due to 
increased bone metabolism in skeletal metastases, preferential uptake in these lesions 


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compared to normal bone is observed.  A significant radium-223 anti-tumor effect has been 
demonstrated in an experimental skeletal metastases model in nude rats.(41) 
The clinical development of radium-223 dichloride was initiated in August 2001.  A phase I 
clinical study in patients with skeletal metastases from breast and prostate cancer was 
performed in order to evaluate whether the product could be administered safely at 
therapeutically relevant doses.  A total of 31 patients were enrolled.  Twenty-five patients 
received a single intravenous (IV) injection in the dose escalating part of the study, with 
5 patients at each dose level of 46, 93, 163, 213, and 250 kBq/kg body weight radium-223 
dichloride.  The results of this phase I study were encouraging (low toxicity, significant pain 
relief, and decreased serum alkaline phosphatase [ALP]); thus, a phase II trial (BC1-02 study) 
for CRPC was conducted,(40) where patients received multiple doses of either 50 kBq/kg 
body weight radium-223 dichloride or saline 4 times at 4-week intervals.  In both studies, the 
results showed modest dose-dependent reversible hematological toxicity.  No significant 
deleterious changes in chemistry parameters were seen, and the most frequent AE was 
transient diarrhea, which responded well to medication.  In terms of efficacy, the BC1-02 
phase II results showed a significant improvement in serum bone markers, i.e., bone ALP (a 
primary efficacy endpoint), and perhaps more importantly, a delayed time to PSA 
progression.  Median OS at 2 years was 65.3 weeks for radium-223 dichloride and 
46.3 weeks for placebo (HR = 2.1; p = 0.017 based on an intent-to-treat [ITT] population and 
adjusting for baseline covariates). 
Following the positive results of the phase II trial, the phase III, double-blind, randomized, 
BC1-06, ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) trial was started in 
2008.  A total of 922 patients with CRPC and symptomatic bone metastases were randomized 
to receive 6 injections of radium-223 dichloride (50 kBq/kg IV) or matching placebo every 
4 weeks.  Based on data of an interim analysis (n = 809), the study was unblinded in 
June 2011, since radium-223 dichloride significantly improved OS, compared to placebo (the 
median OS was 14.0 versus 11.2 months, respectively; HR = 0.695; p = 0.00185).  
Symptomatic skeletal events (SSEs) were lower in the radium-223 dichloride 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 subjects who received radium-223 
dichloride versus 94% in the placebo arm (Grade 3/4 AEs were described for 51% and 59%, 
respectively).  The updated analysis (performed in June 2012) also showed that radium-223 
dichloride significantly improved OS compared to placebo (median OS 14.9 versus 
11.3 months, respectively; p = 0.00007; HR = 0.695).(42) 
Further details can be found in the investigator’s brochure (IB), which contains 
comprehensive information on the study drug. 
1.2.1.2 
Benefits and risks 
Anticipated benefits of treatment with radium-223 dichloride include prolongation of OS, 
delay of SSEs, and anti-tumor efficacy measured by PSA response, palliation of bone pain, 
and improvement in quality of life. 
The risk profile attributed to radium-223 dichloride is favorable compared with available 
products for the treatment of CRPC.  The anticipated risks attributed to radium-223 
dichloride include the following AEs:  gastrointestinal (constipation, transient but treatable 


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diarrhea, nausea, and vomiting); hematological (transient reduction in neutrophil count, mild 
to moderate myelosuppression, low grade thrombocytopenia); and, because of its radioactive 
nature, it cannot be excluded that radium-223 dichloride may, in the longer term, induce other 
primary cancers and bone marrow changes. 
1.2.1.3 
Dosing rationale 
The proposed dosing regimen in this phase III trial is 50 kBq/kg (55 kBq/kg after 
implementation of National Institute of Standards and Technology [NIST] update) body 
weight every 4 weeks for a 6-month treatment period (6 injections).  In the completed phase I 
safety, tolerability, and pharmacokinetic (PK) clinical study (ATI-BC-1), patients diagnosed 
with prostate or breast carcinoma and skeletal metastases were administered radium-223 
dichloride in single doses of 46, 93, 163, 213, or 250 kBq/kg body weight (25 patients) or 
multiple doses of 5 administrations of 50 kBq/kg body weight at 3-week intervals (3 patients) 
or 2 administrations of 125 kBq/kg body weight at 6-week intervals (3 patients).  In the 
completed phase II study, 64 patients with CRPC and painful skeletal metastases received 
4 injections of 50 kBq/kg body weight radium-223 dichloride (33 patients) or placebo 
(31 patients) at 4-week intervals, to examine the effects of radium-223 dichloride on 
biomarkers of disease progression, SSEs, pain palliation, survival, and safety parameters.  
The completed phase III trial, ALSYMPCA, enrolled 922 patients diagnosed with CRPC and 
symptomatic bone metastases who received 6 injections of radium-223 dichloride (50 kBq/kg 
IV) at 4-week intervals.  Endpoints included OS, time to disease-related events, time to 
progression as measured by serum PSA and total ALP concentrations, pain palliation, acute 
and long-term safety profile, and HRQoL.  The efficacy and safety data from the 
ALSYMPCA trial support the selection of a dosing regimen of 6 doses of 50 kBq/kg body 
weight of radium-223 dichloride at 4-week intervals.  This dose and schedule was determined 
to be efficacious, with only minor side effects and no indication of cumulative effect on bone 
marrow suppression following multiple administrations of radium-223 dichloride. 
Currently, no data are available to assess if similar effects could be achieved with a dose 
lower than 50 kBq/kg body weight.  However, patients diagnosed with CRPC have a poor 
prognosis with a median survival of approximately 3 years and, as no curative treatment is 
available, it is important that the dose administered is effective and well tolerated. 
1.2.2 
Abiraterone acetate 
1.2.2.1 
Drug development 
Abiraterone (JNJ-589485, formerly CB7598) is 17-(3-pyridyl) androsta-5,16-dien-3β-ol and 
is a selective irreversible steroidal inhibitor of CYP17 (17α hydroxylase/C17,20-lyase).  This 
enzyme is found in the testes, adrenals, and in prostate tumors and blocks 2 important 
enzymatic activities in the synthesis of testosterone (Figure 1–1).  Abiraterone is a potent 
inhibitor with an apparent inhibition constant of 0.5 nM.  Pharmacodynamic studies 
demonstrated that its effects on adrenal steroid synthesis were consistent with its mechanism 
of action.  Anti-tumor effects were evident with PSA response and durable objective 
responses using Response Evaluation Criteria in Solid Tumors (RECIST) (43) in phase I and 
phase II studies conducted to date. 
Abiraterone acetate (JNJ-2120482, formerly CB7630, Zytiga®) is the 3-acetylated analog of 
abiraterone and, thus, a pro-drug of abiraterone.  The chemical nomenclature of abiraterone 
acetate is 3β-acetoxy-17-(3-pyridyl) androsta-5, 16-diene; its empirical formula is 
C26H33NO2; and molecular weight is 391.55.  Once absorbed after oral administration, 


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abiraterone acetate is rapidly converted to the active form, abiraterone (Figure 1–2).  
Administration as an acetate reduces the variability in absorption seen with abiraterone. 
Figure 1–1:  The enzyme complexes inhibited by abiraterone 
 
Figure 1–2:  Pro-drug abiraterone acetate is converted to abiraterone after absorption 
 
1.2.2.2 
Abiraterone in chemotherapy-naïve castration-resistant prostate 
cancer 
Following selection of the 1000-mg dosing regimen, chemotherapy-naïve men (n = 54) with 
CRPC resistant to multiple hormonal therapies were treated in the second part of the 2-stage 
phase I/II study, COU-AA-001.  Declines in PSA ≥ 30%, ≥ 50%, and ≥ 90% were observed 
in 43 (80%), 38 (70%), and 14 (24%) of patients, respectively.  Radiological evaluation 
reported objective response by RECIST (complete response or progressive response) in 52% 


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of patients.  Declines in circulating tumor cell counts,(44) normalization of lactate 
dehydrogenase (LDH), and improving symptoms with a reduction in analgesic use were 
commonly documented.  Twenty-three patients received abiraterone acetate capsules for 
more than 12 months as part of an extension protocol.(45) Similar response rates were 
observed in COU-AA-002, a parallel phase I/II study investigating tablet formulation.(46) 
In the double-blind phase III study (COU-AA-302), 1088 chemo-naïve patients with 
asymptomatic or mildly symptomatic metastatic CRPC were randomized and received 
abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus 
prednisone.(47) The co-primary endpoints were radiological progression-free survival (rPFS) 
and OS.  The study was unblinded after the Independent Data Monitoring Committee 
(IDMC) unanimously recommended unblinding treatment and allowing subjects in the 
placebo group to receive abiraterone acetate.  This was after a planned interim analysis that 
was performed after 43% of the expected deaths had occurred.  The median rPFS was 
16.5 months with abiraterone–prednisone and 8.3 months with prednisone alone (HR = 0.53; 
95% CI, 0.45 to 0.62; p < 0.001).  Over a median follow-up period of 22.2 months, OS was 
improved with abiraterone–prednisone (median not reached, versus 27.2 months for 
prednisone alone; HR = 0.75; 95% CI, 0.61 to 0.93; p = 0.01) but did not cross the efficacy 
boundary.  Abiraterone–prednisone showed superiority over prednisone alone with respect to 
time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, PSA 
progression, and decline in performance status.  Grade 3 or 4 mineralocorticoid-related AEs 
and abnormalities on liver-function tests were more common with abiraterone–prednisone.  
The results of this phase III clinical trial led to the recent approval of abiraterone–prednisone 
for the treatment of patients with asymptomatic or mildly symptomatic metastatic CRPC 
before chemotherapy by the US FDA and European Commission.   
1.2.2.3 
Dosing rationale 
The dose of abiraterone acetate in this study is 1000 mg daily based on results of 2 Phase I 
dose-finding studies (48) and the pivotal phase III trial COU-AA-302.(49)   
In the first phase I study with capsule formulation (COU-AA-001), abiraterone acetate was 
evaluated for safety, PK, and its effects on adrenal steroid synthesis at dose levels ranging 
from 250 to 2000 mg.  Preliminary analysis showed that abiraterone acetate had an 
acceptable safety profile at all dose levels.  Patients received abiraterone acetate during the 
study and in an extension protocol, with some patients on treatment for more than 48 months.  
In the second phase I study (COU-AA-002) (45,48) that evaluated the safety and tolerability 
of abiraterone acetate tablet formulation at doses ranging from 250 to 1000 mg, a daily dose 
of 1000 mg was also found to have an acceptable safety profile for further development. 
Consistent with abiraterone acetate’s mechanism of action, hypertension, hypokalemia, and 
lower extremity edema were the most commonly observed drug-related AEs, which were all 
manageable with medication.  Pharmacokinetic studies showed increased systemic drug 
exposure at higher doses.  Adrenal metabolite analysis showed inhibition of CYP17 even at 
low doses of abiraterone acetate and a compensatory increase of corticosterone and 
deoxycorticosterone.  Data from the dose-finding studies indicated that when PK, adrenal 
CYP17 inhibition, and efficacy signals were taken into consideration, the 1000-mg dose 
offered consistent pharmacological effects without additional side effects.  Based upon these 
findings, the 1000-mg dose was chosen for further efficacy and safety evaluation in the 
pivotal phase III studies which led to the approval of this dose in CRPC. 


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1.2.3 
Concurrent prednisone / prednisolone 
Data from early studies have contributed to the current understanding of the mechanism of 
abiraterone action.  These suggest that a state of mineralocorticoid excess can occur after 
pharmacologic inhibition of CYP17, with the resulting reduced cortisol levels leading to a 
compensatory ACTH surge and accompanying hypertension, hypokalemia, and fluid 
retention.(50)  These side effects were readily managed with potassium supplementation, 
eplerenone (selective mineralocorticoid antagonist), antihypertensive agents, and low dose 
corticosteroids.  Grade 1 to 2 fatigue was observed in some patients and was associated with 
discontinuation of corticosteroids as required per phase II protocol entry criteria and extended 
duration of treatment with abiraterone acetate.  Although there was no evidence of an 
abiraterone dose-response relationship, administration of low dose corticosteroids as 
specified in the study improved symptoms of fatigue and tolerability of abiraterone acetate, 
including symptoms of mineralocorticosteroid excess.  The improved tolerability of 
abiraterone acetate after concomitant administration of low-dose corticosteroids was 
associated with suppression of ACTH and upstream adrenal steroids, suggesting that this 
combination may be a better tolerated and safer regimen in this older and frail patient 
population.  Prednisone was selected over other corticosteroids because it is commonly used 
as standard of care (28) in combination with approved chemotherapy agents or as a 
monotherapy for palliation of symptoms.   
The safety and efficacy of abiraterone acetate with concurrently administered prednisone has 
been evaluated in phase II and III studies.  In patients with CRPC without previous 
chemotherapy, fatigue, arthralgia, and peripheral edema were among the AEs reported more 
frequently in the abiraterone–prednisone group than in the prednisone-alone group.  Grade 3 
or 4 AEs classified as hepatotoxicity, consisting primarily of a reversible elevation in 
aminotransferase levels, were reported in 8% of patients in the abiraterone–prednisone group 
and 3% of patients in the prednisone-alone group.  Mineralocorticoid-related toxic effects 
were more common in the abiraterone–prednisone group than in the prednisone-alone group, 
including hypertension (22% versus 13%), hypokalemia (17% versus 13%), and fluid 
retention or edema (28% versus 24%), and were mostly Grade 1 or 2 AEs.(39) The regimen 
of abiraterone acetate 1000 mg daily and low-dose prednisone 5 mg twice daily has been 
chosen in this study. 
1.3 
Study rationale 
The treatment options for asymptomatic or mildly symptomatic patients with bone 
predominant metastasis CRPC are still limited.  
Radium-223 dichloride has shown significant anti-tumor activity in phase II and III studies in 
subjects with bone predominant metastatic CRPC.  Anticipated benefits of the treatment, 
according to previous studies, include prolongation of OS, delay of SSEs, anti-tumor efficacy 
measured by PSA response, palliation of cancer pain, and improvement in HRQoL.  The 
safety profile and tolerability for radium-223 dichloride appear to be acceptable in this study 
population. 
Although this study is blinded, randomized, and placebo controlled for radium-223 
dichloride, the subjects on the control arm will receive active treatment in the form of 
abiraterone acetate and prednisone.  Abiraterone acetate plus prednisone constitutes the 
standard of care in patients with CRPC who are asymptomatic or mildly symptomatic and, 
therefore, not eligible for cytotoxic chemotherapy with docetaxel. 


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As the side effect profiles for radium-223 dichloride and abiraterone acetate are not 
overlapping, a dose-finding study or a run-in dose escalation evaluation is not considered 
necessary for an analysis of combination treatment.  The mode of action differs for both 
compounds, as abiraterone targets androgen synthesis in testes, adrenal glands, and prostate 
cancer cells; whereas, radium-223 dichloride delivers alpha radiation to bone lesions of 
prostate cancer.  Based upon these individual effects, it is expected that the combination of 
both agents will prolong symptomatic skeletal event-free survival (SSE-FS) compared to 
treatment with abiraterone acetate alone. 
The study described herein has been designed to investigate the effects of radium-223 
dichloride added to abiraterone acetate and prednisone / prednisolone in subjects with 
chemotherapy-naïve CRPC who are asymptomatic or mildly symptomatic and who have 
bone predominant metastasis, which has progressed during ADT.  The study will be a 
randomized, double-blind, placebo-controlled phase III trial comparing radium-223 
dichloride (50 kBq/kg [55 kBq/kg after implementation of NIST update] body weight, every 
4 weeks for 6 single doses) administered with abiraterone acetate and prednisone / 
prednisolone versus placebo administered with abiraterone acetate and prednisone / 
prednisolone. 
1.4 
Primary efficacy endpoints 
Symptomatic skeletal event-free survival is defined as the time from randomization to the 
occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. 
the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms 
b. 
the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
c. 
the occurrence of spinal cord compression 
d. 
a tumor-related orthopedic surgical intervention. 
(2) Death from any cause 
Since the definition for measuring skeletal events will not use pre-specified imaging 
assessments, the use of imaging to identify a fracture or spinal cord compression will be 
triggered by symptoms.  As such, only symptomatic events will be captured; asymptomatic 
radiographic events are not included in this composite endpoint.  A delay or a reduction of 
SSEs represents an immediate clinical benefit, as it will delay or reduce bone pain, functional 
impairment, and the need for surgical intervention.  
In ALSYMPCA, treatment with radium-223 dichloride increased the time to first SSE from 
9.8 to 15.6 months (HR = 0.658; p = 0.00037; data on file).  
In 2007, Saad and colleagues were able to demonstrate that pathologic fractures correlate 
with reduced survival in patients with malignant bone disease.  After adjustment for baseline 
characteristics, including performance status and prior skeletal complications, patients with 
prostate cancer had a > 20% increased risk of death.(51) As this correlation is not universally 
accepted, in the trial herein, the time to first SSE and OS will be combined as SSE-FS.  Thus, 
either a SSE or death will count as an event.  


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The median SSE-FS in ALSYMPCA was 9.0 and 6.4 months with and without radium-223 
dichloride, respectively (HR = 0.685; p = 0.00004).  An ad-hoc analysis (data on file) in 
patients who did not receive docetaxel prior to radium-223 dichloride indicated that the 
median duration of SSE-FS is preserved in this subgroup of 395 patients (SSE-FS was 
9.5 months with and 6.7 months without radium-223 dichloride). 
In conclusion, SSE-FS is an objective variable that is likely to predict clinical benefit in the 
proposed study populations. 
2. 
Study objectives 
The primary objective is to compare, in subjects with asymptomatic or mildly symptomatic 
chemotherapy-naïve bone predominant metastatic CRPC, the clinical benefit of radium-223 
dichloride versus placebo in combination with abiraterone and prednisone / prednisolone, 
with the primary efficacy endpoint being: 
• SSE-FS 
The secondary objectives are to compare the radium-223 dichloride and placebo treatments 
to establish additional clinically relevant improvements in subjects with CRPC bone 
predominant metastasis using the variables below: 
• OS 
• Time to opiate use for cancer pain 
• Time to pain progression 
• Time to cytotoxic chemotherapy 
• rPFS 
• Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy 
The study will also include the following exploratory endpoints: 
• Time to first on-study SSE 
• Percentage change in total ALP from baseline 
• Time to ALP progression 
• Time to PSA progression 
• ALP response 
• PSA response 
• Bone scan-specific rPFS 
• Time to increase in physical symptoms of disease based on the functional assessment 
of cancer therapy / NCCN prostate cancer symptom index 17 item questionnaire 
(NCCN-FACT FPSI-17) disease related symptoms - physical (FPSI-DRS-P) subscale 
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• Time to increase in physical symptoms of disease based on the FPSI-DRS-P subscale 
score measured during the period between start of treatment and end of active follow-
up with clinic visits 
• Assessment of PK of abiraterone (see Section 7.4) 
• Resource utilization 
• Biomarker assessments 
An explorative objective is to evaluate the impact of baseline total body weight and ideal 
body weight on SSE-FS and AEs. 
Note: Evaluation of efficacy and exploratory endpoints, except for SSE and OS, will be 
discontinued following the final OS analysis. 
3. 
Investigators and other study personnel 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; 
an abbreviated version with personnel relevant for the centers will be available in each 
center’s Investigator Site file. 
Whenever the term ‘investigator’ is noted in the protocol text, it may refer to either the 
principal investigator at the study center, or an appropriately qualified, trained, and delegated 
individual of the investigational study center. 
The principal investigator of each center must sign the protocol signature sheet before subject 
recruitment may start at the respective center.  Likewise, all protocol amendments / integrated 
protocols must be signed and dated by the principal investigator before coming into effect at 
the respective center. 
A complete list of all participating centers and their investigators, as well as all required 
signature documents, will be maintained in the sponsor study file. 
The global sponsor of this study is identified on the title page of this protocol.  If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature page. 
3.1 
Independent Data Monitoring Committee 
An IDMC will be established for this study to review accumulating efficacy and safety data 
at regular intervals throughout the study and monitor overall study conduct.  The IDMC will 
include experts in oncology, biostatistics, and safety who are not participating in this trial and 
do not have affiliation with the investigators or the sponsor or other significant conflicts of 
interest.  Their main objective will be to protect the interests of the subjects in the study and 
of those still to be entered.  They will do this by monitoring the study periodically for safety, 
study progress, and protocol compliance, as well as assessing the risk / benefit of the trial.  
Independent Data Monitoring Committee meetings will be held as per separate IDMC 
Charter, approximately every 6 months throughout the blinded trial phase.  Ad hoc meetings 
will take place if needed. 
Specific areas of concern for the IDMC are: 


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• Subject safety (unblinded safety data will be reviewed at each meeting and any cases 
of unexpected AEs will be considered) 
• Accrual factors that may potentially impact on randomization balance 
• Subject eligibility and adequacy of follow-up  
• Protocol compliance (deviations from outcome assessment schedules which may lead 
to biases will be evaluated) 
The specific duties of the IDMC as well as statistical monitoring guidelines and procedures 
are described in the IDMC Charter. 
Note: No longer applicable after primary analysis. 
3.2 
Independent radiological review  
Radiological progression of subjects will be determined by an independent assessment of 
imaging examinations.  The process for the independent radiological review of radiological 
progression is described in a separate charter. 
All the available scans that confirmed the fracture diagnosis will be sent from clinical sites to 
an independent central review center and will be reviewed by the independent central 
reviewers. The process for the independent radiological review of fracture diagnosis is 
described in a separate charter. 
Note: No longer applicable after primary analysis. 
4. 
Study design 
4.1 
Design overview 
This study is a phase III, multinational, multicenter, randomized, double-blind, 
placebo-controlled study with a randomization allocation ratio of 1:1 (radium-223 dichloride 
plus abiraterone acetate plus prednisone / prednisolone:placebo plus abiraterone acetate plus 
prednisone / prednisolone).  Randomization will be stratified by: 
• Geographical regions (Western Europe / North America / Australia versus Asia versus 
rest of world) 
• Concurrent use of denosumab or bisphosphonates or none   
• Total ALP < 90 U/L versus total ALP ≥ 90 U/L 
This study will be conducted at approximately 170 investigative study centers and 
approximately 800 subjects will be enrolled. 
4.1.1 
Study periods and duration 
Until the final OS analysis, the study period consisted of screening / randomization, 
treatment, active follow-up with clinic visits, active follow-up without clinic visits, and long-
term follow-up phases.  Up until this point, subjects received study treatment (radium-223 
dichloride or placebo in addition to abiraterone acetate plus prednisone / prednisolone for the 
first 6 cycles followed by abiraterone acetate plus prednisone / prednisolone thereafter) until 
an on-study SSE occurred (or other withdrawal criteria were met). 


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After the final OS analysis (Amendment 7), in order to reduce the burden to study subjects, 
evaluation of efficacy and exploratory endpoints will be discontinued, except for SSE and 
OS.  Subjects who are discontinued from study treatment will initiate the long-term follow-up 
period; therefore, active follow-up periods will no longer be applicable.  Subjects who are in 
active follow-up at the time of Amendment 7 is implemented should have the end of active 
follow-up completed (protocol driven decision) and should be directly transitioned into the 
extended safety follow-up study. 
Long term follow-up period will end when the subject has completed 7 years of follow-up, 
dies, is lost to follow-up, withdraws informed consent, actively objects to collection of further 
data, or is transitioned to the extended safety follow-up study. Subjects will be followed for 
safety for up to 7 years, which eventually will be completed in this study or in the extended 
safety follow-up study. 
Screening period:  
All trial-related procedures and evaluations will only be performed after the subject has 
agreed to participate and has signed the informed consent form (ICF).  The screening period 
will consist of multiple evaluations that will take place within 2 weeks (+ 7 days) prior to 
randomization to ensure that all eligibility criteria are met (Section 5.1). 
Randomization:  
Once eligibility is confirmed, eligible subjects will be randomized 1:1 to treatment with 
radium-223 dichloride plus abiraterone and prednisone / prednisolone (Arm A) or placebo 
(normal saline) plus abiraterone and prednisone / prednisolone (Arm B). 
Treatment period:  
Treatment consists of up to 6 cycles of radium-223 dichloride (Arm A) or placebo (Arm B) in 
combination with abiraterone plus prednisone / prednisolone followed by ongoing treatment 
for all subjects with abiraterone plus prednisone / prednisolone. 
• Up to 6 cycles of treatment in Arm A or Arm B:  Treatment consists of 6 IV 
administrations of radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation 
of NIST update) body weight (Arm A) or placebo (Arm B) each separated by an 
interval of 4 weeks plus abiraterone acetate 1000 mg every day plus prednisone / 
prednisolone 5 mg twice daily. 
• Ongoing treatment with abiraterone plus prednisone / prednisolone:  After the 
completion of treatment with radium-223 dichloride (Arm A) or placebo (Arm B), all 
randomized subjects will continue to receive abiraterone acetate 1000 mg every day 
plus prednisone / prednisolone 5 mg twice daily until disease progression occurs (or 
other withdrawal criteria are met). 
After final OS analysis (Amendment 7): 
In order to reduce the burden to study subjects, evaluation of  efficacy and exploratory 
endpoints will be discontinued, except for SSE and OS.  Discontinuation of abiraterone 
acetate plus prednisone/prednisolone will follow standard clinical practice; therefore, subjects 
who present disease progression defined as radiological progression (either by RECIST or 
bone progression by PCWG2), SSE, clinical progression (clinical deterioration or lack of 
clinical benefit, assessed by investigator), or initiation of a new anti-cancer therapy, should be 
discontinued from study treatment. After disease progression, abiraterone acetate will be 


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considered standard of care (i.e., non-investigational medicinal product [non IMP]) and will 
not be supplied as study medication. 
Subject management, unless defined otherwise in this protocol, will be in accordance with 
routine clinical practice, at the discretion of the investigator.  Subjects will be assessed every 
4 weeks (± 7 days) for safety and clinical progression, at each treatment visit and will be 
evaluated every 12 weeks (± 7 days) for radiological progression until disease progression 
occurs or subject is discontinued from study treatment, whichever occurs sooner. After 
discontinuation from study treatment, no additional radiological assessments will be required 
by protocol. 
The treatment period extends from the initiation of treatment until 4 weeks after the last 
administration of abiraterone as IMP and prednisone / prednisolone.  If the subject receives 
abiraterone/prednisone as the standard of care (non-IMP) after disease progression, as defined 
above, this will not be considered part of the treatment period and it will not be considered as 
new anti-cancer therapy.  During the treatment period, subjects will be followed by a visit 
every 4 weeks ± 7 days.  Subjects with a platelet count (PLT) or white blood cell (WBC) 
count less than the lower limit of normal at 6 months will be followed additionally until 
resolution at a frequency based on local clinical practice. 
Active follow-up period with clinic visits and active follow-up period without clinic visits: 
After the final OS analysis (Amendment 7), subjects who are discontinued from study 
treatment will initiate the long term follow-up period; therefore, the active follow-up periods 
will no longer be applicable. Subjects who are in active follow-up at the time Amendment 7 
is implemented should have the end of active follow-up completed (protocol driven decision) 
and should be directly transitioned into the extended safety follow-up study. For additional 
information, please refer to Section 13.6. 
Long-term follow-up: 
After the final OS analysis (Amendment 7), subjects who are discontinued from study 
treatment will initiate the long-term follow-up period in order to collect safety and OS 
information.  The long-term follow-up period will end when the subject has completed 
7 years of follow-up, dies, is lost to follow-up, withdraws informed consent, actively objects 
to collection of further data, or is transitioned to the extended safety follow-up study. 
During this period, subjects will be monitored via telephone call every 6 months for survival; 
treatment-related AEs and SAEs, and all occurrences of leukemia, myelodysplastic 
syndrome, aplastic anemia; and primary bone cancer or any other new primary malignancy.  
All bone fractures and bone associated events (e.g., osteoporosis) need to be reported as 
either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s causality 
assessment.  In addition, subjects who receive cytotoxic chemotherapy will be followed up 
for the development of febrile neutropenia and hemorrhage during their chemotherapy 
treatment and for up to 6 months at a frequency based on local clinical practice. 
Once a separate extended safety follow-up protocol for the inclusion of subjects who received 
radium-223 dichloride / placebo in the course of Bayer sponsored clinical trials has been 
implemented, the surviving study subjects who are in active follow-up or the long-term follow-
up will be transitioned to a separate extended safety follow-up study in order to complete 
7 years of safety follow-up.  All efforts will be made to transition all subjects to the extended 
safety follow-up study. The end of the study (EOS) is defined as the date of the last subject last 


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visit (LSLV) in the study. The EOS will occur at the time the last subject on study completes 
7 years of follow-up unless the subject dies, withdraws consent or is lost to follow-up (FU). 
4.1.2 
Study endpoints 
Primary endpoint:  The primary endpoint is SSE-FS. 
SSE-FS is defined as the time from randomization to the occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor-related orthopedic surgical intervention. 
(2) Death from any cause 
Secondary endpoints  
• OS 
• Time to opiate use for cancer pain* 
• Time to pain progression* 
• Time to cytotoxic chemotherapy* 
• rPFS* 
• Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy 
Exploratory endpoints*: 
• Time to first on-study SSE* 
• Percentage change in total ALP from baseline* 
• Time to ALP progression* 
• Time to PSA progression* 
• ALP response* 
• PSA response* 
• Bone scan-specific rPFS* 
• Time to increase in physical symptoms based on the FPSI-DRS-P subscale score 
measured during the treatment period* 
• Time to increase in physical symptoms of disease based on the FPSI-DRS-P subscale 
score measured during period between start of treatment and end of active follow-up 
with clinic visits* 


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• Assessment of PK of abiraterone (see Section 7.4)* 
• Resource utilization* 
• Biomarker assessments* 
Evaluation of endpoints indicated with an asterisk (*) including all exploratory endpoints will 
be discontinued following the final OS analysis.  
4.2 
Primary variables 
The primary variable is SSE-FS.  The definition for this variable is provided in Section 4.1.2. 
4.3 
End of study 
All efforts will be made to transition all subjects to the extended safety follow-up study. The 
EOS is defined as the date of the LSLV in the study. The EOS will occur at the time the last 
subject on study completes 7 years of follow-up unless the subject dies, withdraws consent or 
is lost to FU.  
In case a subject is still on oral study treatment and still benefits based on the investigator’s 
opinion after 7 years of follow-up, options for treatment continuation (e.g., switch to 
commercial drug supply, a continued access program, or any other means of continued drug 
supply) will be discussed and agreed between the investigator, sponsor, and the subject in 
compliance with local regulations. 
For each participating European Union (EU) country, the EOS according to the EU Clinical 
Trial Directive will be reached when the LSLV in any center has occurred. 
5. 
Study population 
Approximately 800 medically or surgically castrated male subjects with bone predominant 
metastatic CRPC who have shown tumor progression and are non- or mildly symptomatic by 
prospectively defined criteria (Section 5.1) will be enrolled and treated. 
5.1 
Eligibility 
Eligibility should be confirmed within 2 weeks (+ 7 days) of randomization.  At Visit 2, the 
hematology values need to be confirmed to be within the treatment ranges prior to first dose. 
Rescreening 
Rescreening of screen failed subjects may only be allowed after discussion with the medical 
monitor of the sponsor and after his / her approval.  Sponsor approval of rescreening must be 
documented.  Rescreening may be considered under the following circumstances: 
• Subjects who underwent screening procedures (i.e., scans and laboratory work) that 
expired (are outside of the 14-day window) may need the screening procedures to be 
repeated in order to be within the window required prior to randomization.  However, 
rescreening is not permitted in cases in which the initial laboratory test results do not 
support eligibility. 
• Rescreening is also permitted where the screening procedures for subject’s eligibility 
expired due to completion of washout periods as per protocol (e.g., 4 weeks from 


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treatment with an investigational drug), in case of expiry of investigational product 
that requires replacement, or for extraordinary logistical issues. 
The subjects who need to repeat the screening procedures will be asked to repeat the 
consenting process for study participation. 
5.1.1 
Inclusion criteria 
The following criteria are to be met for inclusion into the study:  
1. Have provided written informed consent.  Subjects must be able to understand and be 
willing to sign the written ICF.  A signed, written ICF must be appropriately obtained 
prior to the conduct of the any trial-specific procedure. 
2. Histologically confirmed adenocarcinoma of the prostate 
3. Male subjects of age ≥ 18 years.  The lower limit may be higher if legally required in 
the participating country. 
4. Prostate cancer progression documented by PSA according to the Prostate Cancer 
Working Group 2 (PCWG2) criteria (Section 14.2) or radiological progression 
according to RECIST, version 1.1 (52) 
5. Two or more bone metastases on bone scan within 4 weeks prior to randomization 
with no lung, liver, other visceral, and / or brain metastasis 
6. Asymptomatic or mildly symptomatic prostate cancer. A worst pain score (WPS) of 0 
on the Brief Pain Inventory-Short Form (BPI-SF) (Section 14.9) Question #3 (worst 
pain in last 24 hours) will be considered asymptomatic, and a WPS of 1 to 3 will be 
considered mildly symptomatic.  This is to be assessed once during the screening 
period. 
7. Subjects who received combined androgen blockade with an anti-androgen must have 
shown PSA progression after discontinuing the anti-androgen prior to enrollment 
(≥ 4 weeks since last flutamide, ≥ 6 weeks since last bicalutamide or nilutamide). 
8. Maintenance of medical castration or surgical castration with testosterone less than 
50 ng/dL (1.7 nmol/L).  If the subject is being treated with luteinizing hormone-
releasing hormone (LHRH) agonists or antagonists (subject who has not undergone 
orchiectomy), this therapy must have been initiated at least 4 weeks prior to 
randomization and must be continued throughout the study. 
9. Eastern Cooperative Oncology Group performance status (ECOG PS) score 0 or 1 
10. Life expectancy ≥ 6 months 
11. Laboratory requirements: 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b. PLT ≥ 100 x 109/L 
c. Hemoglobin (Hb) ≥ 9.0 g/dL (90 g/L; 5.6 mmol/L) 
d. Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) (except 
for subjects with documented Gilbert’s disease) 


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e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤ 2.5 x ULN  
f. Estimated glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 
(Section 14.4) 
g. International normalized ratio (INR) of prothrombin time (PT; PT-INR) and 
partial thromboplastin time (PTT) ≤ 1.5 times the ULN.  Subjects treated with 
warfarin or heparin will be allowed to participate in the study if no underlying 
abnormality in coagulation parameters exists per prior history; weekly 
evaluation of PT-INR / PTT will be required until stability is achieved (as 
defined by local standard of care and based on pre-study PT-INR / PTT 
values) 
h. Serum albumin > 30 g/L 
i. Serum potassium ≥ 3.5 mmol/L 
12. Able to swallow abiraterone and prednisone / prednisolone as whole tablets 
13. Subjects who have partners of childbearing potential must be willing to use a method 
of effective birth control during treatment and for 6 months following completion of 
treatment with radium-223 dichloride / placebo or 13 weeks of the last administration 
of abiraterone, whichever occurs later.  The contraception measures must be discussed 
with the subject.  Suitable contraception could be, for example, an oral contraceptive 
combined with the use of condoms. 
5.1.2 
Exclusion criteria 
Eligible subjects must not meet any of the exclusion criteria listed below: 
1. Prior cytotoxic chemotherapy for the treatment of CRPC, including taxanes, 
mitoxantrone, and estramustine 
2. Administration of immunotherapies (e.g., sipuleucel-T) within 4 weeks before 
randomization 
3. Prior treatment with abiraterone acetate 
4. Administration of an investigational therapeutic within 4 weeks of randomization 
5. Active infection or other medical condition that would make 
prednisone / prednisolone (corticosteroid) use contraindicated 
6. Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg 
prednisone / prednisolone twice daily 
7. Pathological finding consistent with small cell carcinoma of the prostate 
8. History of visceral metastasis, or presence of visceral metastasis detected by screening 
imaging examinations 
9. History of or known brain metastasis 
10. Malignant lymphadenopathy exceeding 3 cm in short-axis diameter 


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11. Prior hemibody external radiotherapy is excluded.  Subjects who received other types 
of prior external radiotherapy are allowed provided that the bone marrow function is 
assessed and meets the protocol requirements for Hb, ANC, and PLT. 
12. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, 
rhenium-188, or radium-223 
13. Blood transfusion or erythropoietin stimulating agents prior 4 weeks of screening and 
during the whole screening period before randomization 
14. Other malignancy treated within the last 5 years (except non-melanoma skin cancer or 
low-grade superficial bladder cancer) 
15. Imminent spinal cord compression based on clinical findings and / or magnetic 
resonance imaging (MRI).  Subjects with history of spinal cord compression should 
have completely recovered. 
16. Use of opiate analgesics for cancer-related pain, including codeine and 
dextropropoxyphene, currently or anytime during the 4- week period prior to 
randomization 
17. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood 
pressure ≥ 95 mmHg).  Subjects with a history of hypertension are allowed provided 
blood pressure is controlled by anti-hypertensive treatment. 
18. Active or symptomatic viral hepatitis or chronic liver disease 
19. History of pituitary or adrenal dysfunction 
20. Any other serious illness or medical condition such as, but not limited to: 
a. Any infection ≥ National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) version 4.03 Grade 2 
b. Clinically significant heart disease as evidenced by myocardial infarction, or 
arterial thrombotic events in the past 6 months, severe or unstable angina, or New 
York Heart Association (NYHA) Class II to IV (Section 14.5) heart disease or 
cardiac ejection fraction measurement of ≤ 50% at baseline 
c. Atrial fibrillation, or other cardiac arrhythmia requiring therapy 
d. Crohn’s disease or ulcerative colitis  
e. Bone marrow dysplasia  
f. Moderate and severe hepatic impairment (Child-Pugh Classes B and C) 
g. Unmanageable fecal incontinence 
21. Hypersensitivity to radium-223 dichloride or abiraterone acetate 
22. Previous assignment to treatment during this study 
23. Any condition which, in the opinion of the investigator, would preclude participation 
in this trial 


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5.2 
Withdrawal of subjects from study 
5.2.1 
Withdrawal 
All subjects who enter the trial should complete all phases of the protocol: 
1. Screening 
2. Randomization 
3. Treatment period 
4. Long-term follow up 
Note:  Study drug discontinuation (i.e., discontinuation during the treatment period) does not 
constitute withdrawal from the study.  Every effort should be made to transition subjects who 
discontinue the treatment period for any reason to the extended safety follow-up study . 
Subjects are expected to participate in the follow-up unless they explicitly object.  
Withdrawal of consent should be documented in the subject’s medical file.  If the subject 
does not wish to be followed up further, he should sign the ‘Declaration of objection to 
collection of study data after withdrawal of consent form.’ 
A “dropout” is defined as a subject who has been randomized and discontinues study 
participation prematurely for any reason. 
A “screening failure” is defined as a subject who has signed informed consent and terminates 
the study for any reason (e.g., failure to satisfy the selection criteria) before randomization.  
Any subject removed from the study will remain under medical supervision until discharge or 
transfer is medically acceptable. 
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject’s 
medical records (consent withdrawal [due to AE or for other reason], lost to follow-up, or 
death). 
When a subject is withdrawn from the study, i.e., is not attending follow-up visits, the 
end-of-study page in the eCRF is to be completed. 
5.2.1.1 
Withdrawal from treatment period (collection of follow-up data) 
Subjects must be withdrawn from the study treatment for the following reasons: 
• If, in the investigator’s opinion, continuation of the study treatment would be harmful 
to the subject’s well-being. 
• If the subject experiences unacceptable toxicities to any study drugs. 
• Delay in all study treatment of > 4 weeks (maximum of 8 weeks between 2 injections 
of radium-223 dichloride / placebo). 
• If the subject starts treatment with a prohibited prostate cancer therapy 
(Section 6.9.1). 
• At his own request or at the request of his legally acceptable representative. 
• At the specific request of the sponsor and in liaison with the investigator (e.g., 
obvious non-compliance, safety concerns). 


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• For disease progression characterized by radiological progression (either by RECIST 
or bone progression by PCWG2), SSE, clinical progression (clinical deterioration or 
lack of clinical benefit, assessed by investigator), or initiation of a new anti-cancer 
therapy. 
After the final OS analysis (Amendment 7): 
In order to reduce the burden to study subjects, evaluation of efficacy and exploratory 
endpoints will be discontinued, except for SSE and OS. Discontinuation of abiraterone 
acetate plus prednisone/prednisolone will follow standard clinical practice, therefore, subjects 
who present disease progression, as defined above, or that start a new anti-cancer therapy 
should be discontinued from study treatment. After disease progression, abiraterone acetate 
will be considered standard of care (i.e., non-investigational medicinal product [non-IMP]) 
and will not be supplied as study medication. 
5.2.1.2 
Withdrawal from treatment period and all follow-up 
Subjects must be withdrawn from the study treatment and / or procedures and no further data 
will be collected for the following reasons: 
• Subject withdraws consent from study treatment and study procedures.  A subject 
must be removed from the study at his own request or at the request of his legally 
acceptable representative.  At any time during the study and without giving reasons, a 
subject may decline to participate further; the subject’s rights will be protected. 
• Subject is lost to follow-up 
• Death 
5.2.2 
Replacement 
Withdrawn subjects will not be replaced. 
5.3 
Subject identification 
A subject number (a unique identification number) will be assigned via an interactive 
voice / web response system (IXRS) when a subject signs the ICF and is evaluated for 
inclusion into the study.  When the subject is eligible for the trial, the study center will send 
an order (using the IXRS) to the manufacturer for drug shipment based on the planned visit 
date of the subject.  See Section 6.3. 
6. 
Treatments 
6.1 
Treatments to be administered 
Investigational product:  Radium-223 dichloride, 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) body weight will be administered IV as a slow bolus 
injection (approximately 1 minute) 6 times at intervals of 4 weeks. 
Reference therapy:  A solution of isotonic saline (0.9% sodium chloride solution for 
injection) will be administered IV as a slow bolus injection (approximately 1 minute) 6 times, 
at intervals of 4 weeks (see Section 6.2.1.2 for supply information). 
Co-administered therapy:  Abiraterone (abiraterone acetate; Zytiga®, Janssen, a division of 
Johnson and Johnson) will be administered orally, 1000 mg every day as a dose of four 


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250-mg tablets.  Prednisone / prednisolone will be administered orally, 5 mg twice daily.  If a 
subject has been receiving glucocorticoids other than prednisone or prednisolone prior to 
randomization, it will be necessary to switch the glucocorticoid to prednisone or prednisolone 
5 mg twice daily prior to Cycle 1, Day 1. 
6.2 
Identity of study treatment 
The alpha particle emitting radiopharmaceutical BAY 88-8223 is a ready-to-use, sterile, 
non-pyrogenic, clear and colorless aqueous solution of radium-223 dichloride for IV 
administration.  Radium-223 dichloride is an alpha particle emitter with a physical half-life of 
11.4 days.  The product is isotonic and has a pH of 6.0 to 8.0.  The radioactive concentration 
at the reference date is 1000 kBq/mL (1100 kBq/mL after implementation of NIST update).  
The product has a pre-calibration of 14 days.  When administered on a day other than the 
reference day, the volume should be corrected according to the physical decay table supplied 
with each shipment.  
For study sites in the US, sites will receive patient ready doses (PRDs) of radium-223 
dichloride prepared by a radiopharmacy (Cardinal Health 414, LLC, Nuclear Pharmacy 
Services).  Dose will be delivered to the sites in pre-filled syringes. 
Abiraterone (abiraterone acetate) is a white to off-white, non-hygroscopic, crystalline 
powder.  Its molecular formula is C26H33NO2 and it has a molecular weight of 391.55.  
Abiraterone is a lipophilic compound and is practically insoluble in water.  The product is 
supplied in 250-mg tablet form with the following inactive ingredients:  lactose monohydrate, 
microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, 
magnesium stearate, and colloidal silicon dioxide. 
Open label prednisone or prednisolone will be provided in 5-mg tablet form.  Where 
prednisone is not commercially available, prednisolone will be substituted. 
6.2.1 
Study medication supply and packaging 
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text for all sponsor-supplied study drugs will be approved according to the sponsor’s 
agreed procedures.  For all sponsor-supplied study drugs, a system of numbering in 
accordance with all requirements of Good Manufacturing Practice (GMP) will be used, 
ensuring that each dose of study drug can be traced back to the respective bulk ware of the 
ingredients.  Lists linking all numbering levels will be maintained by the sponsor for 
sponsor-supplied study drugs.  A complete record of batch numbers and expiry dates of all 
study treatment as well as the labels will be maintained in the sponsor study file. 
Saline will be supplied locally by the study center’s commercial supply.  The unblinded staff 
will record the assignment, batch numbers, and expiry dates, which will be retained at the 
study center with a copy provided for the sponsor unblinded study file. 
6.2.1.1 
Radium-223 dichloride 
The sponsor will provide radium-223 dichloride, which is manufactured by Bayer 
HealthCare.  Radium-223 dichloride is produced according to GMP and will be delivered in a 
glass vial, ready-to-use with a certified activity.  This alpha particle emitting 
radiopharmaceutical is shipped in a lead container and a Type A radioactive package 
according to international transportation guidelines for radioactive materials. 


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The volume per vial is 6 mL, corresponding to 6 MBq (6.6 MBq after implementation of 
NIST update), at the calibration reference day.  Radium-223 dichloride has a shelf life of 28 
days from production day, when stored at ambient temperature.  The shelf life is valid for all 
climate zones I to IV.  In addition, it has been shown that the product quality is not 
jeopardized upon freezing. 
If administration must be postponed for more than 3 days compared to the original schedule, 
replacement of the drug order may be required (in case the available amount of radium-223 at 
site is insufficient or expired for the re-scheduled administration date). 
6.2.1.2 
Saline 
Isotonic saline (0.9% sodium chloride solution for injection) will be provided by the study 
center.  Traceability of the respective manufacturers and batches will be maintained in the 
respective preparation documentation and drug accountability logs. 
The same process must be followed, regardless of treatment arm assignment, to maintain the 
study blind. 
6.2.1.3 
Abiraterone acetate 
Abiraterone acetate will be provided with appropriate labeling to each study center by the 
sponsor. 
As of Amendment 7, after disease progression, abiraterone will be considered standard of 
care (i.e., non-IMP) and will not be supplied as study medication; instead, abiraterone should 
be prescribed locally and recorded on the systemic anti-cancer therapy CRF. 
Abiraterone should be stored at the investigator site.  Store at 20°C to 25°C (68°F to 77°F); 
excursions permitted in the range from 15°C to 30°C (59°F to 86°F). 
6.2.1.4 
Prednisone / prednisolone 
Prednisone / prednisolone (5-mg tablets) will be provided.  Where prednisone is not 
commercially available, prednisolone will be provided instead. 
Prednisone should be stored at the investigator site.  Store at 20°C to 25°C (68°F to 77°F); 
excursions permitted in the range from 15°C to 30°C (59°F to 86°F). 
6.3 
Treatment assignment 
To accomplish random assignment of treatment, a computer-generated randomization list will 
be prepared by the sponsor and provided to the IXRS.  The IXRS will assign each eligible 
subject a randomization number and the respective treatment in a ratio of 1:1 to radium-223 
dichloride or placebo.  In addition, randomization will be stratified by geographical regions 
(Western Europe / North America / Australia versus Asia versus rest of world), concurrent 
use of denosumab or bisphosphonates or none, and by total ALP < 90 U/L versus total ALP 
≥ 90 U/L. 
The IXRS will provide only the randomization number to the caller, i.e., blinded personnel, 
but not the assigned treatment.  A confirmation e-mail containing randomization number and 
treatment will be sent to the unblinded staff member who will be responsible for preparing 
the study drug for the subject for the first administration.  When the subject is allocated to 
radium-223 dichloride, the unblinded person will use IXRS to send an order to the 
manufacturer for drug shipment.  The timing for the drug order should be based on the 


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planned subject visit date.  If the subject is allocated to placebo, the unblinded person at the 
study center will be responsible for providing saline corresponding to the IXRS treatment 
day.  This should not be made available before to avoid unblinding the subject and blinded 
study personnel.   
Subsequent orders for each study drug administration will be made by calling the IXRS from 
the study center on the date of the previous injection.  If after ordering, the order needs to be 
cancelled or amended, the investigator should contact their monitor immediately. 
6.4 
Dosage and administration 
Written information about radium-223 dichloride and instruction about handling and injection 
of radioactive material will be provided to study personnel. 
In general, the administration of radioactive drugs involves a potential risk for third parties, 
due to radiation from the subject and due to possible contamination by spilling urine or feces.  
When radium-223 dichloride has been injected intravenously into a subject, the risk for 
external radiation exposure to third parties is extremely low, due to the short range of the 
alpha particles (< 100 μm) and the low portion of beta and gamma radiation.  For these 
reasons the product can be administered on an out-patient basis.  To minimize the risk of 
contamination, the subject and his caregivers will receive oral and written instructions 
regarding hygiene precautions to abide by after receiving the radioactive drug according to 
the investigational study center radiation protection guidelines.  These instructions will be 
given to all subjects, as neither the principal investigator nor subject will know the 
assignment to radium-223 dichloride or placebo injections. 
Aseptic technique should be used in the administration of radium-223 dichloride.  The 
syringe should be handed to the blinded individual who will perform the injection.  The study 
medication will be administered as a slow bolus IV injection.  The actual radioactivity 
administered must be within the tolerance limits of ± 10% of the calculated radioactivity. 
Abiraterone acetate (ZYTIGA®) 1000 mg (four 250-mg tablets) will be administered orally 
once daily in combination with prednisone / prednisolone 5 mg administered orally twice 
daily.  Abiraterone acetate must be taken on an empty stomach.  No food should be consumed 
for at least 2 hours before the dose of abiraterone acetate is taken and for at least 1 hour after 
the dose of abiraterone acetate is taken.  The tablets should be swallowed whole with water 
and should not be crushed or chewed.  If an abiraterone acetate dose is missed, it should be 
omitted and will not be made up. 
It is not required for the prednisone to be taken at the same time as abiraterone acetate.  The 
dose of prednisone will remain unchanged in the event that the study drug dose is changed.  If 
a prednisone dose is missed, it should be omitted and will not be made up. 
Based on its mechanism of action, abiraterone acetate may harm a developing fetus; 
therefore, women who are pregnant or women who may be pregnant should not handle 
abiraterone acetate without protection, e.g., gloves.  Radium-223 dichloride can be measured 
in a normal dose calibrator instrument.  When all the required written approvals for the use 
and handling of radium-223 dichloride from the Radiation Protection Agency / Agencies for 
the specific center have been received by the sponsor, a vial of radium-223 dichloride for 
technical use will be sent to the study center. 


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Different clinical study centers possess dose calibrators from various suppliers; thus, the 
isotope calibration factor may differ from center to center.  Consequently, each center must 
perform the radium-223 dial setting on their relevant dose calibrator(s), if no isotope 
calibration factor for radium-223 is being provided by the vendor of the dose calibrator.  For 
dial setting, the clinical study center will receive a sealed vial or prefilled syringe containing 
a radium-223 solution for calibration only.  The vial or syringe is identical to the 
vials / syringes used for study treatment.  The amount of radium-223 in the vial / syringe will 
be stated on the label.  Instructions for the dial setting, including the calibration log form, will 
be enclosed with the dispatch of the calibration sample. 
6.4.1 
Radium-223 dichloride dose calibration 
As of Amendment 2, NIST has established an updated standardization for radium-223 
dichloride, which indicates that an approximately 10% difference existed between activity 
values obtained using the current standard and the updated standardization. 
The change in the NIST radium-223 standard has no impact on subjects; subjects are 
receiving, and will continue to receive, the same actual dose and volume that was studied in 
ALSYMPCA and is associated with the proven safety and efficacy of radium-223 dichloride, 
though the stated nominal radiation dose received is being updated to reflect the new 
standard.  Subjects who are on-treatment at the time the new NIST reference standard goes 
into effect will be notified of this change and will be required to sign a Patient Information 
Sheet to acknowledge that they have received information on the updated NIST standard 
calibration.  All subjects randomized after the new reference standard is in effect will sign a 
revised Informed Consent Form that contains the updated NIST standardization. 
The formula for the calculation of the volume to be administered has to be changed 
respectively.  See Section 6.4.3. 
6.4.2 
Radium-223 dichloride dose ordering and handling 
At least 2 unblinded personnel should be nominated at each study center (Section 6.5).  The 
primary dedicated unblinded person (“the unblinded person”), who has the responsibility 
delegated from the principal investigator, will be responsible for the safe handling and 
storage of radium-223 dichloride and placebo control.  The unblinded person also has the 
responsibility of correctly receiving and recording the delivery of radium-223 dichloride in 
accordance with this protocol.  At least one deputy unblinded person should also be 
nominated.  Radium-223 dichloride should be handled by individuals who are qualified by 
training and experience in the safe handling of radionuclides. 
The dose should be ordered through IXRS as soon as possible (i.e., the day of the previous 
dose or at a minimum the country lead time) prior to the planned date of administration.  The 
subject’s weight will be submitted with the dose request.  The site is not required to assess 
safety labs prior to placing the order. 
Assessments other than weight will be repeated (as needed to be within the window prior to 
the dose day / time).  The site must obtain safety labs and review the hematology results 
within 3 days prior to the dose.  If a laboratory result does not meet the criterion for dosing, 
the radium-223 dichloride dose should not be given; the sponsor is aware this may require the 
site to waste / destroy the dose. 
The radium-223 dichloride vials or PRDs must be stored inside their lead container in a 
secure facility.  The study drug should be used within 28 days of production or prior to the 


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expiry date specified for the PRD.  Patient ready doses prepared by Cardinal Health for US 
sites have an extended expiry (see Section 6.4.4).  These doses should be administered within 
the specified shelf-life of the individual PRD. 
Control measurements of both the radium-223 dichloride vial (before and after dispensing) 
and syringes (before and after administration) are performed as part of the clinical trial 
documentation.  Since PRDs will be prepared at the country depot in the US, relevant 
procedures are recorded by the country depot staff.  All administrations of radium-223 
dichloride will be based on the certified activity of radium-223 at the reference date.  Please 
note that all documentation that contains unblinded information should be kept by the 
unblinded person(s) and not shared with the other study center personnel during the conduct 
of the study. 
6.4.3 
Radium-223 dose calculation 
The dosage of radium-223 dichloride is 50 kBq/kg (55 kBq/kg after implementation of NIST 
update) body weight.  The total activity to be injected will be calculated volumetrically using 
the subject’s body weight (kg) within 3 days prior to the injection for non-US sites or 3 to 5 
days prior to the injection for US sites, the 50 kBq/kg (55 kBq/kg after implementation of 
NIST update) dosage level, and the decay correction factor (DK) to correct for physical decay 
of radium-223.  A table with DKs according to physical decay of the study medication will be 
provided with each vial / syringe of radium-223 dichloride.  The total amount (volume to be 
drawn into the syringe) to be administered to a subject should be calculated as follows: 
Body weight (kg) x 50 kBq/kg a  = volume to be injected (mL)c 
DK x 1000 kBq/mLb 
a 55 kBq/kg after implementation of NIST update 
b 1100 kBq/mL after implementation of NIST update 
c The volume to be injected will remain the same before and after implementation of 
the NIST update 
Data regarding activity, calculations, and volume to be injected must be recorded in the 
subject’s medical record by the unblinded person. 
In the US, applicable documentation is required for the country PRD depot.  The subject’s 
weight will be obtained only once for each dose.  In order to ensure time for the country PRD 
depot to prepare and deliver the PRDs to the sites: 
• The subject’s weight measured at the dosing visit will be obtained at the site 3 to 
5 days prior to the planned dosing date. 
• This weight will be communicated to the country PRD depot for preparation of the 
current dose along with a prescription and any other details required by the PRD 
depot; a record of this information transfer will be retained at the site. 
• Documentation by the PRD depot of the required activity and volume in the syringe 
will be retained at the depot with a copy provided to the site. 
Subjects at non-US sites should be reweighed on the day of dose administration; the final 
dose to be administered should be determined using that weight.  Subjects should not be 
weighed more than once or at different departments on the day of the administration to avoid 
the potential use of different weights.  Subjects in the US will receive syringe-ready doses 


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based on the subject weight provided to Cardinal Health within 3 to 5 days prior to the day of 
administration.  Therefore, no other weight measurement is needed. 
For subjects in Arm B (placebo injection), the volume of saline to be injected will provided 
by the IXRS based on the subject’s weight.  Data regarding the saline batch number and the 
volume to be injected should be recorded on the IMP preparation log and in the eCRF by 
unblinded staff. 
6.4.4 
Study drug dose preparation 
In order to keep the treating physician blinded to the assignment of study medication, the 
unblinded person (e.g., from the hospital pharmacy or nuclear medicine department) will be 
responsible for blinding the syringe and responsible for calculating the required dosage.  Data 
regarding activity and volume to be injected should be recorded in the IMP preparation log 
and in the appropriate eCRF, both of which will not be available to the blinded treating 
physician or other blinded staff.  Copies of the vial label and the syringe serial number are to 
be attached with each entry in the IMP preparation log.  Additional written instructions for 
study drug administration, for blinded and unblinded personnel, will be provided. 
Personnel should use appropriate protective clothing and equipment during syringe filling 
and application to prevent contamination with the radioactive solution (lab coats, medical 
gloves / protective glasses) and to reduce radiation exposure.  Sites should adhere to all 
relevant radiation safety regulations as prescribed by local authorities administering their site 
radiation license, including as low as reasonably achievable principles. 
Filling of the syringe should take place in a safety bench or similar cabinet in the 
radiopharmacy / nuclear medicine department.  The individual responsible for study drug 
preparation will draw the correct volume of study drug into a syringe.  The size of the syringe 
should be chosen according to the applied volume to reach the required dosing accuracy.  In 
the US, a third-party vendor (Cardinal Health) will be used to prepare the injections to be 
used by the study center. 
Patient ready doses prepared by Cardinal Health for US sites have an expiry.  The measured 
activity of the PRD will be within 10% of the ordered amount (planned dose).  The dose 
should be ordered through IXRS at least 3 days prior to the planned date of administration, 
and should be administered within the specified shelf-life of the individual PRD.  The 
subject’s weight will be submitted with the dose request.  The site is not required to assess 
safety labs prior to placing the order.  Assessments other than weight are repeated (as needed 
to be within the window prior to the dose day / time).  The site must obtain safety labs and 
review the hematology results within 3 days prior to the dose.  If a laboratory result does not 
meet the criterion for dosing, the radium-223 dichloride or placebo dose should not be given. 
Radium-223 dichloride should not be diluted or mixed with any solutions.  If the vials have 
been stored in a refrigerator, they should be left at room temperature for 1 hour prior to use, 
since cold material should not be injected in a subject. 
To maintain traceability, each subject will be assigned 1 syringe label set, with a unique serial 
number.  The serial number will link the vial / batch received with the preparation and 
blinded administration of the syringe. 
For subjects in the placebo arm, a syringe with isotonic saline will be prepared in the same 
way as for the active treatment, including the use of unique serial numbers on the syringe. 


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The study medication will be administered as a slow bolus IV injection.  After administration, 
the equipment used in connection with the preparation and administration of drug are to be 
treated as radioactive waste and should be disposed in accordance with hospital procedure for 
the handling of radioactive material and according to local laws.  Written information about 
radium-223 dichloride and instructions for the handling and injection of radioactive material 
will be provided to study personnel. 
6.4.5 
Dose adjustments for study drug-related adverse events 
In this subject population, disease progression is expected.  Bone pain is a prominent 
symptom; other symptoms may include fatigue, nausea, anorexia, depression, constipation 
(also secondary to opioids), bowel and bladder symptoms, lymphedema, neurological and 
hematological complication, as well as metastases to other organs, such as liver and lung. 
The investigator should delay cytotoxic chemotherapy, other systemic radioisotope, 
hemibody external radiotherapy, or other investigational drug until the subject experiences a 
SSE.  If such treatments must be given during the treatment period, further study drug 
administrations must be discontinued.  These treatments should not be given before a 4-week 
wash-out period after last administration of study drug, provided the subject’s bone marrow is 
not compromised. 
Recommendations 
Every effort will be made to administer the full dosing regimen.  Single dose level adjustment 
of radium-223 dichloride is not permitted.  Treatment delays or discontinuations of 
radium-223 dichloride / placebo may be instituted for the AEs described in Section 6.4.6.1 
and dose adjustments, treatment delays, or discontinuations of abiraterone may be instituted 
for AEs described in Section 6.4.6.2. 
6.4.6 
Dose adjustments, delays, and treatment discontinuations 
Radium-223 dichloride / placebo administration may be delayed by no more than 4 weeks 
(maximum 8 weeks between 2 injections) for recovery of AEs.  If treatment is delayed for 
> 4 weeks (maximum 8 weeks between 2 injections), treatment should be discontinued. 
Treatment with abiraterone may be delayed by no more than 4 weeks for recovery of AEs.  If 
treatment is delayed for > 4 weeks, treatment should be discontinued.  Some AEs as 
described in Section 6.4.6.2 will lead to a reduction in dose.  No more than 2 reductions in 
dose are permitted.  If further dose reductions are considered, treatment should be 
discontinued. 
6.4.6.1 
Radium-223 dichloride / placebo 
Myelosuppression 
Changes in hematology parameters may occur after injection of study drug. 
If a subject experiences NCI-CTCAE Grade 3 to 4 neutropenia, the study drug administration 
should be delayed until recovery to Grade 2 (minimum ANC 1.0 x 109/L) or better. 
In case of thrombocytopenia CTCAE Grade 3 to 4, the study drug administration should be 
delayed until recovery to CTCAE Grade 2 (minimum PLT 50 x 109/L) or better. 
In case of anemia CTCAE Grade 3 to 4, the study drug administration should be delayed until 
recovery to CTCAE Grade 2 (minimum Hb 8.0 g/dL) or better before next study drug 
administration. 


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If a subject experiences CTCAE Grade 3 to 4 neutropenia or thrombocytopenia lasting 
> 2 weeks, the subject must be discontinued from treatment with radium-223 
dichloride / placebo. 
Blood transfusion is acceptable between study drug administrations.  Use of biologic 
response modifiers, such as granulocyte-colony stimulating factor (G-CSF) or granulocyte 
macrophage-colony stimulating factor (GM-CSF), is allowed in the management of acute 
toxicity. 
Gastrointestinal events 
Diarrhea:  No prophylactic treatment for diarrhea is recommended.  Anti-diarrheals can be 
used when needed.  A further dose of study medication should not be given before diarrhea 
has recovered to CTCAE Grade ≤ 2. 
Nausea / Vomiting:  No prophylactic treatments for nausea or vomiting are recommended, 
but anti-emetic drugs can be used when needed.  A further dose of study medication should 
not be given before nausea / vomiting has recovered to CTCAE Grade ≤ 2. 
Constipation:  Subjects can continue laxative as concomitant medication, but start of 
prophylactic treatments before study drug injection are not recommended.  Laxative can be 
used when needed.  A further dose of study medication should not be given before 
constipation has recovered to CTCAE Grade ≤ 2. 
Non-pathological fractures 
For traumatic fracture in weight bearing bones during treatment phase, the study drug 
administration should be delayed 2 to 4 weeks from the time of fracture. 
Treatment must be discontinued in the following cases: 
• If a subject experiences any non-hematological CTCAE Grade 4 toxicity lasting 
> 1 week despite adequate treatment 
• If the period between injections is greater than 8 weeks 
6.4.6.2 
Abiraterone 
Based upon experience from a number of clinical studies, abiraterone acetate is generally 
well tolerated. 
The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, 
edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, 
and contusion. 
The most common laboratory abnormalities (> 20%) are anemia, elevated ALP, 
hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, 
hypophosphatemia, elevated ALT, and hypokalemia.  It has been documented that following 
prolonged therapy with corticosteroids, subjects may develop Cushing’s syndrome 
characterized by central adiposity, thin skin, easy bruising, and proximal myopathy.  
Withdrawal of the corticosteroid may result in symptoms that include fever, myalgia, fatigue, 
arthralgia, and malaise.  This may occur even without evidence of adrenal insufficiency. 
If dose-reduction is used for AE management, 2 dose reductions are allowed for abiraterone.  
At each dose reduction, one tablet of abiraterone will be removed, e.g., 4→3 tablets and 


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3→2 tablets.  Any return to protocol dose level after dose reduction may only be instituted 
after documentation of resolution of the AE. 
Hypokalemia 
At the initial observation of Grade 1 hypokalemia (serum potassium < 3.5 mM or below 
lower limit of normal range, but ≥ 3.0 mM), oral potassium supplement will be initiated.  The 
dose of potassium supplement must be carefully titrated to maintain serum potassium at 
≥ 3.5 mM but ≤ 5.0 mM.  Any subject with low potassium while on study or a history of 
hypokalemia from a pre-existing or concurrent medical condition will undergo weekly or 
more frequent laboratory electrolyte evaluation.  The investigator should consider 
maintaining the subject’s potassium level at ≥ 4.0 mM in these subjects. 
If any subject experiences Grade 3 hypokalemia (serum potassium levels < 3.0 to 2.5 mM, 
NCI-CTCAE v4.03) or life-threatening hypokalemia with potassium levels < 2.5 mM 
(NCI-CTCAE v4.03 Grade 4 hypokalemia), abiraterone will be withheld and 
prednisone / prednisolone tapered.  The subject will hospitalized for IV potassium 
replacement and cardiac monitoring.  Prednisone / prednisolone should then be tapered. 
Table 6–1:  Management of hypokalemia 
Serum potassium 
Grade 
Action 
Further action or maintenance 
Low K+ and / or history of 
hypokalemia 
 
Weekly or more 
frequent laboratory 
evaluations 
Titrate subjects to maintain a serum 
K+ ≥ 3.5 mM ≤ 5.0 mM 
(maintenance at ≥ 4.0 mM is 
recommended) 
< 3.5 mM to 3.0 mM 
1, 2 
Initiate oral K+ 
supplementation 
Titrate subjects to maintain a serum 
K+ ≥ 3.5 mM ≤ 5.0 mM 
(maintenance at ≥ 4.0 mM is 
recommended) 
< 3.0 mM to 2.5 mM 
3 
Withhold abi+pred 
treatment and initiate 
IV K+ and cardiac 
monitoring 
Discuss with Medical Monitor prior 
to re-initiating study treatment 
< 2.5 mM 
4 
Withhold abi+pred 
treatment and initiate 
IV K+ and cardiac 
monitoring 
Discuss with Medical Monitor prior 
to re-initiating study treatment 
Abbreviations:  abi+pred = abiraterone plus prednisone / prednisolone; IV = intravenous; K+ = potassium. 
Hypertension 
• Grade 1 to 2:  Management per investigator.  No abiraterone dose reduction. 
• Grade 3:  Hold abiraterone and taper prednisone / prednisolone treatment.  Adjust or 
add medications to mitigate the toxicity and / or consider the specific 
mineralocorticoid receptor blocker, eplerenone (Inspra).  When hypertension 
resolves to ≤ Grade 1 or baseline, resume abiraterone and prednisone / prednisolone 
at full dose. 
• Grade 4:  Hold abiraterone and taper prednisone / prednisolone treatment.  Adjust or 
add medications to mitigate the toxicity and / or consider the specific 
mineralocorticoid receptor blocker, eplerenone (Inspra).  When hypertension 
resolves to ≤ Grade 1 or baseline, resume abiraterone and prednisone / prednisolone 
with the first dose level reduction (3 tablets, 750 mg of abiraterone). 


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• If toxicity recurs, hold abiraterone and taper prednisone / prednisolone, and adjust or 
add medications to mitigate the toxicity.  When resolved to ≤ Grade 1 or baseline, 
resume abiraterone and prednisone / prednisolone with one dose level reduction 
(2 tablets, 500 mg abiraterone or 3 tablets, 750 mg of abiraterone). 
• If toxicity recurs despite optimal medical management and 2 dose level reductions, 
treatment with abiraterone is to be discontinued and prednisone / prednisolone is to 
be tapered. 
Edema or Fluid Retention 
• Pedal edema:  Supportive management per investigator.  No abiraterone dose 
reduction. 
• Anasarca and / or pulmonary edema requiring supplemental oxygen:  Hold treatment 
with abiraterone and taper prednisone / prednisolone.  Adjust or add medications to 
mitigate the toxicity and / or consider the specific mineralocorticoid receptor 
blocker, eplerenone (Inspra).  When toxicity resolves to ≤ Grade 1, resume 
abiraterone and prednisone / prednisolone at full dose. If toxicity recurs, hold 
abiraterone and taper prednisone / prednisolone, and adjust or add medications to 
mitigate the toxicity.  When resolved to ≤ Grade 1, resume abiraterone and 
prednisone / prednisolone with the first dose level reduction (3 tablets, 750 mg of 
abiraterone). 
• If toxicity recurs, hold abiraterone and taper prednisone / prednisolone, and adjust or 
add medications to mitigate the toxicity.  When resolved to ≤ Grade 1, resume 
abiraterone and prednisone / prednisolone with the second dose level reduction 
(2 tablets, 500 mg of abiraterone). 
• If toxicity recurs despite optimal medical management and 2 dose level reductions, 
treatment with abiraterone is to be discontinued and prednisone / prednisolone is to 
be tapered. 
Abnormal liver function 
• If Grade 1 increases in AST, ALT, or bilirubin occur (e.g., increase in AST or ALT 
from ULN to 3.0 x ULN; increase in total bilirubin from ULN to 1.5 x ULN), the 
frequency of liver function test monitoring should be increased, if the investigator 
judges that the laboratory abnormalities are potentially related to study medication.  
No reduction of abiraterone dose is required. 
• If Grade 2 increases in AST, ALT, or bilirubin occur (e.g., increase in AST or ALT to 
> 3.0 to 5 x ULN; increase in total bilirubin from > 1.5 to 3 x ULN), the frequency 
of liver function test monitoring should be increased to ≥ once a week, if the 
investigator judges that the laboratory abnormalities are potentially related to study 
medication.  No reduction of abiraterone dose is required. 
• If Grade 3 increases in AST, ALT, or bilirubin occur (e.g., increase in AST or ALT to 
> 5 x ULN; increase in total bilirubin to > 3 x ULN), hold abiraterone and taper 
prednisone / prednisolone and all other concomitant medications that are potentially 
hepatotoxic.  Frequent laboratory evaluations (at least once weekly) should be 
conducted until the liver function tests return to baseline value or Grade 1.  Liver 


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enzyme measurements should be made immediately, regardless of when the next 
study visit or monitoring interval is scheduled. 
o 
If abiraterone and prednisone / prednisolone resumption is considered for 
subjects who have experienced Grade 3 increases in AST, ALT, or bilirubin, 
and the medical monitor agrees, resume abiraterone and 
prednisone / prednisolone with the first dose level reduction (3 tablets, 
750 mg of abiraterone) when Grade 3 toxicities resolve to Grade 1 or 
baseline. 
o 
If Grade 3 increases in AST, ALT, or bilirubin recur after the first dose 
reduction, hold abiraterone and taper prednisone / prednisolone and all other 
concomitant medications that are potentially hepatotoxic.  Frequent 
laboratory evaluations should be conducted (at least once weekly) until the 
liver function tests return to baseline value or Grade 1.  Liver enzyme 
measurements should be made immediately, regardless of when the next 
study visit or monitoring interval is scheduled. 
o 
If abiraterone and prednisone / prednisolone resumption is considered for 
subjects who have experienced Grade 3 increases in AST, ALT, or bilirubin 
with the first dose reduction, and the medical monitor agrees, resume 
abiraterone and prednisone / prednisolone with the second dose level 
reduction (2 tablets, 500 mg of abiraterone) when AST, ALT, or bilirubin 
returns to baseline value or Grade 1. 
• If Grade 4 increases in AST, ALT, or bilirubin occur (e.g., increase in AST or ALT to 
> 20 x ULN; increase in total bilirubin to > 10 x ULN), subjects must discontinue 
abiraterone and taper prednisone / prednisolone immediately and will not be 
re-challenged.  They should be followed until resolution of abnormal liver function 
tests. 
Non-mineralocorticoid-based side effects  
• If Grade 1 to 2 toxicities occur, give supportive care per institutional guidelines.  No 
reduction of abiraterone dose is required. 
• If Grade 3 or higher toxicities, including headache, nausea, vomiting, or any other 
toxicity judged to be related to study treatment, is observed where the subject’s 
safety is jeopardized, hold abiraterone and taper prednisone / prednisolone.  When 
toxicity resolves to ≤ Grade 1, resume abiraterone and prednisone / prednisolone at 
full dose.  
o 
If toxicity recurs, hold abiraterone, and adjust or add medications to mitigate 
the toxicity.  When resolved to ≤ Grade 1, resume abiraterone and 
prednisone / prednisolone with the first dose level reduction (3 tablets, 
750 mg of abiraterone).  
o 
If toxicity recurs, hold abiraterone and taper prednisone / prednisolone, and 
adjust or add medications to mitigate the toxicity.  When resolved to 
≤ Grade 1, resume abiraterone and prednisone / prednisolone with the second 
dose level reduction (2 tablets, 500 mg of abiraterone).  


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o 
If toxicity recurs despite aggressive medical management and 2 dose level 
reductions, discontinue treatment with abiraterone and taper 
prednisone / prednisolone.  
6.4.7 
Supportive care guidelines 
Ancillary Treatment (guidelines) 
• Persistent neutropenia (neutrophils / granulocytes CTCAE Grade 4 (< 0.5 x 109/L) 
without fever:  These subjects may be started on G-CSF 5 µg/kg/d subcutaneously 
until the neutrophil count has reached the local hospital’s reference range. 
• Neutropenia with fever (neutrophils / granulocytes CTCAE Grade 3 to 4 
(< 1 x 109/L); fever > 38.5°C):  Blood cultures will be obtained and the subject 
started on empiric antibiotics for as long as clinically indicated.  It is highly 
recommended that the subject receive G-CSF 5 µg/kg/d subcutaneously until the 
neutrophil count has reached the local hospital’s reference range with 2 separate 
measurements, at least 12 hours apart. 
• Severe thrombocytopenia (CTCAE Grade 4 [< 25.0 x 109/L] or bleeding with CTCAE 
Grade 3 to 4 (< 50.0 x 109/L):  Platelets will be transfused to maintain PLT 
>50 x 109/L or higher if clinically indicated to control bleeding.  Epsilon 
aminocaproic acid may be given to subjects with mucosal bleeding and PLT 
CTCAE Grade 3 to 4. 
• Severe anemia (Hb CTCAE Grade 3 [< 80 x 109 g/L; 8.0 g/dL; 4.9 mmol/L]):  
Subjects will be transfused with packed red cells to maintain Hb value > 80 g/L; 
8.0 g/dL; 4.9 mmol/L. 
6.5 
Blinding 
Every effort will be made to keep the study blinded.  Subjects will be randomized to receive 
radium-223 dichloride or placebo in a double-blind fashion; however, treatment with 
abiraterone and prednisone / prednisolone will be the same in both treatment arms and will be 
provided in an open-label format. 
Due to the nature of radium-223 dichloride, there must be at least 2 persons in the study 
center’s nuclear medicine department who are unblinded to the treatment arms assigned to 
subjects.  One of these unblinded individuals will serve as back-up for the other.  In order to 
maintain the study blind for the hospital personnel who provide treatment to the subject, the 
unblinded person at the study center will be responsible for filling the syringe with the correct 
amount of radium-223 dichloride or placebo (saline) and labeling it.  Both radium-223 
dichloride and placebo are clear solutions; thus, syringes with radium-223 dichloride and 
placebo cannot be distinguished from each other visually.  The person performing the 
administration of study drug must be blinded to the treatment arm.  The subject will not be 
told whether they have received radium-223 dichloride or placebo.  All treating physicians, 
clinical staff, subjects, and sponsor personnel will be blinded as to the treatment to which a 
subject is randomized, except for named representatives who will perform the verification of 
the drug accountability at the study centers and drug ordering. 


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Unblinding 
In compliance with applicable regulations, in the event of a suspected unexpected serious 
adverse reaction (SUSAR) (see Section 7.5.1.5), the subject’s treatment code will usually be 
unblinded before reporting to the health authorities, ethic committees (see Section 7.5.1.4) if 
the SUSAR was related to the blinded treatment.  Investigators may only unblind subjects 
under emergency unblinding rules.  If a subject is unblinded by the investigator, they must 
discontinue study drug(s). 
Investigators should note that the occurrence of a SAE or progressive disease (PD) should not 
routinely precipitate the immediate unblinding of the label.  If emergency unblinding is 
necessary for the treatment of a subject for a SAE, the study treatment can be unblinded via 
the IXRS (refer to the IXRS manual for instructions). 
The participating site has unrestricted and immediate access to break the treatment code in 
IXRS.  Should the blind code be broken for a subject, the medical monitor or designee should 
be contacted by the Principal Investigator within one working day of unblinding to discuss 
the rationale for the premature unblinding. 
Individual subjects may be unblinded per investigator’s request after they have a SSE, 
allowing the investigator to determine if the subject would be a candidate to receive treatment 
with radium-223 dichloride.  This would be an option if the subject had been randomized to 
the control arm of the trial and radium-223 dichloride was approved in the country where the 
subject was under treatment. 
The study will be unblinded for analysis purposes at the time of the final analysis of SSE-FS.  
However, no subject-level unblinding information will be communicated to the sites until the 
final OS analysis has been completed. 
Following the IDMC’s recommendation, the study was prematurely unblinded in NOV 2017 
and subject level unblinding information has been communicated to the sites. 
6.6 
Drug logistics and accountability 
All study drugs will be stored at the investigational study center in accordance with Good 
Clinical Practice (GCP) and GMP requirements and the instructions given by the clinical 
supplies department of the sponsor and will be inaccessible to unauthorized personnel. 
In some countries / study centers it will be required to use a third party vendor to prepare the 
injections to be used by the study center.  A log of study medication (received, administered 
to subjects, and destroyed) must be maintained and signed by the dedicated person 
responsible for drug handling at each center.  Any labels or mandatory logs provided by the 
sponsor are to be utilized according to instructions.  A copy of study drug documentation will 
be collected for the sponsor file. 
The responsible study center personnel will use the study drug only within the framework of 
this clinical trial and in accordance with this protocol.  Instructions for drug handling, 
logistics, and accountability will be reviewed with study staff prior to the initiation of the 
study.  Summaries of these instructions are provided below. 
For radium-223 dichloride:  
Radium-223 dichloride will be shipped to study center upon IXRS shipment request.  Lead 
times differ per country but the shipment will arrive at the study center one day before the 


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planned treatment at the latest.  The responsible unblinded study center personnel will 
confirm receipt of sponsor-supplied study drug via IXRS. 
The unblinded person at the study center is responsible for drug accountability.  A dedicated 
unblinded person representing the sponsor will monitor the drug accountability logs.  Receipt, 
distribution, and destruction of the study drug must be properly documented according to the 
sponsor’s agreed and specified procedures.  An unblinded monitor will review overall drug 
accountability and destruction per the study center documentation only.  The remains of 
radioactivity and contaminated material (i.e., vials, syringes, containers) should be disposed 
of in accordance with the local regulations and the hospital procedure, respectively.  A log of 
radium-223 dichloride (received, administered to subjects, and destroyed) must be maintained 
and signed and the appropriate eCRF pages completed by the unblinded person responsible 
for drug handling at each center. 
For abiraterone and prednisone / prednisolone: 
Abiraterone and prednisone / prednisolone will be shipped to the study center upon IXRS 
shipment request.  The responsible site personnel will confirm receipt of sponsor-supplied 
study drug in writing and / or via IXRS.  A log of this study medication (assigned, dispensed, 
administered to subjects, returned to site by subject, and destroyed) must be maintained and 
signed by the dedicated person responsible for drug handling at each center in addition to the 
completion of the appropriate pages of the eCRF.  All study drug packages assigned (opened, 
unopened, or empty) must be stored until the drug accountability has been completed by the 
monitor.  Based on its mechanism of action, abiraterone acetate may harm a developing fetus; 
therefore, women who are pregnant or women who may be pregnant should not handle 
abiraterone acetate without protection, e.g., gloves. 
For isotonic saline (placebo): 
Isotonic saline (placebo) will be provided by the study center pharmacy.  Drug accountability 
for saline will also be performed.  At a minimum, storage conditions, dispensing, batch 
numbers, and expiry dates will be retained in the study center files.  All study drug packages 
assigned (opened, unopened, or empty) must be stored until the drug accountability has been 
completed by the monitor or unblinded monitor (for saline accountability).  Thereafter, the 
packages should be disposed in accordance with the local regulations and the hospital 
procedure, respectively.  A log of locally provided study medication (assigned, dispensed, 
administered to subjects, returned to study center by subject, and destroyed) must be 
maintained and signed by the dedicated person responsible for drug handling at each center. 
6.7 
Treatment compliance 
Subjects will receive treatment with radium-223 dichloride / placebo under supervision of a 
physician licensed in the administration of radioisotopes.  Unblinded study personnel will 
check the administration volume and total radioactivity injected.  The dose activity and the 
volume injected will be recorded in a study drug log and the eCRF pages, neither of which 
will be available to the blinded treating physician or blinded site personnel.  Only the 
unblinded monitor will review overall drug accountability and destruction per the site 
documentation. 
Daily intake of abiraterone and prednisone / prednisolone will be the responsibility of the 
subject or his at-home caregiver, or clinic staff if the subject is hospitalized.  Compliance will 
be monitored by pill counts performed on returned used medication bottles at each study 


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visit.  Pill counts will be recorded on the non-investigational product study dispensing log 
and on the appropriate eCRF page. 
6.8 
Post-study treatment therapy 
Treatment with radium-223 dichloride / placebo will be halted following completion of the 
full assigned treatment (6 injections every 4 weeks) or at early termination.  Further treatment 
with abiraterone and prednisone / prednisolone should be continued until the time of disease 
progression or other withdrawal criteria occur. 
At the end of an individual subject’s participation in the trial or the EOS, subjects will be 
treated and followed as per the institutional standard of care and / or according to the 
physician’s clinical judgment.  Details of post-study anti-cancer treatment will be recorded on 
the appropriate eCRF page. 
During follow-up, radium-223 dichloride should not be given concurrently with abiraterone 
plus prednisone/prednisolone. 
In case a subject is still on oral study treatment at the EOS and still benefits based on the 
investigator’s opinion after 7 years of follow-up, options for treatment continuation (e.g., 
switch to commercial drug supply, a continued access program, or any other means of 
continued drug supply) will be discussed and agreed between the investigator, sponsor, and the 
subject in compliance with local regulations. 
6.9 
Prior and concomitant therapy 
At baseline screening, all prior cancer-related treatments are to be recorded. 
All concomitant medications taken by the subject from signing of the ICF to 4 weeks after 
last study drug administration must be recorded in the eCRF.  Thereafter, until the end of the 
active follow-up period, only medications given to treat any grade AEs related to the study 
drug and any subsequent anti-cancer treatment medication need to be recorded in the eCRF.   
The generic name and trade name of each prior or concomitant medication, its indication, 
dosage, and, when applicable, the start and stop dates will be recorded.   
The sponsor’s representative will code all therapy and medication according to 
well-recognized dictionaries of medical codes. 
It is not required to report the administration of contrast media or radioactive tracer in 
conjunction with the protocol-specified radiological procedure (computed tomography [CT] 
or bone scan) on the concomitant medications eCRF page unless there is an AE related to the 
administration of the contrast agent (e.g., an allergic reaction related to the administration of 
a contrast agent) or the tracer. 
6.9.1 
Prohibited concomitant therapy 
Abiraterone is administered as part of the study therapy.  No other anti-androgen therapies 
(except LHRH agonists and antagonists, see Section 6.9.2) are permitted. 
Subjects receiving bisphosphonates or denosumab prior to randomization may be maintained 
on such therapy throughout all or part of the study.  The bisphosphonate or denosumab 
treatment may be stopped at the discretion of the investigator.  Based on the available data on 
radium-223 dichloride, the option of starting a bone health agent (BHA) including 


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bisphosphonates or denosumab should be considered, taking into consideration applicable 
guidelines. 
Other cancer treatment with established efficacy in prostate cancer, including but not limited 
to cytotoxic chemotherapy, estrogens (e.g., stilbestrol), ketoconazole, other systemic 
radioisotope or hemibody external radiotherapy, or other investigational drugs, should not be 
used during the treatment period.  If such treatments are considered to be the best standard of 
care during the treatment period, further study drug administrations must be discontinued and 
the subject should enter the active follow-up period. 
All medication for the clinical benefit or supportive care for the subject may be provided at 
the discretion of the investigator. 
Note that all treatments for prostate cancer, including other investigational drugs taken after 
withdrawal from treatment with radium-223 dichloride or placebo, will be recorded in the 
eCRFs until the end of the active follow-up period without clinic visits. 
The following concomitant therapies are prohibited during screening, between 
randomization and the start of treatment, and during the treatment phase of the study: 
• Systemic glucocorticoids, unless clinically indicated to treat a life-threatening acute 
medical condition 
• 5 α-reductase inhibitor 
• Chemotherapy 
• Immunotherapy, e.g., sipuleucel-T 
• Bicalutamide, nilutamide, flutamide, enzalutamide 
• Systemic ketoconazole (or other azole drugs such as fluconazole and itraconazole) 
• Diethylstilbestrol, PC-SPES, and other preparations such as saw palmetto thought to 
have endocrine effects on prostate cancer 
• Radiopharmaceuticals such as strontium-89 or samarium-153 
• Aldactone, Spironol (spironolactone) 
• Digoxin, digitoxin, and other digitalis drugs 
• Cyproterone acetate 
• Fludrocortisone acetate (Florinef) 
Please note the following cautions: 
• Caution is advised when abiraterone acetate is administered with drugs activated by or 
metabolized by CYP2D6, particularly with drugs that have a narrow therapeutic 
index.  Dose reduction of narrow therapeutic index drugs metabolized by CYP2D6 
should be considered. 
• Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, 
rifapentine, phenobarbital) during treatment with abiraterone acetate are to be 
avoided. 


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• Abiraterone inhibits CYP2C8 in vitro.  Subjects should be monitored closely for signs 
of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone 
acetate. 
During follow-up, radium-223 dichloride should not be given concurrently with abiraterone 
plus prednisone/prednisolone. 
6.9.2 
Permitted concomitant therapy 
The following supportive care medications are considered permissible during the study: 
• LHRH agonists or antagonists to maintain testosterone < 50 ng/dL (< 1.7 nmol/L) 
• Conventional multivitamins, selenium, and soy supplements 
• Additional systemic glucocorticoid administration such as “stress dose” 
glucocorticoid is permitted if clinically indicated for a life threatening medical 
condition, and in such cases, the use of steroids will be documented as concomitant 
drug. 
• Bisphosphonates or denosumab usage is allowed.  Based on the available data on 
radium-223 dichloride, the option of starting a BHA including bisphosphonates or 
denosumab should be considered, taking into consideration applicable guidelines. 
• Blood transfusions and treatment with erythropoietin stimulating agents are allowed 
after randomization (if required to ensure that the treatment range for Hb ≥ 8.0 g/dL 
is met at Day 1 of each cycle) but not within 4 weeks prior to screening and during 
the screening period. 
• Use of biologic response modifiers, such as G-CSF or GM-CSF, is allowed in the 
management of acute toxicity, such as febrile neutropenia, when clinically indicated 
or at the discretion of the investigator. 
• Analgesic use will be captured via electronic patient-reported outcome (ePRO) device 
and the eCRF (analgesic consumption diary and recorded analgesics, respectively, 
see schedule of assessments, Table 7–1).  Subjects will be asked to track their 
analgesic use on an ePRO / analgesic consumption diary for 1 week prior to their 
clinic visit (6 days prior to the visit plus the day of the visit).  Each day the pain 
question is asked of the subject, the subject should be asked to record any pain 
medication they took that day.  Any medication taken for pain, whether for palliation 
of bone pain or relief of other type of pain, and any changes should be recorded in 
the eCRF at each visit.  Note that analgesic medication should be recorded in the 
eCRF until the end of the treatment period while EBRT treatment should be 
recorded in the eCRFs until end of the active follow-up period without clinic visits. 
7. 
Procedures and variables 
7.1 
Schedule of procedures 
All laboratory values will be conducted by local laboratories. 


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7.1.1 
Tabulated overview 
Efficacy and safety measurements obtained during the course of the study are summarized in 
the schedule of assessments (Table 7–1). 


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Table 7–1:  Schedule of assessments 
 
Study Period 
Screeninga 
 
Treatmentb,c 
 
End of Active 
Follow-up 
 
Long-term  
Follow-up 
Radium-223 dichloride / Placebo + Abiraterone 
acetate + Prednisone 
Abiraterone acetate + 
Prednisone 
EOT 
visit 
 
 
 
 
 
LT 
FU 
End 
of 
LT 
FU 
Visit: 
0-1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12+ 
- 
 
 
 
 
- 
- 
Cycle: 
- 
1 
2 
3 
4 
5 
6 
7 
8+ 
- 
 
 
 
 
- 
- 
Timing: 
Day -14 to 
Day 0 
Day 1 
Day 15d 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 1 
Day 1 
28 days 
post-
last 
dose of 
Ra-223 
/ PLC 
q4 wk until disease 
progressiond,e 
4 wk/ 
6 mof 
 
 
 
 
q6 mo 
until 
deathi 
 
Window (days): 
+7 
 
±3 
+7 
±3 
+7 
±3 
+7 
+7 
+7 
± 7 
± 7 
± 7 
 
 
 
 
± 14 
 
Informed consentj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject ID 
assignment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationa 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HRQoL NCCN-
FACT FPSI-17 form 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
HRQoL EQ-5D form 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
BPI-SFk 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Resource utilization 
questionnaire 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
AEs, SAEs, new 1° 
malignancies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Xm,n 
 
Xm,n 
Xm,n 
Bone fractureo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
Prior and con medsp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 


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Table 7-1:  Schedule of assessments (continued) 
Study Period 
Screeninga 
 
Treatmentb,c 
 
End of Active 
Follow-up 
 
Long-term  
Follow-up 
Radium-223 dichloride / Placebo + Abiraterone 
acetate + Prednisone 
Abiraterone acetate + 
Prednisone 
EOT 
visit 
 
 
 
 
 
LT 
FU 
End 
of 
LT 
FU 
Visit: 
0-1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12+ 
- 
 
 
 
 
- 
- 
Cycle: 
- 
1 
2 
3 
4 
5 
6 
7 
8+ 
- 
 
 
 
 
- 
- 
Timing: 
Day -14 to 
Day 0 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 1 
Day 1 
28 days 
post-
last 
dose of 
Ra-223 
/ PLC 
q4 wk until 
disease 
progression d,e 
4 wkf 
 
 
 
 
q6 mo 
until 
deathi 
 
Window (days): 
+7 
 
±3 
+7 
±3 
+7 
±3 
+7 
+7 
+7 
± 7 
± 7 
± 7 
 
 
 
 
± 14 
 
Cancer-related txq 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Xn 
 
X 
X 
Analgesic 
consumption diary 
(ePRO)r 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Record 24h analgesic 
user 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Vital signss 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
12-lead ECG (at the 
discretion of the 
investigator) 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
Weight (kg) 
X 
Xt 
X 
Xt 
X 
Xt 
X 
Xt 
Xt 
Xt 
X 
X 
X 
 
 
 
 
 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
ECOG-PS 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
Hematologyu 
Xv 
Xw 
 
Xw 
 
Xw 
 
Xw 
Xw 
Xw 
X 
X 
X 
 
 
X 
 
 
 
Clinical chemistryx 
X 
Xy 
X 
Xy 
X 
Xy 
X 
Xy 
Xy 
Xy 
X 
X 
X 
 
 
X 
 
 
 
Coagulation panelz 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum testosterone (at 
the discretion of the 
investigator) 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
PSA 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 


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Table 7-1:  Schedule of assessments (continued) 
Study Period 
Screeninga 
 
Treatmentb,c 
 
 
End of Active 
Follow-up 
 
Long-term  
Follow-up 
Radium-223 dichloride / Placebo + Abiraterone acetate + 
Prednisone 
Abiraterone acetate + 
Prednisone 
EOT 
visit 
 
 
 
 
 
LT FU 
End of LT FU 
Visit: 
0-1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12+ 
- 
 
 
- 
- 
- 
- 
Cycle: 
- 
1 
2 
3 
4 
5 
6 
7 
8+ 
- 
 
 
- 
- 
- 
- 
Timing: 
Day -14 to 
Day 0 
Day 1 
Day 15d 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 1 
Day 1 
28 days 
post-last 
dose of 
Ra-223 / 
PLC 
q4 wk until 
disease 
progressiond,e 
4 wkf 
 
 
 
 
q6 mo 
until 
deathi 
 
Window (days): 
+7 
 
±3 
+7 
±3 
+7 
±3 
+7 
+7 
+7 
± 7 
± 7 
± 7 
 
 
 
 
± 14 
 
Serum and urine for 
bone biomarkersaa 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Serum and plasma for 
tumor-related 
biomarkersbb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival prostate 
cancer tissue sample 
once 
ECHO or MUGA scan 
Xcc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Technetium-99m bone 
scandd 
Xee 
 
 
 
 
Xff 
 
 
Xff 
 
X 
q12 wkff 
 
 
 
X 
 
 
 
Chest, abdominal and 
pelvic CT scanff,gg,hh 
Xii 
 
 
 
 
Xff 
 
 
Xff 
 
X 
q12 wkff 
 
 
 
X 
 
 
 
Progression 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
SSEs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Xn 
 
 
 


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Table 7-1:  Schedule of assessments (continued) 
Study Period 
Screeninga 
 
Treatmentb,c 
 
End of Active 
Follow-up 
 
Long-term  
Follow-up 
Radium-223 dichloride / Placebo + Abiraterone acetate + 
Prednisone 
Abiraterone acetate + 
Prednisone 
EOT 
visit 
 
 
 
 
 
LT FU 
End 
of LT 
FU 
Visit: 
0-1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12+ 
- 
 
 
 
 
- 
- 
Cycle: 
- 
1 
2 
3 
4 
5 
6 
7 
8+ 
- 
 
 
 
 
- 
- 
Timing: 
Day -14 to 
Day 0 
Day 1 
Day 15d 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Day 1 
Day 1 
28 days 
post-last 
dose of 
Ra-223 / 
PLC 
q4 wk until 
disease 
progressiond,e 
4 wkf 
 
 
 
 
q6 mo 
until 
deathi 
 
Window (days): 
+7 
 
±3 
+7 
±3 
+7 
±3 
+7 
+7 
+7 
± 7 
± 7 
± 7 
 
 
 
 
± 14 
 
Ra-223 order (if 
applicable)jj 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Abi+pred orderjj 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Survival status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Xn 
 
Xn 
Xn 
Radium-223 Cl2 or 
placebo injectionkk 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Abi+pred 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
PK samplingll 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug accountabilitymm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Abbreviations:  abi+pred = abiraterone plus prednisone / prednisolone; AE = adverse event; BPI-SF = brief pain index-short form; Cl2 = dichloride; con med = concomitant medication; CT = 
computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; eCRF = electronic case report form; 
EOT = end of treatment; ePRO = electronic patient reported outcome; EQ-5D = European quality of life-5 dimensions; HRQoL = health-related quality of life; ID = identification number; IMP = 
investigational medicinal product; IXRS = interactive voice / web response system; LT FU = long-term follow-up; mo = month; MUGA = multi-gated acquisition; NCCN-FACT FPSI-17 = 
functional assessment of cancer therapy / National Comprehensive Cancer Network prostate cancer symptom index 17 item questionnaire; PK= pharmacokinetic; PLC = placebo; PRD = patient 
ready dose; PSA = prostate specific antigen; PT-INR = prothrombin time-international normalized ratio; PTT = partial thromboplastin time; Ra-223 = radium-223 dichloride; q = every; SAE = 
serious adverse event; SSE = symptomatic skeletal event; tx = treatment; US = United States; wk = week; W/O = without. 
 
 
 


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a. 
All screening evaluations must be complete and reviewed prior to randomization.  Screening evaluations must be complete within 2 weeks (+ 7 days) prior to randomization.  If all screening 
data are available and the subject is eligible for the study, randomization may occur at the end of the screening visit.  In the US, Cycle 1, Day 1 should occur at least 7 days after 
randomization, whenever possible. 
b. 
All assessments at treatment visits should be performed before study drug administration. 
c. 
Footnote removed in Amendment 7; not applicable after the final OS analysis. . 
d. 
Any unscheduled visits are to be conducted in the same manner as visits described for Visits 12+. 
e. 
Every 4 weeks until the discontinuation of abiraterone as IMP plus prednisone / prednisolone  
f. 
EOT follow-up visit will be conducted 4 weeks after last dose of abiraterone as IMP and prednisone / prednisolone  
g. 
Footnote removed in Amendment 7; not applicable after the final OS analysis. 
h. 
Footnote removed in Amendment 7; not applicable after the final OS analysis. 
i. 
Telephone follow-up every 6 months (± 14 days) for a maximum of 7 years post the last study treatment, until death, or the subject is transitioned to a separate extended safety follow-up 
study for radium-223 dichloride. 
j. 
Informed consent is to be collected before the initiation of any study-related procedures. 
k. 
Footnote removed in Amendment 7; not applicable after the final OS analysis. 
l. 
All (S)AEs, regardless of grade or relatedness, that occur during the treatment period and up to 4 weeks after the last administration of abiraterone as IMP and prednisone / prednisolone 
must be reported. 
m. All treatment-related AEs and SAEs occurring during the long-term follow-up period are to be documented. 
n. 
It is the clinical site’s responsibility to obtain and make available the source documentation for the information collected from the telephone call and to document it in the eCRF. 
o. 
All fractures and bone associated events (e.g., osteoporosis) occurring during the treatment periodand long-term follow up period need to be reported as either AEs or SAEs if the criteria of 
SAE were met, regardless of the investigator’s causality assessment. Since the definition for measuring skeletal events will not use pre-specified imaging assessments, the use of imaging to 
identify a fracture or spinal cord compression will be triggered by symptoms.  As such, only symptomatic events will be captured. Scans will be read locally. 
p. 
At baseline screening, all prior concomitant medications are to be recorded.  Thereafter, collect all concomitant medications up to 4 weeks post last study drug administration.  Analgesic use 
has to be recorded via the analgesic concomitant medication eCRF.   
q. 
Record any cancer-related treatments or medications (including androgen synthesis inhibitors / androgen receptor antagonists; excluding analgesics). 
r. 
Footnote removed in Amendment 7; not applicable after the final OS analysis. 
s. 
The measurement of vital signs will include:  blood pressure, heart rate, respiratory rate, and temperature. 
t. 
Subject’s weight should be re-checked prior to each injection to calculate appropriate drug dosing.  Weight is to be measured within 3 days prior to dosing for non-US sites and 3 to 5 days 
prior to dosing for US sites.  For US sites using the central PRD depot only, the subject weight for the dose day must be reported in a timely manner to the country PRD depot to allow 
adequate time for the PRD preparation and delivery.  All efforts should be made to measure weight at the same visit with the pre-dose laboratory assessments in order to avoid 2 pre-dose 
clinic visits.  Subjects at non-US sites only should be reweighed on the day of dose administration; the final dose to be administered should be determined using that weight.  Subjects should 
not be weighed more than once or at different departments on the day of the administration to avoid the potential use of different weights.  Subjects at US sites will not be measured on the 
day of dosing. 
u. 
Hematocrit, hemoglobin, platelet counts, red blood cell counts, white blood cell counts, and white blood cell differential.  Subjects with abnormal platelet count or white blood cell counts at 
EOT should be followed until resolution. 
v. 
The screening hematology values are recommended to be measured within 1 week prior to randomization if feasible (a 2-week maximum is permitted) and the first injection should be done 
as soon as possible after randomization. 
w. Blood sample for hematology must be taken, analyzed, and evaluated within 3 days prior to each study drug administration. 
x. 
Sodium, potassium, chloride, calcium, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, total alkaline phosphatase, serum creatinine, blood urea nitrogen, 
bilirubin (total), and albumin. 
y. 
Blood sample for clinical chemistry must be taken within 3 days prior to each study drug administration, but may be evaluated after the administration, if results are not available. 


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z. 
Subjects treated with warfarin or heparin will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of PT-
INR / PTT will be required until stability is achieved (as defined by local standard of care and based on pre-study PT-INR / PTT values). 
aa. Footnote removed in Amendment 7; not applicable after the final OS analysis.  
bb. Footnote removed in Amendment 7; not applicable after the final OS analysis. 
cc. A MUGA scan or a cardiac ECHO should be obtained.  A MUGA scan or cardiac ECHO taken within 4 weeks prior to randomization is acceptable. 
dd. Scans to be scheduled for Cycle 3, Day 1, Cycle 5, Day 1, and Cycle 7, Day 1 and then every 12 weeks.  Scans will be read locally .  The time window for the scans is ± 7 days.  If a subject 
experiences radiological progression, whole body technetium-99m bone scan can be discontinued. 
ee. A historic bone scan is acceptable if taken within 4 weeks of randomization.  If one is not available, it will be required as part of the protocol procedures within the screening period. 
ff. Scans to be scheduled for Cycle 3, Day 1, Cycle 5, Day 1, and Cycle 7, Day 1 and then every 12 weeks until discontinuation of study treatment (except in cases where local regulations 
apply).  The time window for the scans is ± 7 days.  If a subject experiences radiological progression, MRI / CT scan of chest, abdomen, and pelvis can be discontinued.  
gg. Chest / abdominal / pelvic magnetic resonance imaging will be accepted instead of chest / abdominal / pelvic CT. 
hh. To maintain a consistent evaluation of each subject, the same imaging technique and procedure must be used through the assessment periods.  Any unexpected abnormality must be reported 
by the site personnel to the treating physician or the subject’s general practitioner. 
ii. 
A historic chest / abdominal / pelvic CT is acceptable if taken within 4 weeks of randomization.  If not available, a scan is required as part of the protocol within the screening period. 
jj. 
IXRS drug (re-)supply order should be coordinated at each study visit to coincide with delivery prior to the subject’s next scheduled study visit. 
kk. The minimum time window between 2 injections of radium-223 dichloride / placebo must be 4 weeks. 
ll. 
For those study sites that participate in abiraterone PK sampling, serial blood samples will be collected for subjects in Subgroup 1 at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours 
post-administration of abiraterone on Cycle 1, Day 8 or Cycle 2, Day 8 only.  These samples will undergo non-compartmental analysis.  Blood samples for subjects in Subgroup 2 will be 
collected prior to abiraterone administration on Cycle 1, Days 8 and 15 (Visit 3) and Cycle 2, Days 1 (Visit 4), 8, and 15 (Visit 5).  In addition, a second blood sample will be collected for 
subjects in Subgroup 2 at each of these visits, 0.5 to 3 hours post administration of abiraterone.  These samples will undergo population PK analysis. 
mm. Based on its mechanism of action, abiraterone acetate may harm a developing fetus; therefore, women who are pregnant or women who may be pregnant should not handle abiraterone 
acetate without protection, e.g., gloves. 
 
 


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7.1.2 
Timing of assessments 
At any time during the study an archival prostate cancer tissue sample should be collected 
and stored.  This sample is only to be collected once. 
7.1.2.1 
Screening period (Visit 1) 
Pre-treatment evaluations will only be performed after the subject has agreed to participate 
and has signed and dated the ICF.  No treatment or trial-related procedures will be initiated 
before the signed consent has been obtained.  Imaging may be done before obtaining 
informed consent if done routinely.  Subjects will not be required to undergo additional 
scanning if suitable images taken within 4 weeks of randomization are available.  
Pre-treatment evaluations will be performed according to the eligibility criteria.  If the subject 
is eligible for the study, the parameters at the screening visit showing subject health status, 
including blood values, will be recorded in the eCRF. 
The following procedure and evaluations will be performed within 2 weeks (+ 7 days) prior 
to randomization: 
• Sign informed consent 
• Subject registration and subject number assignment via IXRS 
• Review of inclusion and exclusion criteria and confirm eligibility 
• Demographics 
• Record disease history 
• Record medical history  
• Record AEs 
• Record concomitant medications / therapy 
• Record prostate cancer-related treatment (prior and current, including androgen 
synthesis inhibitors / androgen receptor antagonists; excluding analgesics) 
• BPI-SF questionnaire (to be completed using paper) 
• Record analgesics 
• Perform full physical examination 
• 12-lead electrocardiogram (ECG).  Potassium levels should be considered when 
obtaining the ECG.  Hypokalemia should be corrected before ECG collection. 
• Record vital signs:  blood pressure, heart rate, respiratory rate, and temperature 
• Record height (cm) and weight (kg).  The subject’s weight should be rechecked prior 
to each injection to calculate appropriate drug dosing.  Weight is to be measured 
within 3 days prior to dosing for non-US sites and 3 to 5 days prior to dosing for US 
sites. 
• ECOG-PS 


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• A multi-gated acquisition (MUGA) scan or a cardiac echocardiogram (ECHO) should 
be obtained.  A MUGA scan or cardiac ECHO taken within 4 weeks prior to 
randomization is acceptable. 
• A chest / abdominal / pelvic CT if no suitable images taken within 4 weeks prior to 
randomization are available.  (Chest / abdominal / pelvic MRI will be accepted in 
place of chest / abdominal / pelvic CT) 
• Bone technetium-99m scan with careful identification of all disease-related hotspots, if 
no scan taken within 4 weeks prior to randomization is available.  Any confirmatory 
scan such as single photon emission tomography (SPECT) or MRI (with and without 
contrast media) should be obtained or collected if performed within 4 weeks of 
randomization. 
• Blood draw for clinical chemistry:  sodium, potassium, chloride, calcium, ALT, AST, 
LDH, total ALP, serum creatinine, blood urea nitrogen (BUN), bilirubin (total), and 
albumin 
• Serum testosterone  
• PSA level 
• The subjects should be given a handheld electronic device to be used for subject 
questionnaires and the analgesic consumption diary and should receive training in its 
use. 
• Record SSEs during the screening period.  The investigator will assess the subject for 
the following disease events: 
o Use of EBRT to relieve skeletal symptoms 
o New symptomatic pathological bone fractures (vertebral and non-vertebral) 
o Tumor-related orthopedic surgical intervention 
o Spinal cord compression 
• Record survival status 
The following procedures and evaluations should be performed within 1 week prior to 
randomization unless infeasible (a 2-week maximum timeframe is permitted).  Results must 
be available, reviewed, and signed and dated by the investigator prior to randomization. 
• Blood draw for hematology:  hematocrit, Hb, PLT, red blood cell (RBC) counts, WBC 
counts, and WBC differential.  If any values are low, transfusions or bone marrow 
growth factors support are permitted as described in Section 6.9.2. 
• A coagulation panel:  PT, PTT, and INR.  Subjects treated with warfarin or heparin 
will be allowed to participate in the study if no underlying abnormality in coagulation 
parameters exists per prior history; weekly evaluation of PT-INR / PTT will be 
required until stability is achieved (as defined by local standard of care and based on 
pre-study PT-INR / PTT values) 


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The following should occur 3 to 5 days prior to dosing: 
• For US sites using the central PRD depot ONLY, the subject weight for the dose day 
must be reported in a timely manner to the country PRD depot to allow adequate time 
for PRD preparation and delivery.  All efforts should be made to measure weight at 
the same visit with the pre-dose laboratory assessments in order to avoid 2 pre-dose 
clinic visits. 
Important Note:  If rescreening is indicated, it must be completed with approval from the 
medical monitor of the sponsor.  No more than one rescreening attempt will be allowed for 
each subject.  Please refer to Section 5.1 for further guidance on cases in which rescreening is 
allowed and the time window for rescreening. 
7.1.2.2 
Randomization 
Randomization in the IXRS may occur only after the completion of the screening evaluations 
and re-confirmation of subject eligibility.  Randomization may coincide with the end of a 
screening visit if all evaluations are complete; otherwise, randomization may be performed in 
a separate clinic visit.  Once the subject is registered in IXRS, the initial drug shipment will 
be triggered.  In the US, Cycle 1, Day 1 should occur at least 7 days after randomization, 
whenever possible. 
7.1.2.3 
Treatment period 
The treatment period extends from the day of first treatment with radium-223 dichloride / 
placebo to 4 weeks post the final abiraterone as IMP and prednisone / prednisolone treatment. 
The time between randomization and first injection should be as brief as possible in 
accordance with the country-specific drug order lead time. 
During the treatment period, the subject will visit the study center at regular intervals.  
Radium-223 dichloride / placebo will be injected at 4-week intervals for 6 cycles on an 
out-patient basis (Section 7.1).  Abiraterone and prednisone / prednisolone will be taken 
orally on a daily basis. 
It is the responsibility of the unblinded person to calculate the required volume of 
radioactivity (i.e., dose of radium-223 dichloride or saline placebo) for the subject based on 
the subject’s body weight within 3 days prior to administration for non-US sites and 3 to 
5 days prior to administration for US sites and the reference date of the received study 
medication (Section 6.4.3). 
For US sites using the central PRD depot ONLY, the subject weight for the dose day must be 
reported to the country PRD depot in a timely manner to allow adequate time for the PRD 
preparation and delivery.  All efforts should be made to measure weight at the same visit with 
the pre-dose laboratory assessments in order to avoid 2 pre-dose clinic visits. 
Before administration of radium-223 dichloride / placebo, the subject must be well hydrated; 
thus, the subject should be instructed to drink ad libitum.  The blood samples for clinical 
chemistry and hematology should be taken within 3 days before each study drug administration, 
and the hematology parameters must be evaluated before each study drug administration (within 
3 days).  The Hb level should not be lower than 8.0 g/dL within 3 days before any injection. 


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If, prior to first injection, the subject has a Hb level of less than 8.0 g/dL, he should not receive 
study drug and should go directly into the active follow-up period without clinic visits, and may 
then be transfused if needed. 
Between study drug administrations, if Hb levels are below 8 g/dL, the Hb needs to recover to 
8.0 g/dL or higher before next study drug administration.  If there is more than a 4-week delay in 
the next injection (i.e., more than 8 weeks between injections), the study drug should be 
permanently discontinued and the subject should enter the active follow-up period without clinic 
visits.  Treatment of low Hb is acceptable between study drug administrations. 
7.1.2.3.1 
Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each 
visit) 
Assessments to be performed PRIOR to radium-223 dichloride or saline (“study drug”) 
administration: 
• Review handheld device and ensure subjects complete the following: 
o NCCN-FACT FPSI-17 questionnaire 
o European Quality of Life-5 Dimensions (EQ-5D) questionnaire 
o BPI-SF questionnaire for one week (6 days prior to the dosing visit plus the 
day of the dosing visit) 
• Resource utilization questionnaire (to be completed by the site in the eCRF) 
• Recording of analgesic use will be performed by: 
o Analgesic use recorded via the analgesic concomitant medication eCRF 
o Analgesic consumption diary recorded directly on ePRO (handheld device 
completion to be checked by site) to be filled in by the subjects for one week 
(6 days prior to the dosing visit plus the day of the dosing visit) 
o Analgesic use during the last 24 hours recorded in eCRF, by site, assessing 
subject pain medication.  Subjects should bring all pain medication to each 
visit. 
• Record AEs and SAEs; all occurrences of bone fractures and bone associated events 
(e.g., osteoporosis); all occurrences of leukemia, myelodysplastic syndrome, and 
aplastic anemia; and primary bone cancer or any other new primary malignancy. 
o All the imaging scans that confirmed the diagnosis of fractures should be sent 
to the independent review center for central review. 
• Record concomitant medications / therapy 
• Record prostate cancer-related treatment (including androgen synthesis 
inhibitors / androgen receptor antagonists; excluding analgesics) 
• Record weight (kg) (subjects at non-US sites only need to be reweighed on the day of 
dosing) 


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• Record vital signs:  blood pressure, heart rate, respiratory rate, and temperature 
• 12-lead ECG (Cycle 3, Day 1 and Cycle 5, Day 1).  Potassium levels should be 
considered when obtaining the ECG.  Hypokalemia should be corrected before ECG 
collection. 
• Perform full physical examination 
• ECOG-PS 
• Blood draw for hematology evaluation (within 3 days before radium-223 dichloride or 
placebo administration):  hematocrit, Hb, PLT, RBC count, WBC count, and WBC 
differential.  Results to be assessed and documented prior to study drug treatment.  
The Hb values need to be confirmed to be at least 8 g/dL prior to each dose. 
• Blood draw for clinical chemistry:  sodium, potassium, chloride, calcium, ALT, AST, 
LDH, total ALP, creatinine, BUN, bilirubin (total), and albumin (blood sample for 
clinical chemistry must be taken and evaluated within 3 days prior to each study drug 
administration).  Results should be assessed and documented prior to study drug 
treatment, if the clinical chemistry results are available. 
• Serum testosterone (Cycle 1, Day 1 only) (as of Amendment 7, laboratory 
confirmation of testosterone level is only done at the discretion of the investigator) 
• PSA level 
• Blood draws and urine samples for exploratory bone biomarker analysis:  serum and 
urine samples will be collected at Cycle 1, Day 1 and Cycle 4, Day 1. 
• Blood draw for exploratory tumor-related biomarker analysis:  serum and plasma 
samples will be collected at Cycle 1, Day 1. 
• At Visit 6 (Cycle 3, Day 1) and Visit 9 (Cycle 5, Day 1) only: 
o A chest / abdominal / pelvic CT.  The same imaging modalities are to be used 
as were used at baseline.  A chest / abdominal / pelvic MRI will be accepted 
instead of chest / abdominal / pelvic CT only if MRI chest / abdomen / pelvis 
was performed at baseline. 
o Bone technetium-99m scan with careful identification of all disease-related 
hotspots and any confirmatory SPECT or MRI scan (with and without contrast 
media) 
o Bone scans and CT / MRI scans will be read both locally and by independent 
assessment. 
• Record progression 
• Record SSEs.  The investigator will assess the subject for the following disease events: 
o Use of EBRT to relieve skeletal symptoms 
o New symptomatic pathological bone fractures (vertebral and non-vertebral) 


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o Tumor-related orthopedic surgical intervention 
o Spinal cord compression 
• Administer radium-223 dichloride or placebo 
• Dispense abiraterone plus prednisone / prednisolone 
• Perform drug accountability  
• Record survival status 
Assessments to be performed AFTER each injection of radium-223 dichloride or 
placebo: 
• IXRS must be called for drug re-supply in preparation for the next study visit.  This 
should be done on the day of the current treatment visit (where possible) to provide 
the maximum time in advance of the next scheduled subject visit date and in 
accordance with country-specific order lead-times. 
• For US sites using the central PRD depot ONLY, the subject weight for the dose day 
must be reported to the country PRD depot in a timely manner to allow adequate time 
for the PRD preparation and delivery.  All efforts should be made to measure weight 
at the same visit with the pre-dose laboratory assessments in order to avoid 2 pre-dose 
clinic visits. 
For those study sites that participate in abiraterone PK sampling: 
• Subjects in Subgroup 1 will return to the site on Cycle 1, Day 8 or Cycle 2, Day 8.  
Serial blood samples will be collected prior to abiraterone administration and 0.5, 1, 
2, 3, 4, 6, 8, 10, and 24 hours post administration of abiraterone. 
• Subjects in Subgroup 2 will return to the site on Cycle 1 Day 8, Cycle 2, Day 1 
(Visit 4), and Cycle 2, Day 8 (see also Section 7.1.2.3.2).  Blood samples will be 
collected twice at each of these visits:  prior to abiraterone administration and 0.5 to 
3 hours post administration of abiraterone. 
7.1.2.3.2 
Visits 3, 5, and 7 (Cycles 1, 2, and 3, Day 15 ± 3 days)  
Radium-223 dichloride or placebo will not be administered at these visits. 
• Record AEs and SAEs, all occurrences of bone fractures and bone associated events 
(e.g., osteoporosis); all occurrences of leukemia, myelodysplastic syndrome, and 
aplastic anemia; and primary bone cancer or any other new primary malignancy. 
o All the imaging scans that confirmed the diagnosis of fractures should be sent 
to the independent review center for central review. 
• Record concomitant medications / therapy 
• Record prostate cancer-related treatment (including androgen synthesis 
inhibitors / androgen receptor antagonists; excluding analgesics) 
• Recording of analgesic use will be performed by: 


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o Analgesic use recorded via the analgesic concomitant medication eCRF 
• Record vital signs:  blood pressure, heart rate, respiratory rate, and temperature 
• Record weight 
• Blood draw for clinical chemistry:  sodium, potassium, chloride, calcium, ALT, AST, 
LDH, total ALP, creatinine, BUN, bilirubin (total), and albumin 
• Record progression 
• Record SSEs 
• Perform drug accountability 
For those study sites that participate in abiraterone PK sampling: 
• Subjects in Subgroup 2 return to the site on Cycle 1, Day 15 (Visit 3) and Cycle 2, 
Day 15 (Visit 5) (see also Section 7.1.2.3.1).  Blood samples will be collected twice at 
each of these visits:  prior to abiraterone administration and 0.5 to 3 hours post 
administration of abiraterone. 
• Record survival status 
7.1.2.3.3 
Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks 
thereafter ± 7 days) and unscheduled visits up until discontinuation 
of abiraterone as IMP and prednisone / prednisolone  
During these visits, subjects will no longer receive treatment with radium-223 dichloride or 
placebo, but should continue to receive therapy with abiraterone plus 
prednisone / prednisolone.  The following assessments are to be performed on Cycle 7, Day 1 
and every 4 weeks thereafter until discontinuation of abiraterone as IMP and 
prednisone / prednisolone. 
• Record AEs and SAEs; all occurrences of bone fractures and bone associated events 
(e.g., osteoporosis); all occurrences of leukemia, myelodysplastic syndrome, and 
aplastic anemia; and primary bone cancer or any other new primary malignancy. 
• Record concomitant medications / therapy 
• Record prostate cancer-related treatment (including androgen synthesis 
inhibitors / androgen receptor antagonists; excluding analgesics) 
• Full physical examination 
• At the discretion of the investigator, a 12-lead ECG can be ordered, if deemed 
necessary.  Potassium levels should be considered when obtaining the ECG.  
Hypokalemia should be corrected before ECG collection. 
• Record vital signs:  blood pressure, heart rate, respiratory rate, and temperature 
• Record weight 
• ECOG-PS 


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• Blood draw for hematology:  hematocrit, Hb, PLT, RBC count, WBC count, and WBC 
differential 
• Blood draw for clinical chemistry:  sodium, potassium, chloride, calcium, ALT, AST, 
LDH, total ALP, creatinine, BUN, bilirubin (total), and albumin 
• Serum testosterone (Cycle 7, Day 1 only) (at the discretion of the investigator) 
• PSA level 
• Starting at Visit 11 (Cycle 7, Day 1): 
o A chest / abdominal / pelvic CT scan every 12 weeks (± 7 days).  The same 
imaging modalities are to be used as were used at baseline.  An 
abdominal / pelvic MRI will be accepted instead of abdominal / pelvic CT 
scan only if MRI abdomen / pelvis was performed at baseline.* 
o Bone technetium-99m scan every 12 weeks (± 7 days) with careful 
identification of all disease related hotspots* 
*except in cases where local regulations apply 
o Note:  Bone scans and CT / MRI scans will be read locally 
•  Record progression 
• Record SSEs 
• Dispense abiraterone plus prednisone / prednisolone until termination of treatment as 
IMP  
• Perform drug accountability 
• Record survival status 
7.1.2.3.4 
End of treatment visit 
An EOT visit will be performed within 4 weeks (± 7 days) post discontinuation of abiraterone 
as IMP and prednisone / prednisolone and the subject will proceed to the long-term follow-up 
After the final OS analysis, the  following procedures / evaluations should be performed at 
this visit: 
• Record AEs and SAEs 
• All bone fractures and bone associated events (e.g., osteoporosis) need to be reported 
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment. 
• Record all occurrences of leukemia, myelodysplastic syndrome, aplastic anemia, and 
primary bone cancer or any other new primary malignancy 
• Record concomitant medications / therapy for 4 weeks after the last study drug 
administration 


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• Record prostate cancer-related treatment (including androgen synthesis 
inhibitors / androgen receptor antagonists; excluding analgesics) 
• Perform full physical examination 
• At the discretion of the investigator, a 12-lead ECG can be ordered, if deemed 
necessary.  Potassium levels should be considered when obtaining the ECG.  
Hypokalemia should be corrected before ECG collection. 
• Record vital signs:  blood pressure, heart rate, respiratory rate, and temperature 
• Record weight 
• ECOG-PS 
• Blood draws for hematology:  hematocrit, Hb, PLT, RBC counts, WBC counts, and 
WBC differential 
• Blood draws for clinical chemistry:  sodium, potassium, chloride, calcium, ALT, AST, 
LDH, total ALP, creatinine, BUN, bilirubin (total), and albumin 
• Serum testosterone (at the discretion of the investigator) 
• PSA level 
• Record progression 
• Record SSEs 
• Perform drug accountability 
• Site staff should record the answer to the following question:  What treatment arm do 
you believe this subject was on? 
• Record survival status 
If subjects cannot travel to the clinical site due to deterioration of disease, the EOT visit will 
be replaced by a follow-up telephone call from the clinical site.  Adverse events; all 
occurrences of bone fractures and bone associated events (e.g., osteoporosis); information on 
all occurrences of leukemia, myelodysplastic syndrome, and aplastic anemia; and primary 
bone cancer or any other new primary malignancy, as well as any anti-cancer therapies, will 
be discussed and captured in the eCRFs.  Since this information will be collected over the 
telephone from the subject, it is the clinical site’s responsibility to obtain and make available 
the source documentation for the information collected from the subject and document it in 
the eCRF. 
7.1.2.4 
Active follow-up 
After the final OS analysis (Amendment 7), subjects who are discontinued from study 
treatment will initiate the long term follow-up period; therefore, active follow-up periods will 
no longer be applicable. Subjects who are in active follow-up at the time Amendment 7 is 
implemented should have the end of active follow-up completed (protocol driven decision) 


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and should be directly transitioned into the extended safety follow-up study. For additional 
information, please refer to Section 13.5. 
7.1.2.4.1 
Active follow-up with clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
Section removed in Amendment 7 
7.1.2.4.2 
Active follow-up without clinic visits assessments (Every 12 weeks 
± 7 days at each visit) 
Section removed in Amendment 7 
7.1.2.4.3 
End of active follow-up 
 After the final OS analysis (Amendment 7), the procedures for subjects who complete the 
active follow-up will include: 
•  All AEs and SAEs must be documented and reported if considered to be related to 
study medication or study-related procedures. 
• All bone fractures and bone associated events (e.g., osteoporosis) need to be reported 
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment. 
• All occurrences of leukemia, myelodysplastic syndrome, aplastic anemia, and primary 
bone cancer or any other new primary malignancy must be reported as SAEs 
regardless of the investigator’s causality assessment.  The anti-cancer therapies 
associated with these events will be collected.  If a subject is unable to provide 
required details for events of interest, this information may need to be obtained from 
the primary provider. 
• Record concomitant medications / therapy only if used to treat adverse drug reaction 
(any grade) 
• Record prostate cancer-related treatment (including androgen synthesis 
inhibitors / androgen receptor antagonists; excluding analgesics) 
• Perform full physical examination 
• Record vital signs:  blood pressure, heart rate, respiratory rate, and temperature 
• ECOG-PS 
• Blood draws for hematology:  hematocrit, Hb, PLT, RBC counts, WBC counts, and 
WBC differential 
• Blood draws for clinical chemistry:  sodium, potassium, chloride, calcium, ALT, AST, 
LDH, total ALP, creatinine, BUN, bilirubin (total), and albumin 
• PSA level 
• Record progression 


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• Record SSEs 
• Record survival status 
• A chest / abdominal / pelvic CT.  The same imaging modalities are to be used as were 
used at baseline.  An abdominal / pelvic MRI will be accepted instead of 
abdominal / pelvic CT only if MRI abdomen / pelvis was performed at baseline. 
• Bone technetium-99m scan with careful identification of all disease-related hotspots 
and any confirmatory SPECT or MRI scan (with and without contrast media) 
For subjects who die > 30 days after the administration of last study treatment, submission of 
the AE page of the eCRF is not required unless the death is considered related to study 
treatment.  For all deaths, the date of death information will be collected in the 
end-of-follow-up page of the eCRF. 
Subjects who are in active follow-up at the time of Amendment 7 should have the end of 
active follow-up completed (protocol driven decision) and should be directly transitioned into 
the extended safety follow-up study.  For additional information, please refer to Section 13.5. 
7.1.2.5 
Long-term follow-up  
After the final OS analysis (Amendment 7), this period will start when subjects have 
discontinued study treatment, and will end when the subject has completed 7 years of 
follow-up, dies, is lost to follow-up, withdraws informed consent, actively objects to 
collection of further data, or is transitioned to the extended safety follow-up study. 
Once a separate extended safety follow-up protocol for the inclusion of subjects who received 
radium 223 dichloride / placebo in the course of Bayer sponsored clinical trials, has been 
implemented, the study subjects who are in active or long-term follow-up will be transitioned 
to a separate extended safety follow-up study in order to complete 7 years of safety follow-
up.  All efforts will be made to transition all subjects to the extended safety follow-up study. 
The EOS is defined as the date of the LSLV in the study. The EOS will occur at the time the 
last subject on study completes 7 years of follow-up unless the subject dies, withdraws consent 
or is lost to FU.  
In case a subject is still on oral study treatment and still benefits based on the investigator’s 
opinion after 7 years of follow-up, options for treatment continuation (e.g., switch to 
commercial drug supply, a continued access program, or any other means of continued drug 
supply) will be discussed and agreed between the investigator, sponsor, and the subject in 
compliance with local regulations. For each participating European Union (EU) country, the 
EOS according to the EU Clinical Trial Directive will be reached when the LSLV in any center 
has occurred. 
7.1.2.5.1 
Long-term follow-up (telephone follow-up) 
Subjects will be contacted by telephone every 6 months (± 14 days) to determine the 
following: 
• Record survival status 


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• All AEs and SAEs must be documented and reported if considered to be related to 
study medication or study-related procedures  
• All bone fractures and bone associated events (e.g., osteoporosis) need to be reported 
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment. 
• All occurrences of leukemia, myelodysplastic syndrome, aplastic anemia, and primary 
bone cancer or any other new primary malignancy must be reported as SAEs 
regardless of the investigator’s causality assessment.  The anti-cancer therapies 
associated with these events will be collected. If a subject is unable to provide 
required details for events of interest, this information may need to be obtained from 
the primary provider. 
• Record prostate cancer-related treatment (including androgen synthesis 
inhibitors / androgen receptor antagonists; excluding analgesics) 
Note:  As this information will be collected over the telephone from the subject, it is the 
clinical site’s responsibility to obtain and make available the source documentation for the 
information collected from the subject and document it in the eCRF. 
7.1.2.5.2 
End of long-term follow-up 
The EOS procedures for subjects who are in the long-term follow-up period will include the 
following: 
• Record survival status 
• All AEs and SAEs must be documented and reported if considered to be related to 
study medication or study-related procedures. 
• All bone fractures and bone associated events (e.g., osteoporosis) need to be reported 
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment. 
• All occurrences of leukemia, myelodysplastic syndrome, aplastic anemia, and primary 
bone cancer or any other new primary malignancy must be reported as SAEs 
regardless of the investigator’s causality assessment.  The anti-cancer therapies 
associated with these events will be collected.  If a subject is unable to provide 
required details for events of interest, this information may need to be obtained from 
the primary provider. 
• Record prostate cancer-related treatment (including androgen synthesis 
inhibitors / androgen receptor antagonists; excluding analgesics) 
Note:  As this information will be collected over the telephone from the subject, it is the 
clinical site’s responsibility to obtain and make available the source documentation for the 
information collected from the subject and document it in the eCRF. 


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7.1.2.6 
End of study 
The EOS is defined as the date of the LSLV in the study. The EOS will occur at the time the 
last subject on study completes 7 years of follow-up unless the subject dies, withdraws consent 
or is lost to FU.  
In case a subject is still on oral study treatment and still benefits based on the investigator’s 
opinion after 7 years of follow-up, options for treatment continuation (e.g., switch to 
commercial drug supply, a continued access program, or any other means of continued drug 
supply) will be discussed and agreed between the investigator, sponsor, and the subject in 
compliance with local regulations. 
Note: 
• If the study is terminated by the sponsor and the latest follow-up visit has taken place 
within the previous 3 months, the end of follow-up will be the date of the latest 
follow-up. 
• If subjects are receiving subsequent treatments with radium-223 dichloride as part of 
non-Bayer studies such as investigator-sponsored studies or through commercially 
available drugs, follow-up and data collection should continue in the 15396 study 
until the subject’s death or termination of the program by the sponsor. 
7.2 
Population characteristics 
7.2.1 
Demographic 
The following demographic characteristics will be collected: 
• Date of birth 
• Age at randomization 
• Race and ethnicity (where it is allowed by local regulation) 
7.2.2 
Medical history 
Medical history findings (i.e., previous diagnoses, diseases, or surgeries) meeting all criteria 
listed below will be collected: 
• Not pertaining to the study indication 
• Start before signing of the informed consent 
• Considered relevant to the study 
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 7.5.1.1. 
7.2.3 
Other baseline characteristics 
The following other baseline characteristics will be collected: 
• Date of prostate cancer diagnosis 


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• Date of diagnosis of metastatic prostate cancer 
• Stage of prostate cancer at diagnosis 
• Treatment of prostate cancer before enrollment (e.g., surgery, radiation) 
• Gleason score at diagnosis of prostate cancer 
• PSA and total ALP at diagnosis of prostate cancer 
• Weight (kg) 
• Vital signs:  blood pressure (mmHg), heart rate, respiratory rate, and temperature (°C) 
• ECOG-PS 
• Cancer pain assessment 
• Laboratory assessments 
o Hematology:  hematocrit, Hb, PLT, RBC count, WBC count, and WBC 
differential 
o Clinical chemistry:  sodium, potassium, chloride, calcium, ALT, AST, LDH, 
total ALP, creatinine, BUN, total bilirubin, and albumin 
o PSA 
o Testosterone 
7.3 
Efficacy 
7.3.1 
Efficacy variables 
The primary efficacy variable is: 
• SSE-FS 
The secondary efficacy variables are specified below: 
• OS 
• Time to opiate use for cancer pain* 
• Time to pain progression* 
• Time to cytotoxic chemotherapy* 
• rPFS* 
Exploratory efficacy variables are:* 
• Time to first on-study SSE* 
• Percentage change in total ALP from baseline* 
• Time to ALP progression* 
• Time to PSA progression* 


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• ALP response* 
• PSA response* 
• Bone scan-specific rPFS* 
• Time to increase in physical symptoms of disease based on the FPSI-DRS-P subscale 
score measured during the treatment period* 
• Time to increase in physical symptoms of disease based on the FPSI-DRS-P subscale 
score measured during the period between start of treatment and end of active 
follow-up with clinic visit.* 
Note: Variables indicated with an asterisk (*) including all exploratory variables will not be 
assessed following final OS analysis. 
7.3.2 
Definition of efficacy variables 
7.3.2.1 
Primary endpoint 
Symptomatic skeletal event-free survival is defined as the time from randomization to the 
occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
• the use of EBRT to relieve skeletal symptoms 
• the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
• the occurrence of spinal cord compression 
• a tumor-related orthopedic surgical intervention. 
(2) Death from any cause 
7.3.2.2 
Secondary efficacy endpoints 
Overall survival is defined as the time (days) from the date of randomization to the date of 
death due to any cause.  For subjects who are still alive, their OS will be censored at the last 
known alive date or the database cutoff date, whichever occurs first. 
Time to opiate use for cancer pain is defined as the interval from the date of randomization 
to the date of opiate use.  Subjects who have no opiate use at the time of analysis will be 
censored at the last known date of no opiate use.  Subjects with no on-study assessment or no 
baseline assessment will be censored at the date of randomization. 
Time to opiate use will be determined by analgesic use captured via ePRO device and / or the 
eCRF (analgesic consumption diary and recorded analgesics, respectively, see schedule of 
assessments). 


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Time to pain progression is defined as the interval from randomization to the first date a 
subject experiences pain progression based on WPS: 
For asymptomatic subjects (WPS 0 at baseline), pain progression is defined as an increase 
of 2 or more points in the average (i.e., average of 7-day assessments) “worst pain in 
24 hours” score from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart 
OR 
initiation of short- or long-acting opioid use for pain. 
Assessments will occur daily for one week (including the visit date).  An evaluable pain 
assessment interval requires completion of a minimum of 4 out of 7 daily questions.  Subjects 
who have not experienced pain progression at the time of analysis will be censored on the last 
date the subject was known to have not progressed.  Subjects with no on-study assessment or 
no baseline assessment will be censored at the date of randomization. 
For mildly symptomatic subjects (WPS 1 to 3 at baseline), pain progression is defined as an 
increase of 2 or more points in the average (i.e., average of 7-day assessments) “worst pain in 
24 hours” score from baseline observed at 2 consecutive evaluations ≥ 4 weeks apart and an 
average WPS of ≥ 4 
OR 
initiation of short- or long-acting opioid use for pain. 
Assessments will occur daily for one week (including the visit date).  An evaluable pain 
assessment interval requires completion of a minimum of 4 out of 7 daily questions.  Subjects 
who have not experienced pain progression at the time of analysis will be censored on the last 
date the subject was known to have not progressed.  Subjects with no on-study assessment or 
no baseline assessment will be censored at the date of randomization.  The BPI-SF 
(Section 14.9) is a short, self-administered questionnaire with 11 items, which was designed 
to evaluate the intensity of, and the impairment caused by pain.  All BPI-SF items are scored 
using rating scales.  Four items measure pain intensity (pain now, average pain, worst pain, 
and least pain) using 0 (“no pain”) to 10 (“pain as bad as you can imagine”) numeric rating 
scales, and 7 items measure the level of interference with function caused by pain (general 
activity, mood, walking ability, normal work, relations with other people, sleep, and 
enjoyment of life) using 0 (no interference) to 10 (complete interference) rating scales. 
The items are aggregated into 2 dimensions:  (1) Pain severity index, using the mean of the 
4 items on the pain intensity, and (2) Function interference index, using the mean of the 
7 pain interference items.  All 4 severity items must be completed for aggregating the pain 
severity index.  The function interference index is scored as the mean of the item scores 
multiplied by 7, given that more than 50% or 4 of 7, of the items have been completed. 
Time to cytotoxic chemotherapy is defined as the time (days) from the date of 
randomization to the date of the first cytotoxic chemotherapy.  
Radiological progression-free survival is defined as the time (days) from the date of 
randomization to the date of confirmed radiological progression or death (if death occurs 
before progression). Subjects without confirmed radiological progression or death at the time 


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of analysis will be censored at their last date of radiological tumor assessment (see statistical 
analysis plan [SAP] for detailed censoring rules).  Bone scans (i.e., whole body 
technetium-99m bone scan) and CT / MRIs will be read both locally and by blinded 
independent central assessment. If there is an inconsistency between local assessment and 
central review, then the assessment will be based on central review.  If progression is 
detected by bone scan, a confirmatory scan is required at least 6 weeks later.  A single 
SPECT or MRI (with and without contrast media) should be obtained to confirm any 
suspicious bone scan findings.  The date of confirmed radiological progression will be the 
date of first observation of radiological progression.  Radiological progression is determined 
if at least one of the following criteria is met: 
• The first bone scan with ≥ 2 new lesions compared to baseline is observed < 12 weeks 
from randomization and is confirmed by a second bone scan taken ≥ 6 weeks later 
showing ≥ 2 additional new lesions (a total of ≥ 4 new lesions compared to baseline); 
or 
• The first bone scan with ≥ 2 new lesions compared to baseline is observed ≥ 12 weeks 
from randomization and the new lesions are verified on the next bone scan ≥ 6 weeks 
later (a total of ≥ 2 new lesions compared to baseline). 
If bone scans are repeated the best scan should be submitted to the core imaging lab as per 
judgment of the site. 
A mask should be placed over the bladder during interpretation to facilitate detection of 
lesions in the pelvis.  If the bladder obscures the pelvis, oblique images of the pelvis should 
be obtained.  If there is concern over underlying bone lesions, a SPECT scan may be 
performed.  Subjects should void before bone scan or, alternatively, may need a urinary 
catheter placed for bladder drainage. 
Progression in soft tissue and occurrence of visceral disease will be assessed by CT or MRI 
every 8 weeks (± 7 days) then every 12 weeks (± 7 days) based on RECIST 1.1.  CT or MRI 
scans will be read both locally and by blinded independent central assessment.  The RECIST 
will be used to assess soft tissue and visceral disease only.  Bone lesions detected by CT or 
MRI cannot be selected as target or non-target lesions.  Bone lesions will be evaluated by 
bone scans. 
Note: Following the final OS analysis, images will only be read locally and confirmatory 
scans will no longer be necessary to document progression. The date of radiological 
progression will be the date of first observation of radiological progression. 
7.3.2.3 
Exploratory efficacy endpoints 
Note:  Exploratory efficacy endpoints will not be assessed following the final OS analysis. 
Time to first on-study SSE is defined as the time (days) from the date of randomization to 
the date of the first on-study SSE.  
Percentage change in total ALP from baseline to 12 weeks and the percentage change in 
total ALP from baseline to 24 weeks will be calculated for each subject, based on laboratory 
data collected as of the 12- and 24-week assessments, respectively. 


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Time to ALP progression is defined as the time (days) from the date of randomization to the 
date of first ALP progression.  Alkaline phosphatase progression is defined as a ≥ 25% 
increase from the baseline value, at least 12 weeks from baseline in subjects with no ALP 
decline from baseline; or a ≥ 25% increase above the nadir value, which is confirmed by a 
second value obtained 3 or more weeks later in subjects with an initial ALP decline from 
baseline. 
Time to PSA progression is defined as the time (days) from the date of randomization to the 
date of first PSA progression.  Prostate specific antigen progression is defined as ≥ 25% 
increase from the baseline value and an increase in absolute value of ≥ 2 ng/mL, at least 
12 weeks from baseline in subjects with no PSA decline from baseline; or ≥ 25% increase 
and an absolute increase of ≥ 2 ng/mL above the nadir value, which is confirmed by a second 
value obtained 3 or more weeks later in subjects with an initial PSA decline from baseline. 
Alkaline phosphatase response is defined as ≥ 30% reduction of the blood level, compared 
to the baseline value.  Confirmed ALP response is defined as a ≥ 30% reduction of the blood 
level, compared to the baseline value, confirmed by a second ALP value 4 or more weeks 
later.  ALP responses will be evaluated at Weeks 12 and 24 after treatment is started. 
Prostate specific antigen response is defined as ≥ 30% reduction of the blood level, 
compared to the baseline value.  A confirmed PSA response is defined as ≥ 30% reduction of 
the blood level, compared to the baseline value, confirmed by a second PSA value 4 or more 
weeks later.  PSA responses will be evaluated at Weeks 12 and 24 after treatment is started. 
Radiological progression free survival based on bone scans (bone rPFS) is defined as the 
time (days) from the date of randomization to the date of confirmed radiological progression 
detected by bone scans or death (if death occurs before progression).  Subjects without 
confirmed radiological progression or death at the time of analysis will be censored at their 
last date of radiological tumor assessment (see the SAP for detailed censoring rules).  Bone 
scans will be read both locally and by blinded independent central assessment.  If there is an 
inconsistency between local assessment and central review, then the assessment will be based 
on central review.  If progression is detected by bone scan, a confirmatory scan is required at 
least 6 weeks later.  The date of confirmed radiological progression will be the date of first 
observation of central assessment of radiological progression.  Radiological progression is 
determined if at least one of the following criteria is met: 
• A subject is considered to have progressed by bone scan if: 
o The first bone scan with ≥ 2 new lesions compared to baseline is observed 
< 12 weeks from randomization and is confirmed by a second bone scan taken 
≥ 6 weeks later showing ≥ 2 additional new lesions (a total of ≥ 4 new lesions 
compared to baseline); or 
o The first bone scan with ≥ 2 new lesions compared to baseline is observed 
≥ 12 weeks from randomization and the new lesions are verified on the next 
bone scan ≥ 6 weeks later (a total of ≥ 2 new lesions compared to baseline). 
If bone scans are repeated the best scan should be submitted to the core imaging lab as per 
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A mask should be placed over the bladder during interpretation to facilitate detection of 
lesions in the pelvis.  If the bladder obscures the pelvis, oblique images of the pelvis should 
be obtained.  If there is concern over underlying bone lesions, a SPECT scan may be 
performed.  Subjects should void before bone scan or, alternatively, may need a urinary 
catheter placed for bladder drainage. 
Time to increase in physical symptoms of disease based on the FPSI-DRS-P subscale 
score measured during the treatment period will be assessed using the NCCN-FACT 
FPSI-17 questionnaire (Section 14.7).  
The NCCN-FACT FPSI-17 is a validated instrument that was developed to assess symptoms 
prostate cancer, symptoms of treatment of prostate cancer, and HRQoL of prostate cancer 
patients.(52)  The instrument was developed in accordance with recent FDA guidance for 
development of instruments for ePRO.  The instrument contains 17 items, each of which 
utilize a Likert scale with 5 possible responses.  The 10 items reflect disease-related physical 
symptoms of disease and the responses on the items are to be summed to calculate a 
disease-related physical symptom subscale score.  One item represents emotion symptom of 
disease and the response to that item is used to calculate a disease-related emotional symptom 
subscale score.  Four items represent treatment-related symptoms and the responses to these 
items are summed to calculate a treatment side effect subscale score.  Finally, 2 items 
represent functional well-being and responses to those items are summed to calculate a 
functions / well-being subscale score. 
The NCCN-FACT FPSI-17 will be self-administered by the subject via ePRO device.  Some 
subjects may skip an item altogether if they feel that it is not applicable to them. 
Time to increase in physical symptoms of disease based on the FPSI-DRS-P subscale 
score measured during the period from start of treatment to end of active follow-up 
with clinic visits will be assessed using the NCCN-FACT FPSI-17 questionnaire 
(Section 14.7). 
The NCCN-FACT FPSI-17 is a validated instrument that was developed to assess symptoms 
of prostate cancer, symptoms of treatment of prostate cancer, and HRQoL of prostate cancer 
patients.(52)  The instrument was developed in accordance with recent FDA guidance for 
development of instruments for ePRO.  The instrument contains 17 items, each of which 
utilize a Likert scale with 5 possible responses.  The 10 items reflect disease-related physical 
symptoms of disease and the responses on the items are to be summed to calculate a 
disease-related physical symptom subscale score.  One item represents emotional symptoms 
of disease and the response to that item is used to calculate a disease-related emotional 
symptom subscale score.  Four items represent treatment-related symptoms and the responses 
to these items are summed to calculate a treatment side effect subscale score.  Finally, 2 items 
represent functional well-being and responses to those items are summed to calculate a 
functions / well-being subscale score. 
The NCCN-FACT FPSI-17 will be self-administered by the subject via ePRO device.  Some 
subjects may skip an item altogether if they feel that it is not applicable to them. 


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7.4 
Pharmacokinetics (selected sites only) 
Note: Pharmacokinetic data will not be assessed following final OS analysis. 
7.4.1 
Drug measurement 
Pharmacokinetics of radium-223 dichloride will not be evaluated in this study; however, the 
PK of abiraterone will be investigated in 2 subgroups.  In each subgroup, 40 subjects 
(approximately 20 per treatment arm) will be enrolled.  Blood samples will be collected at 
pre-defined times as specified below. 
The following time ranges are provided: 
• for planned time points ≤ 6 hours, PK samples should be collected within ± 15 minutes 
of the planned time 
• for planned time points > 6 hours, PK samples should be collected within ± 30 minutes 
Subgroup 1 (Non-compartmental analysis): 
Serial blood samples will be collected at the following time points:  Pre-dose, 0.5, 1, 2, 3, 4, 
6, 8, 10, and 24 hours post-abiraterone administration, 1 week after the first or second 
administration of radium-223 dichloride / placebo (collection on Cycle 1, Day 8 or Cycle 2, 
Day 8). 
Sampling times outside these suggested intervals will not be considered to be protocol 
deviations.  It is of importance that the actual date and time of blood sampling are 
documented in the eCRF because PK calculations will be based on the actual sampling times 
relative to dosing times. 
Subgroup 2 (Population PK analysis): 
Blood samples will be collected prior to the abiraterone administration at Cycle 1, Days 8 and 
15 (Visit 3) and Cycle 2, Days 1 (Visit 4), 8, and 15 (Visit 5).  In addition, a second blood 
sample will be collected at each of these visits within the time window of 0.5 to 3 hours post 
abiraterone administration. 
Plasma will be prepared from the collected blood samples and analyzed using a validated 
analytical method for abiraterone. 
Special Meal Instruction: 
For the 3 nights preceding each PK visit, subjects must have an overnight fast (approximately 
10 hours) before taking abiraterone.  Subjects should not eat until 1 hour after abiraterone 
dosing.  Food intake prior to the PK fasting periods should be recorded in the eCRF. 
Detailed instructions for sample collection and handling will be provided in a Laboratory 
Manual. 
7.4.2 
Pharmacokinetic evaluation 
Subgroup 1: 
Pharmacokinetic parameters will be calculated using a non-compartment approach.  Based on 
the plasma concentration time data, the following PK parameters will be calculated for 


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abiraterone 1 week after the first or second administration of radium-223 
dichloride / placebo: 
• Maximum concentration at a steady state 
• Time to maximum concentration at a steady-state 
• Area under the curve from zero to 24 hours 
Subgroup 2: 
A population PK analysis of plasma concentration-time data of abiraterone will be performed 
to assess the similarity or difference in PK of abiraterone between subjects treated with 
radium-223 dichloride plus abiraterone and prednisone / prednisolone and placebo plus 
abiraterone and prednisone / prednisolone using nonlinear mixed-effects modeling.  The 
population PK modeling will include all subjects with sufficient and interpretable PK 
assessments.  The data from Subgroup 2 will be combined together with the data from 
Subgroup 1 for the analysis.  The effect of diarrhea on the PK of abiraterone may be 
explored.  The population PK analysis results will be presented in a separate report. 
7.5 
Safety 
Safety variables 
Safety variables will include the analysis of acute and long-term effects and the appearance of 
new primary malignancies.  The complete list of variables to be analyzed for this study will 
be provided in the SAP. 
All subjects who receive at least one dose of study drug will be valid for safety analysis.  All 
AEs will be reported and graded according to NCI-CTCAE v4.0.  Laboratory evaluations, 
vital signs, and changes in physical examination findings will also be assessed. 
7.5.1 
Adverse events 
7.5.1.1 
Definitions 
Adverse event 
In a clinical study, an AE is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom, or disease) in a patient 
or clinical investigation subject after providing written informed consent for participation in 
the study.  Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as AE (however, the condition for which the surgery is 
required may be an AE). 
The clinical manifestation of any failure of expected pharmacological action is not recorded 
as an AE if it is already reflected as a data point captured in the eCRF.  If, however, the event 
fulfills any of the criteria for a SAE (see below) then it must be recorded and reported as 
such.  If PD leads to signs and symptoms that meet the serious criteria (i.e., hospitalization, 


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disability, death, or important medical event), the signs and symptoms must be reported as a 
SAE and not the underlying disease (i.e., PD). 
Adverse event versus medical history 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory findings, or 
scans.  
• Conditions that started before signing of informed consent and for which no symptoms 
or treatment are present until signing of informed consent are considered as medical 
history (e.g., seasonal allergy without acute complaints).  
• Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
considered as medical history (e.g., allergic pollinosis).  
• Symptoms that were present prior to signing of informed consent but for which the 
diagnosis was confirmed after signing of informed consent should be documented as 
medical history. 
• Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  
Serious adverse event  
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – f): 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition refers to an event in which the subject was at 
risk of death at the time of the event, it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
c. Requires in-subject hospitalization or prolongation of existing hospitalization 
A hospitalization or prolongation of hospitalization will not be regarded as a SAE if at 
least one of the following exceptions is met: 
• The admission results in a hospital stay of less than 12 hours 
• The admission is pre-planned  
(i.e., elective or scheduled surgery arranged prior to the start of the study) 
• The admission is not associated with an AE  
(e.g., social hospitalization for purposes of respite care). 
However, it should be noted that invasive treatment during any hospitalization may fulfill 
the criterion 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 precedence. 


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d. Results in persistent or significant disability / incapacity 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
e. Is a congenital anomaly / birth defect 
f. Is another medically important serious event as judged by the investigator 
7.5.1.2 
Classifications for adverse event assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below.  
7.5.1.2.1 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 7.5.1.1. 
7.5.1.2.2 
Intensity 
The intensity of an AE should be documented using the NCI-CTCAE v4.03, JUN 2010.   
7.5.1.2.3 
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a clinical decision based on all available information at the time of the completion of the 
eCRF.  The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question. 
Possible answers are “yes” or “no” 
An assessment of “no” would include: 
• The existence of a clear alternative explanation, e.g., mechanical bleeding at surgical 
study center. 
Or 
• Non-plausibility (e.g., the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration). 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is associated 
with the use of the study treatment. 
Important factors to be considered in assessing the relationship of the AE to study treatment 
include: 
• The temporal sequence from drug administration:  The event should occur after the drug 
is given.  The length of time from drug exposure to event should be evaluated in the 
clinical context of the event. 
• Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge):  Subject’s response after de-challenge or subject’s response after 


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re-challenge should be considered in the view of the usual clinical course of the event in 
question. 
• Underlying, concomitant, intercurrent diseases:  Each event should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the subject may have. 
• Concomitant medication or treatment:  The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them may 
be suspected to cause the event in question. 
• The pharmacology and PK of the study treatment:  The PK properties (absorption, 
distribution, metabolism, and excretion) of the study treatment, coupled with the 
individual subject’s pharmacodynamics should be considered. 
Causal relationship to protocol-required procedure(s) 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s). Possible answers are “yes” or “no” 
7.5.1.2.4 
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
- 
Drug withdrawn 
- 
Drug interrupted 
- 
Dose reduced 
- 
Dose not changed 
- 
Not applicable 
- 
Unknown 
7.5.1.2.5 
Other specific treatment(s) of adverse events 
- 
None 
- 
Remedial drug therapy 
- 
Other 
7.5.1.2.6 
Outcome 
The outcome of the AE is to be documented as follows:  
- 
Recovered / resolved 
- 
Recovering / resolving 
- 
Recovered / resolved with sequelae 
- 
Not recovered / not resolved 


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- 
Fatal 
- 
Unknown 
7.5.1.3 
Assessments and documentation of adverse events 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the trial), requiring treatment, causing apparent clinical manifestations, or 
judged as relevant by the investigator should be reported as an AE.  Each event should be 
described in detail along with start and stop dates (onset and resolution of event), intensity, 
temporal and causal relationship to investigational product and / or protocol-related 
procedures, possible alternative factors (co-morbidities, co-medications), therapeutic action 
taken, result of therapeutic action, and ultimate outcome of the AE. 
All (S)AEs, regardless of grade or relatedness, that occur during the treatment period and up 
to 4 weeks after the last administration of abiraterone as IMP and prednisone / prednisolone 
or 6 months after the last administration of radium-223 dichloride / placebo, whichever 
occurs later, unless a new anti-cancer therapy is initiated, must be reported in the appropriate 
eCRF (SAEs must be reported within 24 hrs of the investigator’s awareness).  If more than 
one AE occurs, each event should be recorded separately.  All AEs and SAEs are to be 
followed until resolved or as clinically required. 
All AEs and SAEs occurring after the EOT visit until the EOS must be documented and 
reported if considered to be related to study medication.  However, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, and primary bone cancer or any other 
new primary malignancy must be reported as SAEs at any time, and regardless of the 
investigator’s causality assessment. 
All bone fractures and bone associated events (e.g., osteoporosis) need to be reported as 
either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s causality 
assessment. All the imaging scans that confirmed the diagnosis of fractures should be sent to 
the independent review center for central review. 
Adverse events may be reported spontaneously by the subject or elicited through open 
(non-leading) questioning during each visit to the clinic and at the end of the active follow-up 
period without clinic visits.  As far as possible, all AEs must be described by their duration 
(start and stop date), severity (graded according to the CTCAE), relationship to treatment, 
and according to the need of other specific therapy.  All information will be recorded in the 
Adverse Event eCRF. 
Note: After Amendment 7, scans will only be read locally. 
7.5.1.4 
Reporting of serious adverse events 
The definition of SAEs is given in Section 7.5.1.1.  Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to the designated recipient. 
If disease progression leads to signs and symptoms that meet the criteria for seriousness, the 
associated signs and symptoms should be reported as SAE, not the underlying cause (i.e., 
“progressive disease” should not be recorded as SAE).  In this case, disease progression 
should be mentioned on the SAE form as “alternative explanation.” 


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Investigator’s notification of the sponsor 
All investigators will be thoroughly instructed and trained on all relevant aspects of the 
investigator’s reporting obligations for SAEs.  This information, including all relevant 
contact details, is summarized in the Investigator Site file.  This information will be updated 
as needed. 
All SAEs occurring during the observation period defined in Section 7.5.1.3 must 
immediately (within 24 hours of the investigator’s awareness) be reported to the contact at 
the contract research organization (CRO), detailed in the study manual.  An SAE form must 
also be completed within 24 hours of the investigator awareness and forwarded to the 
designated recipient.  Each SAE must be followed up until resolution or stabilization by 
submission of updated reports to the designated recipient. 
Additionally, all occurrences of leukemia, myelodysplastic syndrome, aplastic anemia, and 
primary bone cancer or any other new primary malignancy must be reported as SAEs at any 
time, and regardless of the investigator’s causality assessment (Section 7.5.1.3).  All bone 
fractures and bone associated events (e.g., osteoporosis) need to be reported as either AEs or 
SAEs if the criteria of SAE were met, regardless of the investigator’s causality assessment. 
All the imaging scans that confirmed the diagnosis of fractures should be sent to the 
independent review center for central review. Grade 4 baseline laboratory abnormalities that 
are part of the disease profile should not be reported as a SAE, specifically when they are 
allowed or not excluded by the protocol inclusion / exclusion criteria.  If an investigator is in 
doubt about the applicable reporting obligations, he / she should consult with the medical 
monitor. 
For subjects who die after the treatment period defined in Section 7.5.1.3, submission of the 
AE page of the eCRF is not required.  However, the SAE Complementary Form should be 
submitted to the applicable Bayer HealthCare Pharmacovigilance department if the death is 
considered related to study treatment.  In addition, this death information will also be 
collected in the end of active follow-up page of the eCRF. 
Serious adverse events occurring after the protocol-defined observation period will be 
processed by the sponsor according to all applicable regulations. 
Note:  After Amendment 7, scans will only be read locally.  
Notification of the independent ethics committees/ institutional review boards  
Notification of the independent ethics committees / institutional review boards (IECs / IRBs) 
about all relevant events (e.g., SAEs, SUSARs) will be performed by the sponsor and / or by 
the investigator according to all applicable regulations. 
Notification of the authorities 
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations. 
Sponsor’s notification of the investigational study center 
The sponsor will inform all investigational study centers about reported relevant events (e.g., 
SUSARs) according to all applicable regulations. 


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7.5.1.5 
Expected adverse events and suspected unexpected adverse reactions 
For this study, the most current version of the IB for radium-223 dichloride will be the 
reference document for the determination of whether an AE is expected or 
unexpected.  Overview listings of frequent events that have occurred so far in the clinical 
development are shown in the current IB.  If relevant new safety information is identified, the 
information will be integrated into an update of the IB and distributed to all participating 
study centers.  The applicable reference document for abiraterone and 
prednisone / prednisolone is the most current summary of product characteristics. 
The expectedness of AEs will be determined by the sponsor according to the applicable 
reference document and according to all local regulations. 
7.5.2 
Pregnancies 
The investigator must report to the sponsor any pregnancy occurring in a study subject’s 
partner, during the subject’s participation in this study.  The report should be submitted 
within the same timelines as a SAE, although a pregnancy per se is not considered a SAE. 
Bayer usually does not gather information of drug exposure via father; however, if those 
cases are reported, all efforts should be made to obtain information on course and outcome, 
subject to the partner’s consent. 
For all reports, the forms provided are to be used. 
7.5.3 
Symptomatic skeletal events 
A SSE is defined as: 
• The use of EBRT to relieve skeletal symptoms 
• The occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
• The occurrence of spinal cord compression 
• A tumor-related orthopedic surgical intervention 
7.6 
Other procedures and variables 
Other exploratory variables including self-reported health status scores, and biomarkers will 
not be assessed following final OS analysis.  
Other exploratory variables that will be explored in this study are utility scores and 
self-reported health status scores based on EQ-5D, NCCN-FACT FPSI-17 disease-related 
symptoms - emotional subscale score, resource utilization, and assessment of biomarkers. 
7.6.1 
Self-reported health status 
Patient reported outcomes will also be assessed with the EQ-5D questionnaire at each study 
visit during each visit when treatment is administered and at each in-clinic follow-up visit. 
The EQ-5D questionnaire (Section 14.8) developed by the HRQoL group is a generic, 
standardized instrument that provides a simple, descriptive profile and a single index value 


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for health status that can be used in the clinical and economic evaluation of healthcare as well 
as in population health surveys.  The EQ-5D comprises 5 health dimensions of health:  
mobility, self-care, usual activities, pain / discomfort, and anxiety / depression.  Each 
dimension consists of 3 levels of response to reflect the degree of problems subjects have 
experienced:  no problem (level 1), some problems (level 2), and extreme problems (level 3), 
generating a total of 243 theoretically possible health states. 
These 5 health dimensions are summarized into a single score, the EQ-5D index score.  The 
EQ-5D index score ranges between 0 and 1, with 0 representing the worst imaginable health 
state or death and 1 representing perfect health.  This questionnaire also contains a European 
Quality-Visual Analogue Scale (EQ-VAS), which records the respondents self-rated health 
status on a vertical graduated visual analogue scale ranging from 0 (worst imaginable health 
state) to 100 (best imaginable health state).  On average, it requires 5 minutes to complete the 
questionnaire. 
The NCCN-FACT FPSI-17 (Section 14.7) is a validated instrument that was developed to 
assess symptoms of prostate cancer, symptoms of treatment of prostate cancer, and HRQoL 
of prostate cancer patients.(54)  The instrument was developed in accordance with recent 
FDA guidance for development of instruments for ePRO.  The instrument contains 17 items, 
each of which utilize a Likert scale with 5 possible responses.  The 10 items reflect 
disease-related physical symptoms of disease and the responses on the items are to be 
summed to calculate a disease-related physical symptom subscale score.  One item represents 
emotional symptoms of disease and the response to that item is used to calculate a 
disease-related emotional symptom subscale score.  Four items represent treatment-related 
symptoms and the responses to these items are summed to calculate a treatment side effect 
subscale score.  Finally, 2 items represent functional well-being and responses to those items 
are summed to calculate a functions / well-being subscale score. 
The NCCN-FACT FPSI-17 will be self-administered by the subject via ePRO device.  Some 
subjects may skip an item altogether if they feel that it is not applicable to them. 
7.6.2 
Resource utilization 
Information on healthcare resource use that is associated with the management of AEs as well 
as subject monitoring will be collected by questionnaire (Section 14.10). 
7.6.3 
Biomarker assessments 
Biomarker analyses planned within this study may include predictive, prognostic, and 
pharmacodynamic biomarkers analyzed from blood, urine, and tumor samples.  Blood, urine, 
and tumor biomarker analyses will be dependent upon the availability of appropriate 
biomarker assays and may be deferred or not performed, if during or at the EOS, it becomes 
clear that the analysis will have no scientific value, or there are not enough samples or not 
enough responders to allow for adequate biomarker evaluation. In the event the study is 
terminated early or does not reach a positive primary endpoint, completion of the biomarker 
assessments will be based on justification and intended utility of the data. 


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7.6.3.1 
Urine, serum, and plasma based biomarker analysis 
Blood samples will be obtained from all subjects at the following time points:  Cycle 1, Day 1 
(Visit 2), Cycle 4, Day 1 (Visit 8), Cycle 7, Day 1 (i.e., 28 days post-last dose of radium-223 
dichloride / placebo), Cycle 13, Day 1, and at EOT or disease progression, whichever occurs 
first.  Urine samples will be collected on Cycle 1, Day 1 (Visit 2), Cycle 4, Day 1 (Visit 8), 
Cycle 7, Day 1, and at EOT or disease progression, whichever occurs first. 
Urine and serum from blood samples (Cycle 1, Day 1, Cycle 4, Day 1, Cycle 7, Day 1 [i.e., 
28 days post-last dose of radium-223 dichloride / placebo], and EOT / disease progression) 
may be evaluated for expression levels of bone-related biomarkers.  Elevated levels of bone 
biomarkers are indicative for e.g., more aggressive disease and are prognostic of worse long-
term clinical outcome.  In this study, levels of bone biomarkers (measured before, during, and 
after treatment) that are indicative of bone remodeling (e.g., ALP and bone ALP) and bone 
resorption (e.g., n-telopeptide, c-telopeptide, carboxyterminal telopeptide of type I collagen, 
procollagen I N-terminal propeptide, and osteocalcin) may be evaluated and correlated with 
clinical outcomes (including SSEs, survival, and levels of other biomarkers). 
In addition, serum and plasma samples (Cycle 1, Day 1, Cycle 13, Day 1, and EOT / disease 
progression) may be used to analyze levels of circulating messenger ribonucleic acid 
(mRNA) / micro-ribonucleic acid (miRNA) and anomalies of tumor-related genes.  Analyses 
will not include germline genetic mutations.  The genes of interest will include genes in 
androgen / androgen receptor (AR) signaling axis (AR and its splice variants, AR-regulated 
genes, cell cycle genes, steroidogenic genes, etc.) and other genes relevant to abiraterone 
resistance or prostate cancer.  
7.6.3.2 
Tumor based biomarker analysis 
Archival formalin-fixed, paraffin-embedded (FFPE) tumor samples will be requested from all 
subjects.  If a tissue block cannot be sent, unstained slides containing FFPE tumor tissue will 
be accepted. 
Requests to return any unused tumor tissue material at study completion will be honored.  
Tumor tissue may be used for global or targeted mRNA and miRNA expression profiling.  
The genes of interest will include genes in androgen / AR signaling axis or other genes 
relevant to abiraterone resistance or prostate cancer.  Data from expression profiling of 
mRNA and miRNA may be compared to data obtained from prior studies, e.g., in 
chemotherapy-naïve CRPC, newly-diagnosed metastatic prostate cancer (M1), or primary 
prostate cancer to identify RNA profiles that correlate with clinical outcome.  Data may also 
be combined from similar data collected in other studies to further characterize the diverse 
biology of prostate cancer with the anticipation that the disease may be segmented into major 
subtypes. 
In addition, tumor-related DNA analysis, such as targeted or whole exome sequencing of 
tumor DNA, may be performed to characterize somatic anomalies that are associated with 
clinical outcome to abiraterone or to prognosis of prostate cancer. 
Detailed instructions for sample collection and handling will be provided in a Laboratory 
Manual. 


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7.7 
Appropriateness of procedures / measurements 
The procedures chosen for the evaluation of safety in this study population are consistent 
with the appropriate and ethical standards used in phase III trials of oncology drugs. 
Procedures and variables following OS analysis are appropriate for safety follow-up and 
limited efficacy.  
8. 
Statistical methods and determination of sample size 
8.1 
General considerations 
Subjects will be randomized to radium-223 dichloride or placebo in a 1:1 ratio.  
Randomization will be stratified by:  
• Geographical regions (Western Europe / North America / Australia versus Asia versus 
rest of world) 
• Concurrent use of denosumab or bisphosphonates or none 
• Total ALP < 90 U/L versus total ALP ≥ 90 U/L 
To prevent sparse data, strata for current use of denosumab and current use of 
bisphosphonates will be combined in all stratified analysis for this study. 
Exploratory analysis of the primary variable will be performed for each subgroup for 
individual stratification factors. 
Statistical analysis will be performed using Statistical Analysis System (SAS); the version 
used will be specified in the SAP.  Analysis details for all efficacy and safety endpoints will 
be specified in the SAP. 
8.2 
Analysis sets 
The following 3 populations will be analyzed: 
Intent-to-treat:  All randomized subjects.  The ITT population will be used in the analysis of 
all efficacy endpoints.  Subjects will be included in all ITT analyses according to the 
treatment to which they are randomized. 
Safety:  All randomized subjects who have received at least one dose of any study drug.  This 
safety population will be used in the analyses of all safety endpoints.  Subjects will be 
included in the analyses according to the treatment they received. 
PK set:  All subjects in Subgroup 1 with a valid PK profile for abiraterone will be included in 
the PK set. 
8.3 
Efficacy variables 
Definition for each variable is given in Section 7.3. 
The primary efficacy variable is SSE-FS.  


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The secondary efficacy variables following final OS analysis are specified below: 
• OS 
No other secondary and exploratory efficacy variables will be assessed following final OS 
analysis. 
8.4 
Statistical and analytical plans 
8.4.1 
Primary efficacy analysis 
The overall 2-sided type I error rate for the analysis of primary efficacy endpoint SSE-FS is 
0.05. 
The hypotheses to be tested are: 
H0:  S Radium-223 dichloride = S Placebo 
Ha:  S Radium-223 dichloride ≠ S Placebo, 
where S is the survival distribution. 
The SSE-FS will be analyzed using a stratified log-rank test with the same stratification 
factors as for randomization.  The HR (radium-223 dichloride / placebo) will be computed 
together with the 2-sided 95% CI using a Cox regression model stratified by the same factors.  
Kaplan-Meier estimates and plots for both treatment groups will be produced to accompany 
these analyses. 
Additional details for the analyses of primary efficacy endpoint will be provided in the SAP. 
8.4.2 
Secondary efficacy analysis 
Secondary efficacy endpoints are specified in Section 7.3. 
Each secondary variable will be tested using an overall 2-sided alpha of 0.025. 
The secondary efficacy time-to-event endpoints will be analyzed using a stratified log-rank 
test, with the factors from the randomization used for stratification.  An HR with a 95% CI 
from a stratified Cox proportional hazards model will also be provided.  Kaplan-Meier plots 
will be produced to accompany these analyses. 
8.4.3 
Safety analysis 
Safety variables will be analyzed using frequency tables and descriptive statistics. 
8.4.4 
Pharmacokinetic data 
No pharmacokinetic data will be assessed following final OS analysis. 
Statistical analysis will be done only for Subgroup 1; Subgroup 2 PK analysis results will be 
presented in a separate report. 
The concentration-time courses of abiraterone will be tabulated separated by treatment.  The 
following statistics will be calculated for each of the sampling points:  arithmetic mean, 
standard deviation (SD), and coefficient of variation (CV); geometric mean, geometric SD 


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(re-transformed SD of the logarithms), and CV; minimum, median, maximum value, and the 
number of measurements. 
Means at any time will only be calculated if at least 2/3 of the individual data were measured 
and were above the lower limit of quantification (LLOQ).  For the calculation of the mean 
value, a data point below LLOQ will be substituted by one half of this limit.  In tables 
showing mean values, where values below LLOQ are included in the calculation of mean 
values, these means will be marked. 
Individual and geometric mean concentration versus time curves of abiraterone (using the 
actual sampling times for individual plots and the planned sampling times for mean plots) 
will be plotted by treatment using both a linear and semilogarithmic scale. 
Pharmacokinetic characteristics (tmax excluded) will be summarized by the statistics 
mentioned above.  The tmax will be described utilizing minimum, maximum, and median as 
well as frequency counts. 
8.5 
Planned interim analyses 
There is no formal interim analysis for efficacy planned for the primary endpoint SSE-FS. 
For the secondary efficacy endpoint of OS, one interim analysis (to be performed at the same 
time as the final SSE-FS analysis) and one final analysis are planned.  At the interim OS 
analysis, it is expected that 275 deaths will have occurred (assuming 35.3 months median 
survival in the control arm).  If the analysis of OS after 275 deaths following treatment with 
radium-223 dichloride plus abiraterone plus prednisone / prednisolone is statistically 
significantly better compared to control (p ≤ 0.0015, based on O’Brien-Fleming alpha 
spending function), then OS will be declared positive for the interim analysis, assuming the 
final event number for OS is 500.  The actual nominal alpha levels will be calculated based 
on the actual number of events accrued at the OS interim analysis.  If the interim OS analysis 
is not statistically significant, the final analysis for OS will be performed when approximately 
500 deaths have occurred, corresponding to an approximately 60% power to detect a 25% 
improvement (in OS with radium-223 dichloride compared with placebo) with a 2-sided 
alpha of 0.025. 
Planned updated analysis 
A descriptive updated analysis will be performed after last subject last visit has occurred.  
Data may be reported through listings.  
8.6 
Determination of sample size 
Sample size is calculated based on the primary endpoint, SSE-FS.  Using a test with a 2-sided 
alpha of 0.05, power of 90%, and a randomization ratio of 1:1 between the experimental 
(radium-223 dichloride) and control (placebo) arms, 389 events are required to detect a 39% 
increase in SSE-FS (i.e., an overall 0.05 level 2-sided log-rank test has approximately 90% 
power to detect a difference between the 2 SSE-FS curves if the alternative hypothesis HR is 
0.72 [assuming the median SSE-FS is 29.2 months for radium-223 dichloride versus 21.0 for 
control]).  The expected study duration for SSE-FS is 37 months, assuming subjects enroll at 


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a rate of 50 subjects per month, an enrollment ramp-up time of 9 months, a dropout rate of 
10%, exponentially distributed event time, 21 months in SSE-FS median time for the control 
group, and a total of 800 subjects in the 2 treatment groups combined. 
This study is also powered (~60%) for the analysis of OS.  For the concluding analysis of OS, 
500 deaths are projected to occur by approximately 71.4 months after the first subject is 
randomized, assuming the median OS for the control arm is 35.3 months and a 25% 
improvement for the radium-223 dichloride arm.  If the final analysis of OS after 500 deaths 
reveals that the experimental treatment is statistically significantly better than treatment with 
control (p ≤ 0.0245), then the OS endpoint will be declared positive for the final analysis. 
9. 
Data handling and quality assurance 
9.1 
Data recording 
It is the expectation of the sponsor that all data entered into the eCRF has source 
documentation available at the study center.  The study center must implement processes to 
ensure this happens.  A source document checklist will be used at the study center to identify 
the source data for all data points collected and the monitor will work with the study center to 
complete this. 
Data recorded from “only screened subjects (screening failures)” 
Data of ‘only screened subjects’ will be recorded at least as source data, as far as the reason 
for the premature discontinuation is identifiable.  At minimum, data to be recorded in the 
eCRF are demographic information (subject number, date of birth / age, sex, and, if allowed 
by local regulation, race and ethnicity), the reason for premature discontinuation and date of 
last visit.  These data will be transferred to the respective database. 
For screening failures with a SAE, the following additional data should be collected in the 
eCRF, in addition to demographic information, primary reason for discontinuation and date 
of last visit: 
• All information about the SAE 
• All information related to the SAE such as: 
− Concomitant medication 
− Medical history 
− Other information needed for SAE complementary page 
9.2 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor’s / CRO’s procedures, monitors 
will contact the study center prior to the start of the study to review with the study center staff 
the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
sponsor’s requirements.  When reviewing data collection procedures, the discussion will also 
include identification and documentation of source data items. 


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The sponsor / designee will monitor the study center activity to verify that the: 
• Data are authentic, accurate, and complete 
• Safety and rights of subjects are being protected 
• Study is conducted in accordance with the currently approved protocol  
(including study treatment being used in accordance with the protocol) 
• Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents. 
9.3 
Data processing 
The data collection tool for this study will be a validated electronic system.  Subject data 
necessary for analysis and reporting will be transmitted into a validated database or data 
system (e.g., TOSCA; SAS).  Clinical data management will be performed in accordance 
with applicable sponsor’s standards and data cleaning procedures.  This is applicable for data 
recorded on eCRF as well as for data from other sources (e.g., IXRS, laboratory, adjudication 
committees). 
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used such as the Medical Dictionary for Regulatory Activities and World Health 
Organization Drug Dictionary. 
9.4 
Audit and inspection 
To ensure compliance with GCP and regulatory requirements, a member of the sponsor’s (or 
a designated CRO’s) quality assurance unit may arrange to conduct an audit to assess the 
performance of the study at the study center and of the study documents originating there.  
The investigator / institution will be informed of the audit outcome. 
In addition, inspections by regulatory health authority representatives and IEC(s) / IRB(s) are 
possible.  The investigator should notify the sponsor immediately of any such inspection. 
The investigator / institution agrees to allow the auditor or inspector direct access to all 
relevant documents and allocate his / her time and the time of his / her staff to the 
auditor / inspector to discuss findings and any issues.  Audits and inspections may occur at 
any time during or after completion of the study. 
9.5 
Archiving 
Essential documents shall be archived safely and securely in such a way that ensures that they 
are readily available upon authorities’ request. 
Subject (hospital) files will be archived according to local regulations and in accordance with 
the maximum period of time permitted by the hospital, institution, or private practice.  Where 
the archiving procedures do not meet the minimum timelines required by the sponsor, 
alternative arrangements must be made to ensure the availability of the source documents for 
the required period. 


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The investigator / institution notifies the sponsor if the archival arrangements change (e.g., 
relocation or transfer of ownership). 
The Investigator Site file is not to be destroyed without the sponsor’s approval. 
The contract with the investigator / institution will contain all regulations relevant for the 
study center. 
10. 
Premature termination of the study 
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g., treatment arms; dose steps; centers]) at any time, which may be due but not limited to 
the following reasons: 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this study (e.g., SAEs), upon the recommendation of the 
IDMC 
o Results of any interim analysis which might be necessary after the study 
begins 
o Results of parallel clinical studies 
o Results of parallel animal studies (e.g., toxicity, teratogenicity, 
carcinogenicity, or reproduction toxicity). 
• If the study conduct (e.g., recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame. 
The investigator has the right to close his / her center at any time. 
For any of the above closures, the following applies: 
• Closures should occur only after consultation between involved parties.  Final 
decision on the closure must be in writing. 
• All affected institutions (e.g., IEC[s] / IRB[s]; competent authority[ies]; study center; 
head of study center) must be informed as applicable according to local law. 
• All study materials (except documentation that has to remain stored at study center) 
must be returned to the sponsor or (for radium-223 dichloride samples) be destroyed 
at the study center in accordance with the local radioprotection regulations.  The 
Investigator will retain all other documents until notification given by the sponsor 
for destruction. 
• In case of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner. 
Details for individual subject’s withdrawal can be found in Section 5.2.1. 


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11. Ethical and legal aspects 
11.1 
Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
GCP guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The 
study will also be carried out in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s) / IRBs will be obtained for all participating 
centers / countries before start of the study, according to GCP, local laws, regulations, and 
organizations.  When necessary, an extension, amendment, or renewal of the IEC / IRB 
approval must be obtained and also forwarded to the sponsor.  The responsible unit (e.g., 
IEC / IRB, head of the study center / medical institution) must supply to the sponsor, 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 GCP and applicable laws and 
regulations. 
Strict adherence to all specifications laid down in this protocol is required for all aspects of 
study conduct; the investigator may not modify or alter the procedures described in this 
protocol. 
Modifications to the study protocol will not be implemented by either the sponsor or the 
Investigator without agreement by both parties.  However, the investigator or the sponsor 
may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to the trial subjects without prior IEC / IRB / sponsor approval / favorable opinion.  
As soon as possible, the implemented deviation or change, the reasons for it and if 
appropriate the proposed protocol amendment should be submitted to the IEC / IRB / head of 
medical institution / sponsor.  Any deviations from the protocol must be explained and 
documented by the investigator. 
Details on discontinuation of the entire study or parts thereof can be found in Section 10. 
11.2 
Subject information and consent 
All relevant information on the study will be summarized in an integrated subject information 
sheet and ICF provided by the sponsor or the study center.  A sample subject information and 
ICF is provided as a document separate to this protocol. 
Based on this subject information sheet, the investigator or designee will explain all relevant 
aspects of the study to each subject or legal representative or proxy consenter (if the subject is 
under legal protection), prior to his entry into the study (i.e., before any examinations and 
procedures associated with the selection for the study are performed or any study-specific 
data is recorded on study-specific forms). 
The investigator will also mention that written approval of the IRB / IEC has been obtained. 
Each subject or legal representative or proxy consenter will have ample time and opportunity 
to ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision. 


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Only if the subject or legal representative or proxy consenter voluntarily agrees to sign the 
ICF and has done so, may he enter the study.  Additionally, the investigator and other 
information provider (if any) will personally sign and date the form.  The subject or legal 
representative or proxy consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the Investigator Site file or, if locally 
required, in the subject’s note / file of the medical institution. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
If the subject is not capable of providing a signature, a verbal statement of consent can also 
be given in the presence of an impartial witness (independent of the sponsor and the 
investigator).  This is to be documented by a signature from the informing physician as well 
as by a signature from the witness. 
For adults under legal protection, consent shall be given by the legal guardian(s).  The 
consent of an adult under legal protection shall also be requested where such a person is able 
to express his own will.  His refusal or the withdrawal of his consent may not be disregarded. 
The ICF and any other written information provided to subjects or legal representatives or 
proxy consenters will be revised whenever important new information becomes available that 
may be relevant to the subject’s consent, or there is an amendment to the protocol that 
necessitates a change to the content of the subject information and / or the written ICF.  The 
investigator will inform the subject or legal representative or proxy consenter of changes in a 
timely manner and will ask the subject to confirm his participation in the study by signing the 
revised ICF.  Any revised written ICF and written information must receive the IEC / IRB’s 
approval or favorable opinion in advance of use. 
If at any time during the study the subject would like to withdraw consent, the investigator 
must discuss with the subject the active follow-up period without clinic visits part of the 
study.  If the subject continues to object to having any study data collected, the subject must 
sign the “Declaration of Objection to the Collection of Study Data after Withdrawal of 
Consent” form. 
11.3 
Publication policy 
The sponsor is interested in the publication of the results of every study it performs. 
All relevant aspects regarding publication will be part of the contract between the sponsor 
and the investigator / institution.  Authorship will be determined according to the 
International Committee of Medical Journal Editors uniform requirements for manuscripts 
submitted to biomedical journals. 
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov. 


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11.4 
Compensation for health damage of subjects / insurance 
The sponsor maintains clinical trial insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 
11.5 
Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and / or regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the eCRF, and if the subject name appears on any other document (e.g., pathologist report), 
it must be obliterated before a copy of the document is supplied to the sponsor.  Study 
findings stored on a computer will be stored in accordance with local data protection laws.  
As part of the informed consent process, the subjects will be informed in writing that 
representatives of the sponsor, IEC / IRB, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available 
for inspection will be handled in strictest confidence and in accordance with local data 
protection laws. 
If the results of the study are published, the subject’s identity will remain confidential. 
The investigator will maintain a list to enable subjects to be identified. 
12. Reference list  
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prevalence across five continents: defining priorities to reduce cancer disparities in 
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World Health Organization. International Agency for Research on Cancer. World Cancer 
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Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A 
controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J 
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Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et 
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Schmitt B, Wilt TJ, Schellhammer PF, DeMasi V, Sartor O, Crawford ED, et al. 
Combined androgen blockade with nonsteroidal antiandrogens for advanced prostate 
cancer: a systematic review. Urology. 2001;57:727-32. 
6 
Hedlund PO, Jacobsson H, Vaage S, Hahne B, Sandin T, Kontturi M, et al. Treatment of 
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Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. 
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hormone resistant prostate cancer: a Canadian randomized trial with palliative endpoints. 
J Clin Oncol. 1996;14:1756-64. 
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Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus 
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Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. 
Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced 
refractory prostate cancer. N Engl J Med. 2004;351:1513-20. 
10 Cisternino S, Bourasset F, Archimbaud Y, Semiond D, Sanderink G, Scherrmann JM. 
Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of 
P-glycoprotein at the blood-brain barrier in mice and rats. Br J Pharmacol. 
2003;138(7):1367-75. Epub 2003 Apr25. 
11 Mita AC, Denis LJ, Rowinsky EK, Debono JS, Goetz AD, Ochoa L, et al. Phase I and 
pharmacokinetic study of XRP6258 (RPR 116258A), a novel taxane, administered as a 
1-hour infusion every 3 weeks in subjects with advanced solid tumors. Clin Cancer Res. 
2009;15(2):723-30. Epub 2009 Jan 17. 
12 Bissery C, Bouchard H, Riou JF, Vrignaud P, Combeau C, Bourzat JD, et al. Preclinical 
evaluation of TXD258, a novel taxoid. Proc Am Assoc Cancer Res. 2000;41: abstract 
1364. 
13 de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone 
plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer 
progressing after docetaxel treatment: a randomised open-label trial. Lancet. 
2010;376(9747):1147-54. Epub 2010 Oct 5. 
14 Mohler J, Bahnson RR, Boston B, Busby JE, D’Amico A, Eastham JA, et al. Prostate 
cancer. J Natl Compr Canc Netw. 2010;8:162-200. 
15 Small EJ, Baron A, Bok R. Simultaneous antiandrogen withdrawal and treatment with 
ketoconazole and hydrocortisone in subjects with advanced prostate carcinoma. Cancer. 
1997;80:1755-9. 
16 Millikan R, Baez L, Banerjee T, Wade J, Edwards K, Winn R, et al. Randomized Phase 2 
trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate 
cancer. Urol Oncol. 2001;6:111-5. 
17 Small EJ, Baron AD, Fippin L, Apodaca D. Ketoconazole retains activity in advanced 
prostate cancer subjects with progression despite flutamide withdrawal. J Urol. 
1997;157:1204-7. 
18 Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen 
withdrawal alone or in combination with ketoconazole in androgen-independent prostate 
cancer subjects: a Phase 3 trial (CALGB 9583). J Clin Oncol. 2004;22:1025-33. 
19 Itakura H, Vaughn D, Haller DG, O’Dwyer PJ. Rhabdomyolysis from cytochrome p-450 
interaction of ketoconazole and simvastatin in prostate cancer. J Urol. 2003;169:613. 


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20 Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, 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. 1989;7:590-7. 
21 Nishimura K, Nonomura N, Satoh E, Harada Y, Nakayama M, Tokizane T, et al. 
Potential mechanisms for the effects of dexamethasone on growth of androgen-
independent prostate cancer. J Natl Cancer Inst. 2001;93:1739-46. 
22 Li Z, Chen Y, Cao D, et al. Glucocorticoid up-regulates transforming growth factor-
{beta} (TGF-{beta}) type II receptor and enhances TGF-{beta} signaling in human 
prostate cancer PC-3 cells. Endocrinology. 2006;147:5259-67. 
23 Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. 
Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic 
hormone resistant prostate cancer: a Canadian randomized trial with palliative endpoints. 
J Clin Oncol. 1996;14:1756-64. 
24 Fossa SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, et al. Flutamide 
versus prednisone in subjects with prostate cancer symptomatically progressing after 
androgen-ablative therapy: a Phase 3 study of the European organization for research and 
treatment of cancer genitourinary group. J Clin Oncol. 2001;19:62-71. 
25 Smith DC, Redman BG, Flaherty LE, Li L, Strawderman M, Pienta KJ. A phase II trial 
of oral diethylbestrol as a second line hormonal agent in advanced prostate cancer. 
Urology. 1998;52:257-60. 
26 Klotz L, McNeill I, Fleshner N. A phase 1-2 trial of diethylbestrol plus low dose warfarin 
in advanced prostate carcinoma. J Urol. 1999;161:169-72. 
27 Oh WK, Kanthoff PW, Weinberg V, Jones G, Rini BI, Derynck MK, et al. Prospective, 
multicentre, randomized phase II trial of the herbal supplement PC-SPES and 
diethylbestrol in subjects with androgen-independent prostate cancer. J Clin Oncol. 
2004;22:3705-12. 
28 Heidenreich A, Aus G, Abbou CC, Bolla M, Joniau S, Matveev V, et al. Guidelines on 
prostate cancer. European Association of Urology. 2008. 
29 Logothetis C, Tu SM, Navone N. Targeting prostate cancer bone metastases. Cancer. 
2003;97(3 Suppl):785-8. Epub 2003 Jan 28. 
30 Saad F, Markus R, Goessl C. Targeting the receptor activator of nuclear factor-kappaB 
(RANK) ligand in prostate cancer bone metastases. BJU Int. 2008;101(9):1071-5. Epub 
2007 Dec 12. 
31 Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-
term efficacy of zoledronic acid for the prevention of skeletal complications in subjects 
with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879-
82. Epub 2004 Jun 03. 
32 Fizazi K, Carducci MA, Smith MR, Damião R, Brown JE, Karsh L, et al. Denosumab 
versus zoledronic acid for treatment of bone metastases in men with castration-resistant 


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prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-22. Epub 2011 
Feb 25. 
33 Tu SM, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, et al. 
Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a 
randomised phase II trial. Lancet. 2001;357(9253):336-41. Epub 2001 Feb 24. 
34 Morris MJ, Pandit-Taskar N, Carrasquillo J, Divgi CR, Slovin S, Kelly WK, et al. Phase 
I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic 
prostate cancer. J Clin Oncol. 2009;27(15):2436-42. Epub 2009 Apr 15. 
35 Logothetis C, Provenge, FDA Presentation, Mar 29, 2007, 
http://www.fda.gov/ohrms/dockets/ac/07/transcripts/2007-4291T1.pdf. 
36 Calabro F, Sternberg CN. Current indications for chemotherapy in prostate cancer 
subjects. Eur Urol. 2007;51:17-26 
37 Basch EM, Somerfield MR, Beer TM, Carducci MA, Higano CS, Scher HI. American 
Society of Clinical Oncology endorsement of the Cancer Care Ontario Practice 
guidelines on nonhormonal therapy for men with metastatic hormone-refractory 
(castration-resistant) prostate cancer. J Clin Oncol. 2007;25:5313-18. 
38 Horwich A, Parker C, Kataja V. Prostate cancer: ESMO clinical recommendations for 
diagnosis, treatment and follow-up. Ann Oncol. 2008;19(Supplement 2):ii45-ii46. 
39 Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. 
Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 
2013;368(2):138-48. 
40 Nilsson S, Franzen L, Parker C, Tyrrell C, Blom R, Tennvall J, et al. Bone-targeted 
radium-223 in symptomatic, hormone-refractory prostate cancer: a randomized, 
multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587-94. 
41 Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH. Significant antitumor 
effect from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an 
experimental skeletal metastases model. Cancer Res. 2002;62:3120-5. 
42 Parker C, et al. Updated analysis of the phase III, double-blind, randomized, 
multinational study of radium-223 chloride in castration-resistant prostate cancer (CRPC) 
patients with bone metastases (ALSYMPCA). J Clin Oncol. 2012;30(suppl). Abstract 
LBA4512. 
43 Attard G, Reid A, Barrett M, Karavasilis V, Molife R, Thompson E, et al. Inhibition of 
androgen synthesis results in a high response rate in castration refractory prostate cancer. 
In: American Association for Cancer Research Annual Meeting: Proceedings; 
2007 Apr 14-18; Los Angeles, CA. Philadelphia (PA): AACR; 2007, Abstract LB-180. 
44 Ryan CJ, Rosenberg J, Lin AM, Huey V, Kim JJ, Martins V, et al. C2 Effect of 
concomitant food intake on pharmacokinetics of abiraterone acetate, a 17 
alphahydroxylase C17,20-lyase inhibitor in castration-resistant prostate cancer (CRPC). 
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45 de Bono JS, Attard G, Reid A, Parker C, Dowsett M, Mollife R, et al. Abiraterone acetate 
(AA), a CYP17 inhibitor of androgen synthesis, has significant and durable anti-tumor 
activity in both chemotherapy naïve and docetaxel pre-treated castration-resistant 
prostate cancer (CRPC). J Clin Oncol. 2008 ASCO Annual Meeting Proceedings; 26: 
Abstract 5005. 
46 Ryan CJ, Rosenberg J, Lin A, Small EJ. Phase I evaluation of abiraterone acetate 
(CB7630), a 17-alpha hydroxylase C17,20-lyase inhibitor in androgen-independent 
prostate cancer (AiPCa). J Clin Oncol. 2007 ASCO Annual Meeting Proceedings; 25: 
Abstract 278. 
47 Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, et al. Effect of 
abiraterone acetate and prednisone compared with placebo and prednisone on pain 
control and skeletal-related events in subjects with metastatic castration-resistant prostate 
cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet 
Oncol. 2012;12:1210-7. 
48 Attard G, Reid A, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical 
trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-
resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 
2008;26(28):4563-71. 
49 Ryan CJ, Rosenberg J, Lin A, Valiente J, Kim J, Small, EJ. Phase I evaluation of 
abiraterone acetate (CB7630), a 17 alpha hydroxylase C17, 20-Lyase inhibitor in 
androgen-independent prostate cancer (AiPC). J Clin Oncol. 2007 ASCO Annual 
Meeting Proceedings 2007;Part I (25)18S (June 20 Supplement):5064. 
50 Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of 
P450c17. Endocrinol Metab Clin North Am. 2001;30(1):101-19. 
51 Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures 
correlate with reduced survival in patients with malignant bone disease. Cancer. 
2007;110(8):1860-7. 
52 Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and 
end points of clinical trials for patients with progressive prostate cancer and castrate 
levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working 
Group. J Clin Oncol. 2008;26:1148-59. 
53 Cleeland CS. The Brief Pain Inventory User Guide. www.mdanderson.org, 2009. 
54 Cella D, Rosenbloom SK, Beaumont JL, Yount SE, Paul D, Hampton D, et al. 
Development and validation of eleven symptom indexes to evaluate response to 
chemotherapy for advanced cancer. J Natl Compr Canc Netw. 2011;9(3):268-78. 
55 Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation 
counting. Appl Radiat Isot. 2010;68(7-8):1523-8. 
56 Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R, Pibida L. Revision of the NIST 
standard for 223Ra: new measurements and review of 2008 data. Journal of Research of 
the National Institute of Standards and Technology. 2015;120:37-57. 


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13. Protocol amendments  
13.1 
Amendment 1 
Amendment 1 (dated 26 AUG 2014) is an amendment to the original protocol dated 
05 Nov 2013.  Changes to the protocol include: 
• Changed the short title of the study and added the study acronym 
• Added the exploratory objective to the synopsis 
• Clarified that subjects must provide “written” informed consent 
• Modified the inclusion criterion to clarify the permitted age range 
• Corrected inconsistencies between the synopsis and body of the protocol 
• Modified the inclusion criterion to expand the permitted estimated GFR 
• Clarified the birth control requirements 
• Added a 7-day window to the screening period 
• Clarified study treatment is either radium-223 dichloride (Arm A) or placebo (Arm 
B) 
• Clarified the maximum radium-223 dichloride treatment duration 
• Clarified that abiraterone is not considered study medication after an on-study SSE 
• Corrected inconsistencies in the text versus the schedule of assessments table 
• Clarified the long-term follow-up period would end after a maximum of 7 years 
• Clarified that the EOS may occur when the last subject is transferred to a separate 
follow-up study 
• Specified the analysis of PK data 
• Clarified the eCRF will be used for recording data 
• Clarified the term bone scan 
• Updated the number of study centers to 170 
• Clarified the administration of study drug 
• Updated information regarding PRDs 
• Clarified that abiraterone acetate and prednisone / prednisolone will be centrally 
sourced and saline will be sourced locally 
• Clarified the process for maintaining the blind 
• Updated the manufacturer of radium-223 dichloride 
• Clarified the storage conditions and expiry for radium-223 dichloride 
• Clarified the radium-223 dichloride ordering process 
• Clarified body weight must be measured within 3 days prior to dosing and on the day 
of dosing for non-US sites or 3 to 5 days prior to dosing for US sites 


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• Corrected the Hb level that must be met for dosing 
• Clarified when the analgesic consumption diary and BPI-SF would be assessed with 
respect to the visit 
• Corrected the window for the dosing visits 
• Corrected the window for the active follow-up without clinic visits 
• Clarified that the HRQoL forms will not be administered at the screening visit 
• Added completion of the resource utilization questionnaire to the active follow-up 
without clinic visits 
• Added completion of the analgesic consumption diary and recording 24 hour 
analgesic use to the end of active follow-up without clinic visits 
• Clarified bone and tumor-related biomarker assessment in serum, plasma, and / or 
urine 
• Added collection of SSEs during the screening period 
• Clarified when radium-223 dichloride versus abiraterone and prednisone / 
prednisolone will be ordered 
• Clarified that survival status will be collected throughout the study 
• Clarified that in the US, dosing should occur at least 7 days after randomization, 
whenever possible 
• Corrected the study days to be in relation to the cycle number (i.e., Cycle 1, Day 8) 
and added corresponding visits 
• Clarified that collection of cancer-related treatments includes androgen synthesis 
inhibitors / AR antagonists and excludes analgesics 
• Corrected when the handheld device will be provided to subjects 
• Specified that biochemistry results should be evaluated before study drug 
administration if the results are available 
• Clarified the resource utilization questionnaire will be completed by the sites 
• Clarified that both subjects and sites should record to which treatment they believe 
the subjects were randomized 
• Clarified when the active follow-up period begins 
• Corrected how the BPI-SF items are calculated 
• Specified the time points for ALP response and PSA response 
• Clarified the fasting requirements prior to each PK visit 
• Corrected the expected study durations used for the sample size calculations 
• Clarified that race and ethnicity will only be collected if allowed by local regulation 
• Added the modified RECIST 1.1 criteria 
• Added the correction factor for Black subjects to the Modification of Diet in Renal 
Disease formula 


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• Corrected typographical errors 
 
13.1.1 
Overview of changes 
Modification 1 
Changed the short title of the study to reflect the study acronym. 
Sections affected include: 
• Title page 
• Synopsis:  Short title 
• List of abbreviations 
 
Modification 2 
Added the exploratory objective (to evaluate the impact of baseline total body weight and 
ideal body weight on SSE-FS and AEs) to the synopsis to be consistent with the body of the 
protocol. 
Sections affected include: 
• Synopsis:  Study objectives 
 
Modification 3 
Clarified that subjects must provide “written” informed consent for this study. 
Sections affected include: 
• Synopsis:  Diagnosis and main criteria for inclusion 
• 5.1.1 Inclusion criteria 
 
Modification 4 
Modified the inclusion criterion to clarify subjects must be at least 18 years old, or older if 
legally required in their participating country. 
Sections affected include: 
• Synopsis:  Diagnosis and main criteria for inclusion 
• 5.1.1 Inclusion criteria 
 
Modification 5 
Corrected inconsistencies between the synopsis and the body of the protocol. 


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Sections affected include: 
• Synopsis:  Diagnosis and main criteria for inclusion 
• Synopsis:  Methodology 
• 3.1 Independent Data Monitoring Committee  
• 4.1.1 Study periods and duration  
• Figure 4-1 Study design schematic 
• 5.1.1 Inclusion criteria 
• 7.1.2.5 Long-term follow-up for up to 7 years following last dose 
 
Modification 6 
Changed the minimum estimated GFR from 60 to 30 mL/min/1.73 m2 to increase subject 
eligibility.  This change will not compromise subject safety based on available data on the 
investigational drugs. 
Sections affected include: 
• Synopsis:  Diagnosis and main criteria for inclusion 
• 5.1.1 Inclusion criteria 
 
Modification 7 
Clarified the birth control requirements to be consistent with the requirements in Spain. 
Sections affected include: 
• Synopsis:  Diagnosis and main criteria for inclusion 
• 5.1.1 Inclusion criteria 
 
Modification 8 
Added a window of + 7 days to the screening period to increase flexibility for the sites and 
for consistency among the radium-223 dichloride program. 
Sections affected include: 
• Synopsis:  Methodology 
• 4.1.1 Study periods and duration 
• 5.1 Eligibility 
• Table 7-1 Schedule of assessments 
• 7.1.2.1 Screening period (Visit 1) 
 


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Modification 9 
Clarified that study treatment is either radium-223 dichloride (Arm A) or placebo (Arm B). 
Sections affected include: 
• Synopsis:  Methodology 
• 4.1.1 Study periods and duration 
• Figure 4-1 Study design schematic 
• 4.3 End of study 
• 5.2.1.1 Withdrawal from treatment period (collection of follow-up data) 
• 6.4.4 Dose adjustments for study drug-related adverse events 
• 6.4.5 Dose adjustments, delays, and treatment discontinuations 
• 6.4.5.1 Radium-223 dichloride / placebo 
• 6.7 Treatment compliance 
• 6.8 Post-study treatment therapy 
• Table 7-1 Schedule of assessments 
• 7.1.2.3 Treatment period 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 7 
days) up until discontinuation of abiraterone and prednisone / prednisolone or until 6 
months post last radium-223 dichloride / placebo administration, whichever occurs 
later 
• 7.1.2.3.4 End of treatment visit 
• 7.1.2.4.3.1 End of active follow-up with clinic visits 
• 7.1.2.5 Long-term follow-up for up to 7 years following last dose 
• 7.1.2.6 End of study 
• 7.4.1 Drug measurement 
• 7.4.2 Pharmacokinetic evaluation 
 
Modification 10 
Clarified that a maximum of 6 doses of radium-223 dichloride treatment will be administered 
every 4 weeks. 
Sections affected include: 
• Synopsis:  Methodology 
• 4.1.1 Study periods and duration 
• 5.2.1.1 Withdrawal from treatment period (collection of follow-up data) 
• 6.8 Post-study treatment therapy 


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• Table 7-1 Schedule of assessments 
 
Modification 11 
Clarified that abiraterone is not considered study medication when administered after an 
on-study SSE. 
Sections affected include: 
• Synopsis:  Methodology 
• 4.1.1 Study periods and duration 
• 5.2.1.1 Withdrawal from treatment period (collection of follow-up data) 
• 6.2.1.3 Abiraterone acetate 
• Table 7-1 Schedule of assessments 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 7 
days) up until discontinuation of abiraterone as IMP and prednisone / prednisolone or 
until 6 months post last radium-223 dichloride / placebo administration, whichever 
occurs later 
• 7.1.2.3.4 End of treatment visit 
• 7.5.1.3 Assessments and documentation of adverse events 
 
Modification 12 
Corrected inconsistencies in the text versus the schedule of assessments.  These include 
clarifying the timing of the visits; the timing of the collection of vital signs, weight, 
progression, SSEs, AEs, cancer related treatments, 24-hour analgesic use, drug 
accountability, and PK sampling; when the ePRO device is dispensed; the timing of the bone 
scans and CT / MRI during Cycles 12+; concomitant medication recording; and the 
assessments performed during the Active Follow-up period without clinic visits. 
Sections affected include: 
• Synopsis:  Methodology 
• 4.1.1 Study periods and duration 
• Figure 4-1 Study design schematic 
• Table 7-1 Schedule of assessments 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.2 Visits 3, 5, and 7 (Cycles 1, 2, and 3, Day 15 ± 3 days) and unscheduled 
visits 
• 7.1.2.3.4 End of treatment visit 
• 7.1.2.4.1 Active follow-up with clinic visits assessments (Every 12 weeks ± 7 days at 
each visit) 


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• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
• 7.1.2.4.3.1 End of active follow-up with clinic visits 
• 7.1.2.4.3.2 End of active follow-up without clinic visits 
• 7.1.2.5.1 Long-term follow-up (telephone follow-up) 
• 7.1.2.5.2 End of long-term follow-up 
• 7.3.2.2 Secondary efficacy endpoints: 
 
Modification 13 
Clarified the duration of the long-term follow-up period is a maximum of 7 years. 
Sections affected include: 
• Synopsis:  Methodology 
• 4.1.1 Study periods and duration 
• Figure 4-1 Study design schematic 
• 4.3 End of study 
• Table 7-1 Schedule of assessments 
• 7.1.2.5 Long-term follow-up for up to 7 years following last dose 
• 7.1.2.5.1 Long-term follow-up (telephone follow-up) 
• 7.1.2.6 End of study 
 
Modification 14 
Clarified that the end of study may occur when the last subject is transferred to a separate 
extended safety follow-up protocol. 
Sections affected include: 
• Synopsis:  Methodology 
• 4.1.1 Study periods and duration 
• 4.3 End of study 
• Table 7-1 Schedule of assessments 
• 7.1.2.4.3.1 End of active follow-up with clinic visits 
• 7.1.2.5 Long-term follow-up for up to 7 years following last dose 
• 7.1.2.5.2 End of long-term follow-up 
 
Modification 15 
Described how the PK parameters will be handled during analysis to provide clarification. 


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Sections affected include: 
• List of abbreviations 
• 8.2 Analysis sets 
• 8.4.4 Pharmacokinetic data 
 
Modification 16 
Clarified the eCRF will be used for recording data rather than using the terms CRF, eCRF, 
and Medidata Rave interchangeably. 
Sections affected include: 
• List of abbreviations 
• 6.4.2 Radium-223 dose calculation 
• Table 7-1 Schedule of assessments 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.2 Visits 3, 5, and 7 (Cycles 1, 2, and 3, Day 15 ± 3 days) and unscheduled 
visits 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 7 
days) up until discontinuation of abiraterone and prednisone / prednisolone or until 6 
months post last radium-223 dichloride / placebo administration, whichever occurs 
later 
• 7.1.2.3.4 End of treatment visit 
• 7.1.2.4.1 Active follow-up with clinic visits assessments (Every 12 weeks ± 7 days at 
each visit) 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
• 7.1.2.4.3.1 End of active follow-up with clinic visits 
 
Modification 17 
Clarified that the term bone scan as used in this protocol refers to a whole body 
technetium-99m bone scan. 
Sections affected include: 
• Definitions of terms 
• 7.3.2.2 Secondary efficacy endpoints 
 


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Modification 18 
Updated the number of study centers to 170 sites to reflect the additional sites required to 
recruit this study. 
Sections affected include: 
• 4.1 Design overview 
 
Modification 19 
Clarified the administration of study drug to provide missing information, including the 
duration of the bolus injection. 
Sections affected include: 
• 6.1 Treatments to be administered 
• 6.4 Dosage and administration 
 
Modification 20 
Updated information regarding PRDs.  Patient ready doses prepared by Cardinal Health for 
US sites have an extended expiry, as agreed by Bayer with FDA.  Thus, Cardinal Health has 
additional time to ensure delivery prior to expiry and sites may have additional flexibility 
with actual dosing day (i.e., 1 more day) when logistical delays occur (i.e., either subject or 
PRD do not arrive as planned), as long as the PRD has not expired / dose is given prior to 
expiry date and time, assessments other than weight are repeated (to be within window prior 
to dose day / time), and measured activity of the PRD is within 10% of the ‘ordered amount’ 
(planned dose). 
Sections affected include: 
• 6.2 Identity of study treatment 
• 6.4 Dosage and administration 
• 6.4.1 Radium-223 dichloride dose handling 
• 6.4.2 Radium-223 dose calculation 
• 6.4.3 Study drug dose preparation 
• Table 7-1 Schedule of assessments 
 
Modification 21 
Clarified that abiraterone acetate and prednisone / prednisolone will be centrally sourced and 
saline will be supplied locally. 
Sections affected include: 
• 6.2 Identity of study treatment 


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• 6.2.1 Study medication supply and packaging 
• 6.2.1.4 Prednisone / prednisolone 
• 6.6 Drug logistics and accountability 
 
Modification 22 
Clarified the processes for maintaining the blind. 
Sections affected include: 
• 6.2.1 Study medication supply and packaging 
• 6.2.1.2 Saline 
• 6.4.2 Radium-223 dose calculation 
• 6.4.3 Study drug dose preparation 
• 6.7 Treatment compliance 
 
Modification 23 
Updated the manufacturer of radium-223 dichloride from Algeta ASA to Bayer HealthCare. 
Sections affected include: 
• 6.2.1.1 Radium-223 dichloride 
 
Modification 24 
Clarified the storage conditions and expiry for radium-223 dichloride to reflect the most 
recent information. 
Sections affected include: 
• 6.2.1.1 Radium-223 dichloride 
• 6.4.1 Radium-223 dichloride dose ordering and handling 
• 6.4.3 Study drug dose preparation 
 
Modification 25 
Clarified the process for ordering radium-223 dichloride. 
Sections affected include: 
• 6.4.1 Radium-223 dichloride dose ordering and handling 
 


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Modification 26 
Clarified body weight must be measured within 3 days prior to dosing and on the day of 
dosing for non-US sites and 3 to 5 days prior to dosing for US sites to account for the 
requirements of the US PRDs versus non-US sites, which will not use PRDs. 
Sections affected include: 
• 6.4.2 Radium-223 dose calculation 
• Table 7-1 Schedule of assessments  
• 7.1.2.1 Screening period (Visit 1) 
• 7.1.2.3 Treatment period 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
 
Modification 27 
Corrected an inconsistency in the required Hb level that must be met (> 8.0 g/dL) prior to 
radium-223 dichloride / placebo dosing. 
Sections affected include: 
• 6.9.2 Permitted concomitant therapy 
 
Modification 28 
Clarified the analgesic consumption diary and BPI-SF would be assessed daily for one week 
(6 days prior to the visit and the day of the visit), except at the screening visit when the 
BPI-SF will be assessed once using a paper version. 
Sections affected include: 
• 6.9.2 Permitted concomitant therapy 
• Table 7-1 Schedule of assessments 
• 7.1.2.1 Screening period (Visit 1) 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.4 End of treatment visit 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
• 7.1.2.4.3.1 End of active follow-up with clinic visits  
• 7.1.2.4.3.2 End of active follow-up without clinic visits 
 
Modification 29 
Corrected the window for the dosing visits from ± 7 days to + 7 days to reflect the minimum 
period between 2 doses of radium-223 dichloride / placebo of 28 days. 


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Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
 
Modification 30 
Corrected the window for the active follow-up without clinic visits from ± 14 days to 
± 7 days. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
 
Modification 31 
Clarified that the HRQoL NCCN-FACT FPSI-17 and HRQoL EQ-5D forms will not be 
administered at the screening visit. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
 
Modification 32 
Added completion of the resource utilization questionnaire to the active follow-up without 
clinic visits to capture this additional information. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
• 7.1.2.4.3.2 End of active follow-up without clinic visits 
 
Modification 33 
Added completion of the analgesic consumption diary and recording 24 hour analgesic use to 
the end of active follow-up without clinic visits to be consistent with the active follow-up 
without clinic visits. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.4.3.2 End of active follow-up without clinic visits 


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Modification 34 
Clarified that exploratory bone biomarkers will be assessed in serum and urine, and 
exploratory tumor-related biomarkers will be assessed in serum and plasma.  Added the 
analysis of serum c-telopeptide, carboxyterminal telopeptide of type I collagen, and 
procollagen I N-terminal propeptide. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 7 
days) up until discontinuation of abiraterone as IMP and prednisone / prednisolone or 
until 6 months post last radium-223 dichloride / placebo administration, whichever 
occurs later  
• 7.1.2.3.4 End of treatment visit 
• 7.6.3.1 Urine, serum, and plasma based biomarker analysis 
 
Modification 35 
Added collection of SSEs during the screening period. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.1 Screening period (Visit 1) 
 
Modification 36 
Clarified when radium-223 dichloride versus abiraterone and prednisone / prednisolone will 
be ordered to reflect the continuation of treatment with abiraterone and 
prednisone / prednisolone after the last dose of radium-223 dichloride / placebo. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
 
Modification 37 
Clarified that death (i.e., survival status) will be collected throughout the study. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.1 Screening period (Visit 1) 


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• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.2 Visits 3, 5 and 7 (Cycles 1, 2, and 3, Day 15 ± 3 days) and unscheduled 
visits 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day  1 and every 4 weeks thereafter 
± 7 days) up until discontinuation of abiraterone as IMP and prednisone / 
prednisolone or until 6 months post last radium-223 dichloride / placebo 
administration, whichever occurs later 
• 7.1.2.3.4 End of treatment visit 
 
Modification 38 
Clarified that in the US, randomization should occur at least 7 days before Cycle 1, Day 1, 
whenever possible.  This allows time for subjects to complete the BPI-SF completion for one 
week prior to dosing regardless of the time for shipment of study drug from the PRD. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.2 Randomization 
• 7.4.1 Drug measurement 
 
Modification 39 
Corrected the study days to be in terms of the cycle number (e.g., Cycle 1, Day 8) and added 
the corresponding visits.  The previous version inconsistently referred to Days 0, 7, etc.  The 
first dose will be administered on Cycle 1, Day 1; therefore, 7 days after dosing is Cycle 1, 
Day 8 not Cycle 1, Day 7. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.2 Visits 3, 5 and 7 (Cycles 1, 2, and 3, Day 15 ± 3 days) and unscheduled 
visits 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 7 
days) up until discontinuation of abiraterone as IMP and prednisone / prednisolone or 
until 6 months post last radium-223 dichloride / placebo administration, whichever 
occurs later 
• 7.6.3.1 Urine, serum, and plasma based biomarker analysis 
 


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Modification 40 
Clarified that collection of cancer-related treatments includes androgen synthesis inhibitors / 
AR antagonists and excludes analgesics. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.1 Screening period (Visit 1) 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.2 Visits 3, 5 and 7 (Cycles 1, 2, and 3, Day 15 ± 3 days) and unscheduled 
visits 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 7 
days) up until discontinuation of abiraterone as IMP and prednisone / prednisolone or 
until 6 months post last radium-223 dichloride / placebo administration, whichever 
occurs later 
• 7.1.2.3.4 End of treatment visit 
• 7.1.2.4.1 Active follow-up with clinic visits assessments (Every 12 weeks ± 7 days at 
each visit) 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
• 7.1.2.4.3.1 End of active follow-up with clinic visits 
• 7.1.2.4.3.2 End of active follow-up without clinic visits 
 
Modification 41 
Corrected that the handheld device will be provided to subjects at least 6 days prior to dosing 
not prior to randomization. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.1 Screening period (Visit 1) 
 
Modification 42 
Specified that biochemistry results should be evaluated before study drug administration if 
the results are available. 
Sections affected include: 
• Table 7-1 Schedule of assessments 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
 


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Modification 43 
Clarified the resource utilization questionnaire will be completed by the sites not the subjects. 
Sections affected include: 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 7 
days) up until discontinuation of abiraterone as IMP and prednisone / prednisolone or 
until 6 months post last radium-223 dichloride / placebo administration, whichever 
occurs later 
• 7.1.2.3.4 End of treatment visit 
• 7.1.2.4.1 Active follow-up with clinic visits assessments (Every 12 weeks ± 7 days at 
each visit) 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
• 7.1.2.4.3.1 End of active follow-up with clinic visits 
• 7.1.2.4.3.2 End of active follow-up without clinic visits 
 
Modification 44 
Clarified that both subjects and sites should record to which treatment they believe the 
subjects were randomized. 
Sections affected include: 
• 7.1.2.3.4 End of treatment visit 
 
Modification 45 
Clarified when the active follow-up period begins to be consistent with long-term follow-up. 
Sections affected include: 
• 7.1.2.4 Active follow-up 
 
Modification 46 
Corrected the calculation of the BPI-SF items from sums to means. 
Sections affected include: 
• 7.3.2.2 Secondary efficacy endpoints 
 


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Modification 47 
Specified the time points for ALP response and PSA response to add clarity to the definitions 
of these terms. 
Sections affected include: 
• 7.3.2.3 Exploratory efficacy endpoints 
 
Modification 48 
Clarified the fasting requirements before or after abiraterone dosing prior to each PK visit. 
Sections affected include: 
• 7.4.1 Drug measurement 
 
Modification 49 
Corrected the expected study durations used for the sample size calculations.  The durations 
were rounded to the nearest integer; therefore, displaying numbers to the first decimal point 
was inaccurate. 
Sections affected include: 
• 8.6 Determination of sample size 
 
Modification 50 
Clarified that subjects’ race and ethnicity will only be collected where permitted by local 
regulations. 
Sections affected include: 
• 9.1 Data recording 
 
Modification 51 
Added the changes to the modified RECIST 1.1 criteria to provide further clarification of the 
modified RECIST criteria. 
Sections affected include: 
• 14.3 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
 
Modification 52 
Added the correction factor for Black subjects to the Modification of Diet in Renal Disease 
formula so GFR will be accurately calculated for these subjects. 


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Sections affected include: 
• 14.4 Calculation for glomerular filtration rate 
13.1.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 1 are provided in Section 13.1.2 of 
integrated protocol Version 2.0. 
13.2 
Amendment 2  
Amendment 2 (dated 12 JUN 2015) is an amendment to Integrated Protocol version 2.0 dated 
26 AUG 2014. Changes to the integrated protocol include: 
• Update dosing and dose calibration of radium-223 dichloride to reflect revised NIST 
standardization for radium-223 
• Removed cytological confirmation of adenocarcinoma of the prostate from inclusion 
criteria; histological confirmation only 
• Clarified that the treatment period ended when a subject received 
abiraterone/prednisone as the standard of care (non-IMP) after an SSE 
• Added an exclusion for immunotherapy (e.g., sipuleucel-T) within 4 weeks before 
the first dose of radium-223 dichloride 
• Clarified duration of prohibited concomitant therapy is from Screening onwards 
• Clarified potassium requirement for ECG collection 
• Editorial updates 
13.2.1 
Overview of changes 
Modification 1 
Update of the radium-223 dichloride dosing and dose calibration to reflect the revised NIST 
standard. 
Rationale: 
The quantification of radium-223 radioactivity in Xofigo® is based on the primary 
standardization performed by the US National Institute of Standards and Technology (NIST).  
The NIST Standard Reference Material is used to calibrate the instruments in production and 
quality control of both the drug substance and drug product.  Additionally, the calibrated 
instruments in production at the Institute for Energy Technology (Norway) are used to 
prepare the NIST traceable radium-223 reference material, which are then sent to the 
treatment sites (e.g., nuclear medicine laboratory physicians or technicians) for dial setting of 
their dose calibrators, to allow verification of the subject dose.  A reassessment of the 
primary standardization was initiated by the NIST.  A discrepancy of approximately 10% 
between the published NIST primary standardization (55) and current measurements was 
confirmed and a revised NIST primary reference standard has been issued (56).  As a result 
of the revised NIST primary standardization, an adaption of the numerical description of 
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becomes necessary.  This concerns Xofigo® for commercial use and product used in clinical 
trials.   
After the implementation of the new standard (56), the numerical description of the subject 
dose will be adjusted from 50 kBq/kg to 55 kBq/kg, and the numerical description of the 
radioactivity in the vial will be changed from 1,000 kBq/mL to 1,100 kBq/mL.  A respective 
variation application and substantial amendment to our Clinical Trial Applications have been 
initiated.  The current standard (55), dial setting, and dose will remain in effect until a unique 
implementation date in Q2 2016 as agreed with FDA and the European Medicines Agency.  
All clinical sites using radium-223 dichloride will be notified in writing about the exact date 
of implementation prior to the effective date. 
Justification for changing the dose to 55 kBq/kg body weight: 
A systematic approximately 10% error in the radium-223 NIST standardization (55) means 
that the current subject dose and the dose documented as safe and efficacious throughout 
development is 55 kBq/kg body weight and not 50 kBq/kg body weight as declared during 
clinical trials and in the marketing authorization application / new drug application.  
However, as this is a systematic error, the actual dose has been the same all the time.  In order 
to keep the actual dose for subjects identical to what has been documented and administered 
so far, also when implementing the new official standard, the nominal value of the subject 
dose will be changed to 55 kBq/kg body weight (56).  This change keeps the same accuracy 
in the nominal value of the dose.  Thus, there will be no actual change in the subject dose 
(amount of radioactivity); it will be only a change in the dose nominal value when corrected 
according to the new official radium-223 NIST standard.  All sites will continue to use the 
current dial setting (55) for the activity measurements until the implementation date in Q2 
2016. 
Justification for changing the description of the radioactivity in the vial to 
1,100 kBq/mL: 
A systematic approximately 10% error in the radium-223 NIST standard (55) means that the 
Xofigo® solution for injection with a radioactivity concentration claim of 1,000 kBq/mL, 
which has been tested in pivotal clinical trials and is currently marketed, actually has a 
concentration of 1,100 kBq/mL.  If the drug product concentration is adjusted to 
1,100 kBq/mL, the total activity in the vial (6 mL) must be changed from 6,000 kBq/vial to 
6,600 kBq/vial (changed from 6.0 MBq/vial to 6.6 MBq/vial in many countries).  Xofigo® 
solution for injection produced according to the new NIST standardization (56), is the same 
product as before.  NOTE:  All product received by sites will be labelled with the current 
standard activity of 1000 kBq/mL until the implementation date in Q2 2016.   
Now that the new radium-223 standard has been published, Bayer has applied for labeling 
and packaging changes, in accordance with the new standards, with each Health Authority for 
which Bayer holds a marketing application for radium-223 dichloride.  Once all approvals 
have been received, the updated standard will be applied to all active protocols that include 
radium-223 dichloride, including this one, and the verification of the subject dose in 
treatment sites has to be performed using updated dial settings of dose calibrators.   


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The change in the NIST radium-223 standard has no impact on subjects; subjects are 
receiving, and will continue to receive, the same actual dose that was studied in ALSYMPCA 
and is associated with the proven safety and efficacy of radium-223 dichloride, though the 
stated nominal radiation dose received is being updated to reflect the new standard.  Subjects 
who are on-treatment at the time the new NIST calibration standard goes into effect will be 
notified of this change and will be required to sign a Patient Information Sheet to 
acknowledge that they have received information on the updated NIST standard calibration.  
All subjects randomized after the new calibration standard in effect will sign a revised 
Informed Consent Form that contains the updated NIST standard calibration. 
NOTE:  Throughout this document, the dose of radium-223 dichloride is given as 50 kBq/kg, 
which is based on the original NIST standardization (55); however, when NIST issues the 
updated radium-223 dichloride standardization, the dose administered will actually be 
55 kBq/kg (based on a change to the reference standard [56] only), though the volume of 
radium-223 dichloride given to each subject will remain the same.   
Sections affected include: 
• Synopsis 
• List of abbreviations 
• 1.2.1.3 Dosing rationale 
• 1.3 Study rationale 
• 4.1.1 Study periods and duration 
• 6.1 Treatments to be administered 
• 6.2 Identity of study treatment 
• 6.2.1.1 Radium-223 dichloride 
• 6.4.1 Radium-223 dichloride dose calibration (new section) 
• 6.4.3 Radium-223 dose calculation 
• 12 Reference list 
Modification 2 
Removed cytological confirmation of adenocarcinoma of the prostate from inclusion criteria; 
histological confirmation only 
Sections affected: 
• Synopsis 
• 5.1.1 Inclusion criteria 
Modification 3 
Clarified that the treatment period ended when a subject received abiraterone/prednisone as 
the standard of care (non-IMP) after an SSE 
Section affected: 
• 4.1.1 – Study periods and duration 


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Modification 4 
Added an exclusion for immunotherapy (e.g., sipuleucel-T) within 4 weeks before 
randomization 
Section affected: 
• 5.1.2 Exclusion criteria 
Modification 5 
Clarified duration of prohibited concomitant therapy and added a prohibited medication 
Section affected: 
• 6.9.1 Prohibited concomitant therapy 
Modification 6 
Clarified potassium requirement for ECG collection 
Sections affected: 
• Section 7.1.2.1 Screening period (Visit 1)  
• Section 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each 
visit)  
• Section 7.1.2.3.3 Visits 11 and 12 + (Cycles 7 and 8, Day 1 and every 4 weeks 
thereafter ± 7 days) up until discontinuation of abiraterone as IMP and prednisone / 
prednisolone or until 6 months post last radium-223 dichloride / placebo 
administration, whichever occurs later  
• Section 7.1.2.3.4 End of treatment visit 
Modification 7 
Editorial update to remove language deemed unclear 
Sections affected: 
• Section 7.1.1 Tabulated overview – Table 7-1 – footnote “s”  
• Section 7.1.2.1 Screening period (Visit 1)  
• Section 7.1.2.3 Treatment period, and Section 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 
1 through 6, Day 1 + 7 days at each visit) 
13.2.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 2 are provided in Section 13.2.2 of 
integrated protocol Version 3.0. 
13.3 
Amendment 4  
Amendment 4 (dated 13 SEP 2016) is an amendment to Integrated Protocol version 3.0 dated 
12 JUN 2015.  Changes to the integrated protocol include: 
• Update to reflect recent Bayer AG legal entity name change 


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• Update of GCL name 
• Clarification of continuation of medical castration  
• Clarification of documentation of radiological progression  
• Clarification timing of visits, scans, EOT visit, and the collection of anti-cancer 
therapies, AEs, and SAEs 
• Clarification of study drug handling if administration is postponed more than 3 days 
• Removal of obsolete NIST language 
• Clarification of treatment unblinding procedures 
• Removal of bisphosphonate timing requirements 
13.3.1 
Overview of changes 
Modification 1 
Update to reflect recent Bayer AG legal entity name change. 
Rationale: 
Bayer HealthCare AG merged with Bayer AG, an affiliated company within the Bayer 
Group, effective as of 1st July 2016.  Thereby, Bayer Healthcare AG ceased to exist and 
Bayer AG became its legal successor and automatically took over all of the Bayer HealthCare 
AG’s rights, obligations, and liabilities by law.  As a result of the above mentioned merger, 
Bayer AG assumes the role of the sponsor for these trials.  Bayer HealthCare Pharmaceuticals 
Inc. is and has at any time been the sponsor for the US territory for this trial as set forth in 
FDA IND form 1571. 
Sections affected include: 
• Headers 
• Title Page 
Modification 2 
Update of GCL name. 
Rationale: 
Change reflects the current protocol signatory. 
Sections affected include: 
• Signature of the sponsor’s medically responsible person 
Modification 3 
Clarification of continuation of medical castration. 


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Rationale: 
Clarification for sites that medical castration should be maintained during the entire study and 
should not be discontinued after enrollment. 
Sections affected include: 
• Synopsis – Diagnosis and main criteria for inclusion 
• 5.1.1 – Inclusion criteria 
Modification 4 
Clarification of documentation of radiological progression. 
Rationale: 
Clarification for sites that even if a subject has an SSE, the site is still required to document 
radiological progression.  This change also clarifies when subjects can progress to the next 
study period. 
Sections affected include: 
• Synopsis – Methodology 
• 4.1.1 – Study periods and duration  
• Figure 4-1 – Study design schematic 
• 7.1.2.4 – Active follow-up 
• 7.1.2.4.1 – Active follow-up with clinic visits assessments (Every 12 weeks ± 7 days 
at each visit) 
• 7.1.2.5 – Long-term follow-up for up to 7 years following last dose 
Modification 5 
Clarification timing of visits, scans, EOT visit, and the collection of anti-cancer therapies, 
AEs, and SAEs. 
Rationale: 
Clarification for sites on the timing of the EOT visit and prevention of unnecessary AE and 
SAE reporting in subjects who have started new anti-cancer therapy and clarification of the 
need to continue to collect subject anti-cancer therapy data.  Additionally, clarified the timing 
of active follow-up visits and scans. 
Sections affected include: 
• Synopsis – Methodology 
• 4.1.1 – Study periods and duration  
• 7.1.1 – Tabulated overview: Table 7-1 Schedule of assessments 
• 7.1.2.3 – Treatment period 


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• 7.1.2.3.3 - Visits 11 and 12+ (Cycles 7 and 8, Day 1, and every 4 weeks thereafter 
± 7 days) up until discontinuation of abiraterone as IMP and 
prednisone / prednisolone or until 6 months post last radium-223 dichloride / placebo 
administration, whichever occurs later 
• 7.1.2.3.4 – End of treatment visit 
• 7.1.2.4.3.1 – End of active follow-up with clinic visits 
• 7.1.2.4.3.2 – End of active follow-up without clinic visits 
• 7.1.2.4 – Active follow-up 
• 7.1.2.4.1 - Active follow-up with clinic visits assessments (Every 12 weeks ± 7 days 
at each visit) 
• 7.1.2.4.2 – Active follow-up without clinic visits assessments (Every 12 weeks ± 7 
days at each visit) 
• 7.1.2.5 – long-term follow-up for up to 7 years following last dose 
• 7.1.2.5.1 – Long-term follow-up (telephone follow-up) 
• 7.1.2.5.2 – End of long-term follow-up 
• 7.5.1.3 – Assessments and documentation of adverse events 
Modification 6 
Clarification of study drug handling if administration is postponed more than 3 days. 
Rationale: 
If administration of radium-223 dichloride is postponed more than 3 days, the remaining 
activity in the product may not be sufficient for treatment by protocol standards and the site 
may need to re-order the study drug. 
Sections affected include: 
• 6.2.1.1 – Radium-223 dichloride 
• 6.2.1.2 – Saline 
Modification 7 
Removal of obsolete NIST language. 
Rationale: 
As the NIST standards have now been implemented, language referring to future planning for 
the NIST implementation has been removed. 
Sections affected include: 
• 6.4.1 – Radium-223 dichloride dose calibration 


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Modification 8 
Clarification of treatment unblinding procedures. 
Rationale: 
Due to an SOP update, protocol language has been clarified to reflect that investigators are 
not required to contact the medical monitor before unblinding subject treatment. 
Sections affected include: 
• 6.5 – Blinding 
Modification 9 
Removal of bisphosphonate timing requirements. 
Rationale: 
As there is no data supporting a requirement for bisphosphonate to be administered with a 
2-hour separation from study drug, this language has been removed. 
Sections affected include: 
• 6.9.1 – Prohibited concomitant therapy 
13.3.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 4 are provided in Section 13.3.2 of 
integrated protocol Version 4.0. 
13.4 
Amendment 6 
Amendment 6 (dated 03 APR 2018) is an amendment to Integrated Protocol Version 4.0, 
dated 13 SEP 2016. Changes to the integrated protocol include: 
• New request that bone fractures and bone associated events (e.g., osteoporosis) need to 
be reported as (S)AEs, including during long-term follow-up, regardless of the 
investigator’s causality assessment. 
• Addition of independent radiological review of fractures. 
• Based on the available data on radium-223 dichloride, initiation of BHA is now 
allowed. 
• Addition that radium-223 dichloride should not be given in combination with 
abiraterone plus prednisone/prednisolone during follow-up. 
• Additional minor clarifications. 
13.4.1 
Overview of changes 
Rationale: 
The study was unblinded early based on the IDMC recommendation according to an ad hoc 
independent analysis where more treatment emergent fractures, SSE-FS, and total deaths 
events were observed in the active treatment arm compared with the placebo arm. Based on 
these data, European Health Authorities requested that all bone fractures and bone associated 


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events (e.g., osteoporosis) occurring during study and in the follow-up period should be 
documented regardless of the investigator’s causality assessment. In addition, the FDA 
requested a radiological review of all fracture imaging scans. The central radiological review 
of all fracture scans will evaluate the correlation between bone metastasis and fractures, and 
support the root cause analysis of the observed increased incidence of fractures in the 
experimental treatment arm. 
Based on the available data on radium-223 dichloride, the option of starting a BHA including 
bisphosphonates or denosumab should be considered, taking into consideration applicable 
guidelines. 
13.4.1.1 
Modification 1 
Bone fractures and bone associated events (e.g., osteoporosis) need to be reported as (S)AEs, 
including during long-term follow-up, regardless of causality to study treatment. 
Sections affected include: 
• Synopsis 
• 4.1.1 Study periods and duration 
• Schedule of assessments 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.2 Visits 3, 5, and 7 (Cycles 1, 2, and 3, Day 15 ± 3 days) and unscheduled visits 
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 
7 days) up until discontinuation of abiraterone as IMP and prednisone / prednisolone or 
until 6 months post last radium-223 dichloride / placebo administration, whichever 
occurs later 
• 7.1.2.3.4 End of treatment visit 
• 7.1.2.4.1 Active follow-up with clinic visits assessments (Every 12 weeks ± 7 days at 
each visit) 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 days at 
each visit)  
• 7.1.2.4.3.1 End of active follow-up with clinic visits 
• 7.1.2.4.3.2 End of active follow-up without clinic visits 
• 7.1.2.5.1 Long-term follow-up (telephone follow-up) 
• 7.1.2.5.2 End of long-term follow-up 
• 7.5.1.3 Assessments and documentation of adverse events 
• 7.5.1.4 Reporting of serious adverse events 
13.4.1.2 
Modification 2 
Addition of independent radiological review of fractures. 
Sections affected include: 
• Synopsis 


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• 3.2 Independent radiological review 
• 4.1.1 Study periods and duration 
• Schedule of assessments 
• 7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 (Cycles 1 through 6, Day 1 + 7 days at each visit) 
• 7.1.2.3.2 Visits 3, 5, and 7 (Cycles 1, 2, and 3, Day 15 ± 3 days) and unscheduled visits;  
• 7.1.2.3.3 Visits 11 and 12+ (Cycles 7 and 8, Day 1 and every 4 weeks thereafter ± 7 
days) up until discontinuation of abiraterone as IMP and prednisone / prednisolone or 
until 6 months post last radium-223 dichloride / placebo administration, whichever 
occurs later 
• 7.1.2.3.4 End of treatment visit 
• 7.1.2.4.1 Active follow-up with clinic visits assessments (Every 12 weeks ± 7 days at 
each visit) 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 days at 
each visit) 
• 7.1.2.4.3.1 End of active follow-up with clinic visits 
• 7.1.2.4.3.2 End of active follow-up without clinic visits 
• 7.1.2.5.1 Long-term follow-up (telephone follow-up) 
• 7.1.2.5.2 End of long-term follow-up 
• 7.5.1.3 Assessments and documentation of adverse events 
• 7.5.1.4 Reporting of serious adverse events 
13.4.1.3 
Modification 3 
Based on the available data on radium-223 dichloride, new initiation of BHAs is now allowed 
in this study, and the option of starting BHA treatment should be considered, taking into 
consideration applicable guidelines. 
Sections affected include: 
• List of abbreviations 
• 6.9.1 Prohibited concomitant therapy 
• 6.9.2 Permitted concomitant therapy 
13.4.1.4 
Modification 4 
The study was unblinded early based on the IDMC recommendation following an ad hoc 
independent analysis where more treatment emergent fractures, SSE-FS, and total deaths 
events were observed in the active treatment arm compared with the placebo arm. Based on 
the available data, the benefit-risk of radium-223 dichloride in combination with abiraterone 
acetate plus prednisone/prednisolone in metastatic CRPC is considered unfavorable. 
Sections affected include: 
• Synopsis 


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• 6.8 Post-study treatment therapy 
• 6.9.1 Prohibited concomitant therapy 
13.4.1.5 
Minor clarifications 
Clarification of the timeframe of reporting requirements of (S)AEs following the treatment 
period, for consistency across the document. 
Sections affected include: 
• Schedule of assessments 
• 7.1.2.3.4 End of treatment visit 
• 7.5.1.4 Reporting of serious adverse events 
Clarification that subjects in the “active follow-up without clinic visits” period will still be 
followed for radiological progression if they did not have progressive disease in the previous 
period and if they could have scans as part of standard of care. 
Sections affected include: 
• Synopsis 
• 4.1.1 Study periods and duration 
• Figure 4–1 Study design schematic 
• Schedule of assessments 
• 7.1.2.4.2 Active follow-up without clinic visits assessments (Every 12 weeks ± 7 days at 
each visit) 
• 7.1.2.5 Long-term follow-up for up to 7 years following last dose 
For Word-related technical reasons, numbered footnotes have been replaced with a summary 
of changes at the start of each amended section. 
13.4.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 6 are provided in Section 13.4.2 of 
integrated protocol Version 5.0. 
13.5 
Amendment 7 
Amendment 7 is a global amendment dated 26 NOV 2019.  
13.5.1 
Overview of changes 
Overall rationale for the amendment 
At the time of the final OS analysis, after approximately 500 death events, approximately 
70 subjects are still receiving study medication (abiraterone acetate plus prednisone or 
prednisolone). 
To continue providing study medication to these subjects, the protocol remains open with all 
safety-related endpoints, including long term follow-up, still being collected. However, to 


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reduce the burden to study subjects, evaluation of efficacy and exploratory endpoints, except 
for SSE and OS, will be discontinued following the final OS analysis. 
The criteria for discontinuation of abiraterone acetate plus prednisone / prednisolone was 
updated to follow standard clinical practice. Subjects discontinuing study treatment will enter 
long-term follow-up or, once a separate extended safety follow-up protocol has been 
implemented, will be directly transitioned to this extended safety follow-up study, in order to 
complete 7 years of safety follow-up. 
High-level descriptions and rationales of the changes and the affected sections are listed 
below. 
Sections 
Description of change 
Rationale 
Synopsis 
2. Study objectives 
4.1.1 Study periods and 
duration 
4.1.2 Study endpoints 
5.2.1.1 Withdrawal from 
treatment period (collection of 
FU data) 
7.1.1 Tabulated overview 
7.1.2.3.2 Visits 3, 5, and 7 [...] 
7.1.2.3.3 Visits 11 and 12+ […] 
7.1.2.3.4 End of treatment visit 
7.1.2.4 Active follow-up 
7.1.2.5.1 Long-term FU 
(telephone FU) 
7.1.2.5.2 End of long-term FU 
7.3.1 Efficacy variables 
7.3.2.2 Secondary efficacy 
variables 
7.3.2.3 Exploratory efficacy 
variables 
7.4 Pharmacokinetics (selected 
sites only) 
7.5.1.3 Assessments and 
documentation of adverse 
events 
7.5.1.4 Reporting of serious 
adverse events 
7.6 Other procedures and 
variables 
7.7 Appropriateness of 
procedures / measurements 
8.3 Efficacy variables 
8.4.4 Pharmacokinetic data 
Evaluation of efficacy and 
exploratory endpoints will be 
discontinued (except for SSE 
and OS) 
 
 
 
 
 
 
 
 
Updated planned analyses and 
study procedures 
• Discontinuation of pain, 
QoL assessments, and 
biomarker collection  
• Images will be read only 
locally 
 
To reduce the burden to study 
subjects, evaluation of efficacy 
and exploratory endpoints will 
be discontinued, except for 
SSE and OS. To continue 
providing study medication to 
study subjects, the protocol 
remains open with all safety 
related endpoints, including 
long term follow-up, still being 
collected.  
 
Planned analyses and study 
procedures were updated to 
reflect changes in study status. 
The changes are appropriate 
for safety follow-up and limited 
safety. 


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Sections 
Description of change 
Rationale 
Synopsis 
4.1.1 Study periods and 
duration 
5.2.1 Withdrawal  
7.1.1 Tabulated overview 
7.1.2.3.4 End of treatment visit 
7.1.2.4 Active follow-up 
7.1.2.5 Long-term follow-up 
7.1.2.5.2 End of long-term 
follow-up 
Removal of the active follow-up 
periods  
 
Updated criteria to transition 
subjects to separate extended 
safety follow-up study 
As several efficacy endpoints 
are no longer being collected, 
the active follow-up periods 
were removed. Therefore, 
subjects discontinuing study 
treatment will either enter long 
term follow-up or will be directly 
transitioned to the separate 
extended safety follow-up 
study, as both of them allow for 
the collection of safety 
information and OS. 
Synopsis 
4.1.1 Study periods and 
duration 
4.3 End of study 
7.1.2.6 End of study 
Modification of the definition of 
the end of study (EOS) 
The definition of EOS was 
modified to reflect the changes 
in study status. EOS will occur 
at the time the last patient on 
treatment discontinues oral 
treatment and completes end 
of treatment visit or at the time 
the last subject is transitioned 
to a separate extended safety 
follow-up study, whichever 
occurs later.  
 
In addition, guidance was 
included on reporting of safety-
related events for sites and 
subjects not transitioning to 
extended safety follow-up 
study. 
Synopsis 
4.1.1 Study periods and 
duration 
5.2.1.1 Withdrawal from 
treatment period (collection of 
follow-up data) 
6.2.1.3 Abiraterone acetate 
Updated criteria for 
discontinuation of study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minor clarification on eCRF use 
Discontinuation of abiraterone 
+ prednisolone shall also follow 
standard clinical practice, i.e., 
subjects presenting radiological 
progression (either by RECIST 
or bone progression by 
PCWG2), SSE, clinical 
progression (clinical 
deterioration or lack of clinical 
benefit, assessed by 
investigator), or that start a 
new anti-cancer therapy should 
be discontinued from study 
treatment. 
 
Abiraterone use should be 
recorded on the systemic anti-
cancer therapy CRF. 
Synopsis 
3.1 Independent Data 
Monitoring Committee 
3.2 Independent radiological 
review 
Clarification on the role of 
IDMC and independent 
radiological review 
 
After primary analysis, IDMC 
and independent radiological 
review were no longer 
applicable. 


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Sections 
Description of change 
Rationale 
7.1.1 Tabulated overview 
7.1.2.3.1 Visits 2, 4, 6, 8, 9, 10 
[…] 
7.1.2.3.3 Visits 11 and 12+ [...] 
7.1.2.3.4 End of treatment visit 
Serum testosterone 
measurement and ECG will 
only be done at the discretion 
of the investigator 
To reduce patient burden and 
to reflect standard of care 
(local practice), after 
implementation of Amendment 
7 measurements after 
screening are only done at the 
discretion of the investigator. 
6.5 Blinding 
8.5 Planned interim analyses 
Clarification on the blinding of 
the study and on the analysis 
performed after last subject 
last visit 
Following the IDMC’s 
recommendation, study was 
prematurely unblinded in 2017 
and subject-level unblinding 
information has been 
communicated to the sites.  
After last subject last visit has 
occurred, a descriptive updated 
analysis will be performed.  
7.1.1 Tabulated overview 
7.1.2.3.3 Visits 11 and 12+ […] 
The language related to the 
schedule of radiological tumor 
assessments was updated. 
To consider local regulations in 
radiological imaging. 
Title page 
Sponsor’s medical expert was 
changed. 
Administrative change. 
Signature of the sponsor’s 
medically responsible person 
Title of signatory was changed 
Administrative change. 
13.1.2, 13.2.2, 13.3.2 and 
13.4.2 Changes to the protocol 
text 
Throughout 
The detailed old vs. new text 
comparisons for protocol 
amendments 1, 2, 4, and 6 
were replaced with a reference 
to the respective integrated 
protocol document. 
Old annotations from previous 
amendments were removed. 
To improve readability, and to 
reduce complexity of the 
protocol. 
13.5.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 7 are provided in a separate tracked-
changes document. 
13.6 
Amendment 8 
Amendment 8 is a global amendment dated 13 JAN 2023.  
13.6.1 
Overview of changes 
Overall rationale for the amendment 
The rationale for the current protocol amendment is to accommodate the subjects who are 
still on oral study treatment (abiraterone acetate plus prednisone / prednisolone) after the 
study has been completed. The original EOS definition did not foresee that after completing 
all planned analyses, a few subjects would remain on backbone study treatment. 
After all the planned analyses of the protocol, including the 7 years of safety follow-up, have 
been completed, the study will be closed and for the few subjects on backbone treatment, the 
options for treatment continuation such as a switch to commercial drug supply, a continued 


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access program, or any other means of continued drug supply will be discussed and agreed 
between the investigator, sponsor, and the subject in compliance with local regulations.  
High-level descriptions and rationales of the changes and the affected sections are listed 
below. 
Section name and number 
Description of change 
Rationale 
Title page  
Updated date and version 
number per current 
amendment. 
Medical expert details were 
updated 
Administrative changes.  
Synopsis 
4.3 End of study 
7.1.2.6 End of study 
4.1.1 Study periods and 
duration (under the heading 
long-term follow-up) 
 
Modification of the definition of 
the end of study (EOS) 
including potential options for 
treatment continuation. 
The definition of EOS was 
modified to reflect the changes 
in study status. Original EOS 
definition did not foresee that 
after completing all planned 
analyses, a few subjects would 
still be on backbone study 
treatment. 
The EOS is defined as the date 
of the last subject last visit 
(LSLV) in the study. The EOS 
will occur at the time the last 
subject on study completes 
7 years of follow-up unless the 
subject died, withdraws 
consent or is lost to FU. 
6.8 Post-study treatment 
therapy 
7.1.2.5 Long-term follow-up 
7.1.2.6 End of study 
Modification of text about the 
treatment options according to 
the revised EOS definition. 
For including potential options 
for treatment continuation as 
per revised EOS definition. 
Reference to the latest protocol 
amendment and version 
number throughout the 
document 
 
Old annotations/reference 
of/from previous amendments 
were removed and updated 
with amendment number 8 and 
version number 7 
Consistency and template 
requirements. 
 
13.6.2 
Changes to the protocol text 
Changes to the protocol text done in Amendment 8 are provided in a separate 
tracked changes document. 


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14. 
Appendices 
14.1 
National Cancer Institute-Common Terminology Criteria, version 4.03 
This study will utilize the NCI-CTCAE v4.03 for toxicity and SAE reporting.  A copy of the 
CTCAE v4.03 can be downloaded from the website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.  All 
appropriate treatment areas should have access to a copy of the CTCAE v4.03. 
14.2 
Prostate Cancer Working Group 2 Criteria 
Progressive disease after androgen deprivation eligibility criteria: 
The reference value (#1) is the last PSA measured before increases are documented, with 
subsequent values obtained a minimum of 1 week apart.  If the PSA at time point 3 (value 
#3A) is greater than that at point 2, then eligibility has been met.  If the PSA is not greater 
than point 2 (value #3B), but value #4 is, the subject is eligible assuming that other criteria 
are met, if values #3A or #4 are 2 ng/mL or higher. 
 
 
Eligibility based on PSA 


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14.3 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Response and progression will be evaluated in this study using a modified version of the bone 
lesions identified on whole body technetium-99 bone scans will be recorded separately from 
soft tissue lesions detected on CT / MRI.  CT / MRI will not be used to identify bone lesions.  
Radiological progression of bone lesions will be determined according to the radiological 
criteria of the PCWG2 (see Section 7.3.2.2).  CT / MRI will be used to determine progression 
according to RECIST 1.1 (i.e., increase in tumor burden and appearance of new lesions with 
the exception of bone lesions).  The overall time point response and resulting date of 
progression according to modified RECIST 1.1, will take into account disease assessed by 
bone scan and CT / MRI.  For exploratory purposes, the date of progression by bone scan 
only will also be determined. 
Table 14–1:  Overall time point response 
Response 
Response characteristics 
Complete response 
Disappearance of all clinical and radiological evidence of tumor (both 
target and non-target).  Any pathological lymph nodes (whether target or 
non-target) must have a reduction in short axis to < 10 mm. 
Partial response 
At least a 30% decrease in the sum of diameters of target lesions taking as 
reference the baseline sum, no unequivocal progression of existing non-
target lesions and no appearance of new lesions. 
Progressive disease 
At least a 20% increase in the sum of diameters of target lesions taking as 
reference the smallest sum on study (this includes the baseline sum if that 
is the smallest on study).  In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm.  
Unequivocal progression of existing non-target lesions or the appearance 
of one or more new lesions will also constitute progressive disease. 
Stable disease 
Steady state of disease.  Neither sufficient shrinkage to qualify for partial 
response nor sufficient increase to qualify for progressive disease; no 
unequivocal progression of existing non-target lesions and no appearance 
of new lesions. 
Modified RECIST 1.1 
Soft tissue disease (abnormal lymph nodes) and visceral lesions will be detected and 
monitored on chest, abdomen, and pelvic CT / MRI according to modified RECIST 1.1 
criteria.  Bone lesions will not be detected and followed on CT / MRI and will not be 
evaluated by RECIST 1.1.  The described modifications in Table 14–2 represent an 
adaptation of the published criteria based on current radiology practices.  A rationale for the 
modified criteria is provided.  The modified criteria may include further definitions of rules, 
assumptions and/or clarifications of the original RECIST 1.1. 


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Table 14–2:  Modified RECIST 1.1 criteria   
Original RECIST 1.1 reference 
Modified criteria 
Rationale 
Lytic bone lesions or mixed lytic-
blastic lesions, with identifiable 
soft tissue components, that can be 
evaluated by cross sectional 
imaging techniques such as CT or 
MRI can be considered as 
measurable lesions if the soft 
tissue component meets the 
definition of measurability.  
Bone lesions will only be 
evaluated by bone scan using a 
modified PCWG2 criteria defined 
in protocol.  Bone lesions detected 
by CT / MRI cannot be selected as 
target or non-target lesions (to be 
followed quantitatively and 
qualitatively in respective order).  
This approach has been 
successfully used in the 
double-blind phase III study 
(COU-AA-302) in the same 
patient population.  
When more than one measurable 
lesion is present at baseline all 
lesions up to a maximum of 5 
lesions total (and a maximum of 2 
lesions per organ)… should be 
identified as target lesions.  
Up to 5 target lesions may be 
selected at baseline and followed 
quantitatively in all organs 
including lymph nodes (lymph 
node system constituting one 
organ).  
This is to follow the PCWG2 
recommendation, as lymph nodes 
are predominant site of metastasis 
except bone.  
Abbreviations:  CT = computed tomography; MRI = magnetic resonance imaging; PCWG2 = Prostate Cancer 
Working Group 2; RECIST = Response Evaluation Criteria in Solid Tumors. 
 


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14.4 
Calculation for glomerular filtration rate 
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated GFR, calculated using 
the abbreviated Modification of Diet in Renal Disease study formula.  
This equation of 4 variables (serum creatinine level, age, sex, and ethnicity) is recommended 
by the National Kidney Foundation for use in individuals 18 years or older.  The formula is as 
follows: 
GFR (mL / min / 1.73m2) = k x 186 x (serum creatinine)-1.154 x (age)-0.203 x (1.210 if 
Black) 
Where k = 1 (men) or 0.742 (women), GFR indicates glomerular filtration rate, and 
serum creatinine is measured in mg/dL. 
Subjects with a baseline GFR < 30 mL/min calculated by this method will not be allowed to 
participate in the study. 


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14.5 
New York Heart Association functional classification 
 
Class 
NYHA Functional Classification 
I 
Subjects have cardiac disease but without the resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. 
II 
Subjects have cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain. 
III 
Subjects have cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
IV 
Subjects have cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased. 
 


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14.6 
ECOG performance status  
Grade 
Description 
0 
Fully active, able to carry on all pre-diseases performance without 
restriction.  (Karnofsky 90-100) 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (e.g., light housework, office work).  
(Karnofsky 70-80) 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.  (Karnofsky 
50-60) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.  (Karnofsky 30-40) 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair.  (Karnofsky 10-20) 
 


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14.7 
NCCN-FACT FPSI-17 
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days. 
 
Not at 
all 
A little 
bit 
Some
what 
Quite 
a bit 
Very 
much 
D
R
S
-
P 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
P7 
I have difficulty urinating 
0 
1 
2 
3 
4 
C2 
I am losing weight 
0 
1 
2 
3 
4 
BP1 
I have bone pain 
0 
1 
2 
3 
4 
HI7 
I feel fatigued 
0 
1 
2 
3 
4 
NCCN3 I have weakness in my legs 
0 
1 
2 
3 
4 
P3 
My pain keeps me from doing things I want to 
do 
0 
1 
2 
3 
4 
C6 
I have a good appetite 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
D
R
S
-
E 
GE6 
I worry that my condition will get worse 
0 
1 
2 
3 
4 
T
S
E 
GP2 
I have nausea 
0 
1 
2 
3 
4 
P6 
I have trouble moving my bowels 
0 
1 
2 
3 
4 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
F
W
B 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right 
now 
0 
1 
2 
3 
4 
DRS-P=Disease-Related Symptoms Subscale – Physical 
DRS-E=Disease-Related Symptoms Subscale – Emotional 
TSE=Treatment Side Effects Subscale 
FWB=Function and Well-Being Subscale 
English (Universal), Copyright 2001 
03 March 2010 
 


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14.8 
EQ-5D 
 
 
 
 
 
 
 
 
 
 
 
Health Questionnaire 
 
English version for the UK 
(validated for Ireland) 
  
By placing a tick in one box in each group below, please indicate which 
statements best describe your own health state today. 
 
Mobility 
I have no problems in walking about 
 
I have some problems in walking about 
 
I am confined to bed 
 
 
Self-Care 
I have no problems with self-care 
 


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I have some problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
 
Usual Activities (e.g. work, study, housework, family or 
leisure activities) 
I have no problems with performing my usual activities 
 
I have some problems with performing my usual activities 
 
I am unable to perform my usual activities 
 
 
Pain/Discomfort 
I have no pain or discomfort 
 
I have moderate pain or discomfort 
 
I have extreme pain or discomfort 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
I am moderately anxious or depressed 
 
I am extremely anxious or depressed 
 


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EQ-VAS 
 


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14.9 
BPI-SF 
 
STUDY ID #:_ _ _ _ _ _ _ _ _ _ 
DO NOT WRITE ABOVE THIS LINE 
HOSPITAL #: 
_ _ _ _ _ _ _ _ _ _ 
Brief Pain Inventory (Short Form) 
 
Date: _ _ _ _ / _ _ _ _ / _ _ _ _ 
Time: _ _ _ _ _ _ _ 
Name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _    _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Last 
First 
Middle Initial 
1. 
Throughout our lives, most of us have had pain from time to time (such as minor 
headaches, sprains, and toothaches).  Have you had pain other than these every- 
day kinds of pain today? 
1. 
Yes 
2. 
No 
2. 
On the diagram, shade in the areas where you feel pain.  Put an X on the area that 
hurts the most. 
 
3. 
Please rate your pain by circling the one number that best describes your pain at its 
worst in the last 24 hours. 
0
 
1
 
2
 
3
 
4
 
5
 
6
 
7
 
8
 
9
 
10 
No 
Pain 
Pain as bad as 
you can imagine 
4. 
Please rate your pain by circling the one number that best describes your pain at its 
least in the last 24 hours. 
0
 
1
 
2
 
3
 
4
 
5
 
6
 
7
 
8
 
9
 
10 
No 
Pain 
Pain as bad as 
you can imagine 
5. 
Please rate your pain by circling the one number that best describes your pain on  
the average. 
0
 
1
 
2
 
3
 
4
 
5
 
6
 
7
 
8
 
9
 
10 
No 
Pain 
Pain as bad as 
you can imagine 
6. 
Please rate your pain by circling the one number that tells how much pain you have 
right now. 
0
 
1
 
2
 
3
 
4
 
5
 
6
 
7
 
8
 
9
 
10 
No 
Pain 
Pain as bad as 
you can imagine 
Right 
Left 
Left 
Right 
 
Front 
Back 
Page 1 of 2 


Integrated Clinical Study Protocol 
BAY 88-8223 / 15396 
08 FEB 2023 
Version no. 7.0 
Page:  152 of 153 
 
 


Integrated Clinical Study Protocol 
BAY 88-8223 / 15396 
08 FEB 2023 
Version no. 7.0 
Page:  153 of 153 
 
14.10 
Resource utilization questionnaire 
 
 
 

SAP_001.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A phase III randomized, double-blind, placebo-controlled trial of 
radium-223 dichloride in combination with abiraterone acetate and 
prednisone/prednisolone in the treatment of asymptomatic or mildly 
symptomatic chemotherapy-naïve subjects with bone predominant 
metastatic castration-resistant prostate cancer (CRPC) 
NCT Number: 
NCT02043678 
Document Date: 
10-JUL-2017 
 


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
Page:
1 of
50
Title page - amended
A phase III randomized, double-blind, placebo-controlled trial of radium-223 dichloride 
in combination with abiraterone acetate and prednisone/prednisolone in the treatment 
of asymptomatic or mildly symptomatic chemotherapy-naïve subjects with bone 
predominant metastatic castration-resistant prostate cancer (CRPC)  
Short title: Evaluation of Radium-223 dichloride in combination with Abiraterone in CRPC -
ERA 223
BSP Study drug
BAY 88-8223/Radium-223 dichloride 
Study purpose:
To compare the symptomatic skeletal event-free survival of subjects 
with asymptomatic or mildly symptomatic chemotherapy-naïve bone 
predominant metastatic castration-resistant prostate cancer (CRPC) 
treated with radium-223 dichloride or placebo, in combination with 
abiraterone and prednisone/prednisolone
Clinical study phase:
III
Date:
July 10th 2017
Study No.:
BAY 88-8223 / 15396
Version:
V5.0
Author:
Bayer HealthCare 
Pharmaceuticals
Whippany, NJ  07981
Bayer HealthCare 
Pharmaceuticals
Whippany, NJ  07981
Confidential
The information provided in this document is strictly confidential and is intended solely for 
the guidance of the clinical investigation.  Reproduction or disclosure of this document, 
whether in part or in full, to parties not associated with the clinical investigation or its use 
for any other purpose without the prior written consent of the sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
    Page: 2 of 50
Table of Contents
Title page - amended..................................................................................................................1
Table of Contents.......................................................................................................................2
Abbreviations.............................................................................................................................4
Definitions of terms ...................................................................................................................5
1.
Study Objectives.................................................................................................................6
1.1
Primary Objective ............................................................................................................ 6
1.2
Secondary  Objective ....................................................................................................... 6
1.3
Exploratory Objective ...................................................................................................... 6
2.
Study Design ......................................................................................................................7
2.1
Design overview............................................................................................................... 7
2.2
Determination of sample size........................................................................................... 8
3.
General Statistical Considerations......................................................................................8
3.1
General Principles ............................................................................................................ 8
3.2
Adjustments for Covariates.............................................................................................. 8
3.3
Handling of Dropouts....................................................................................................... 9
3.4
Handling of Missing Data ................................................................................................ 9
3.5
Interim Analyses and Data Monitoring............................................................................ 9
3.5.1
Interim Analyses..........................................................................................9
3.5.2
Data Monitoring.........................................................................................10
3.6
Data Rules ...................................................................................................................... 11
4.
Analysis Sets ....................................................................................................................11
4.1
Assignment of analysis sets............................................................................................ 11
5.
Statistical Methodology....................................................................................................11
5.1
Population Characteristics.............................................................................................. 12
5.1.1
Disposition of Subjects..............................................................................12
5.1.2
Demographic and Baseline Characteristics ...............................................12
5.1.3
Medical History .........................................................................................13
5.1.4
Extent of Exposure ....................................................................................13
5.1.5
Prior and Concomitant Medications..........................................................13
5.2
Efficacy Analysis ........................................................................................................... 14
5.2.1
Primary Efficacy Analysis.........................................................................14
5.2.2
Secondary efficacy Analysis......................................................................16
5.2.3
Exploratory efficacy analysis ....................................................................23
5.3
Safety Analysis............................................................................................................... 26
5.3.1
Adverse events...........................................................................................26
5.3.2
Deaths ........................................................................................................27
5.3.3
Clinical Laboratory Data ...........................................................................27
5.3.4
ECG ...........................................................................................................28
5.4
Analysis of Other Endpoints .......................................................................................... 28
5.4.1
ECOG Performance Status ........................................................................28
5.4.2
Quality of Life ...........................................................................................28
5.5
Examination of Subgroups............................................................................................. 29
5.6
Pharmacokinetics / pharmacodynamics ......................................................................... 30


Statistical Analysis Plan
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    Page: 3 of 50
5.6.1
Biomarkers assessment..............................................................................30
5.6.2
Pharmacokinetics.......................................................................................31
6.
Document history and changes in the planned statistical analysis...................................31
7.
References ........................................................................................................................31
8.
SAP amendments - amended............................................................................................32


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
    Page: 4 of 50
Abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
BPI-SF
Brief Pain Inventory – Short Form 
Ca
Calcium
Cl
Chloride
Cmax
Maximum plasma concentration
CRPC
Castration -resistant prostate cancer
CT
Computed tomography
CTCAE 
Common Terminology Criteria for Adverse Events; version 4.03
EBRT
External beam radiation therapy
ECOG
Eastern Co-operative Oncology Group 
ECOG PS
Eastern Co-operative Oncology Group Performance Status
EOD
Extent of disease
eCRF
Electronic case report form
ePRO
Electronic subject report outcome
EQ-5D
European Quality of Life - 5 Dimensions
EU
European Union
GCP
Good Clinical Practice
Hb
Hemoglobin
HR
Hazard ratio
HRQoL
Health related quality of life
ICF
Informed consent form
IDMC
Independent data monitoring committee
IMP
Investigational medicinal product
ITT
Intent-to-Treat
IV
Intravenous
IXRS
Interactive Voice/Web Response System
K
potassium
kBq
KiloBecquerel; SI unit of radioactivity
kg
Kilogram
LDH
Lactate dehydrogenase
mCi
Millicuries
MedDRA
Medical Dictionary for Regulatory Activities
mL
Milliliter
MRI
Magnetic resonance imaging
Na
Sodium
NCA
Non-compartmental analysis
NCI
National Cancer Institute
OS
Overall survival


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
    Page: 5 of 50
PD
Progressive disease
PS
Performance status
PSA
Prostate specific antigen
qd
Every day (quaque die)
QoL
Quality of life
rPFS
Radiological progression-free survival
PKS
Pharmacokinetic analysis set
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Statistical analysis software
SSE
Symptomatic skeletal event
SSE-FS
Symptomatic skeletal event-free survival
ULN
Upper limit of normal
WBC
White blood cell
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
WPS
Worst pain subscale
Definitions of terms
Radium-223 
dichloride 
The investigational product, a targeted alpha particle emitting 
radiopharmaceutical, is a ready-to-use solution for intravenous injection 
containing the drug substance radium-223 dichloride. The active moiety is 
the alpha particle emitting nuclide radium-223, present as a divalent cation 
(223Ra2+). 
Dose 
Doses are given as kiloBecquerel (kBq) per kilogram body weight, with the 
corresponding dose given in millicurie (mCi) per kilogram in parenthesis. 
The term “dose” is used to describe the quantity of radioactivity from 
radium-223 administered. 
Bone scan
Whole body technetium-99m bone scan


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
    Page: 6 of 50
1. Study Objectives
1.1
Primary Objective
The primary objective is to compare, in subjects with asymptomatic or mildly symptomatic 
chemotherapy-naïve bone predominant metastatic CRPC, the clinical benefit of radium-223 
dichloride versus placebo in combination with abiraterone and prednisone/prednisolone, with 
the primary efficacy endpoint being:

Symptomatic skeletal event-free survival (SSE-FS)
1.2
Secondary Objective
The secondary objectives are to compare the radium-223 dichloride and placebo treatments to 
establish additional clinically relevant improvements in subjects with CRPC bone 
predominant metastasis using the variables below:

OS

Time to opiate use for cancer pain

Time to pain progression

Time to cytotoxic chemotherapy

rPFS

Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy
1.3
Exploratory Objective
The study will also include the following exploratory endpoints:

Time to first on-study SSE

Percentage change in total ALP from baseline

Time to ALP progression

Time to PSA progression

ALP response


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
    Page: 7 of 50

PSA response

Bone scan-specific rPFS

Time to increase in physical symptoms of disease based on the NCCN-FACT FPSI-17 
physical disease related symptoms (FPSI-DRS-P) subscale score measured during the 
treatment period

Time to increase in physical symptoms of disease based on the NCCN-FACT FPSI-17 
physical disease related symptoms (FPSI-DRS-P) subscale score measured during 
period between start of treatment and end of active follow-up with clinic visits

Assessment of pharmacokinetics (PK) of abiraterone 

Resource utilization

Biomarker assessments
An additional explorative objective is to evaluate the impact of baseline total body weight 
(TBW) and ideal body weight (IBW) on SSE-FS and adverse events.
2. Study Design
2.1
Design overview
This study is a phase III multinational, multicenter, randomized, double blind, 
placebo-controlled, parallel group study with a randomization allocation ratio of 1:1 
(radium-223 dichloride plus abiraterone acetate plus prednisone/prednisolone :  placebo plus
abiraterone acetate plus prednisone/prednisolone).  Randomization will be stratified by:

Geographical regions (Western Europe/North America/Australia vs. Asia vs. rest of 
world)

Concurrent use of denosumab or bisphosphonates  or none

Total ALP < 90 U/L versus total ALP ≥ 90 U/L
To prevent sparse data, strata for current use of denosumab and current use of 
bisphosphonates will be combined in all stratified analysis for this study. 
This study will be conducted at approximately 170 investigative study centers and 
approximately 800 subjects will be enrolled.


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
Page: 8 of 50
2.2
Determination of sample size
Sample size is calculated based on the primary endpoint SSE-FS.  Using a test with a two-sided 
alpha of 0.05, power of 90%, and a randomization ratio of 1:1 between the experimental 
(radium-223 dichloride) and control (placebo) arms, 389 events are required to detect a 39% 
increase in SSE-FS (i.e., an overall 0.05 level two-sided log rank test has approximately 90% 
power to detect a difference between the two SSE-FS curves if the alternative hypothesis HR is 
0.72 [assuming the median SSE-FS is 29.2 months for radium-223 dichloride vs. 21.0 for 
control]).  The expected study duration for SSE-FS is 37 months, assuming subjects enroll at a 
rate of 50 subjects per month, an enrollment ramp-up time of 9 months, a dropout rate of 10%, 
exponentially distributed event time, 21 months in SSE-FS median time for the control group, 
and a total of 800 subjects in the 2 treatment groups combined.
This study is also powered (~70%) for the analysis of OS if OS is tested at a 0.05 level (2-sided)  
For the concluding analysis of OS, 500 deaths are projected to occur by approximately 71.4 
months after the first subject is randomized, assuming the median OS for the control arm is 35.3 
months and a 25% improvement for the radium-223 dichloride arm.  If the final analysis of OS 
after 500 deaths reveals that the experimental treatment is statistically significantly better than 
treatment with control, then the OS endpoint will be declared positive for the final analysis.
3. General Statistical Considerations
3.1
General Principles
The statistical evaluation will be performed by using the software package SAS version 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). Unless otherwise noted, data will be analyzed by 
descriptive statistical methods: The number of data available and missing data, mean, standard 
deviation, minimum, quartiles, median, and maximum will be calculated for metric data. 
Frequency tables will be generated for categorical data.
Definition of efficacy and safety endpoints, analysis strategies, structure of analysis datasets and 
layout of analysis data displays are following Bayer Healthcare Pharmaceuticals (BHP) 
standards: Xofigo Project Standards, the Therapeutic Area Oncology Standards (TAS) and the 
Global Medical Standards (GMS), respectively. Where the given ordering reflects the priority of 
the different standards, means specifications of the latter ones have to be followed only if not 
specified in standards mentioned before. 
3.2
Adjustments for Covariates
The three categorical variables that define the randomization strata: geographical regions 
(Western Europe/North America/Australia vs. Asia vs. rest of world), concurrent use of 
denosumab or bisphosphonates (yes vs. no), and total ALP < 90 U/L versus total ALP ≥ 90 U/L 
will be accounted for in all statistical tests and models using appropriate methods as defined in 
Section 5.2.


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
Page: 9 of 50
The following additional baseline covariates which are considered to be potentially
prognostic will also be included in the statistical modeling of the primary efficacy
data, as an exploratory analysis:
• Baseline albumin value (< or ≥ median);
• Baseline hemoglobin value (< or ≥ median);
• Baseline LDH value (< or ≥ median);
• Baseline ECOG performance status (0, 1);
• Baseline PSA value (< or ≥ median);
• Age (<65, ≥65).
A step-wise selection method will be used to choose the final statistical model with entry alpha 
level 0.1 and exit alpha level 0.1. The stratification factors are always included as covariates in 
the final model. If deemed necessary, additional variables may also be added in the model 
selection process. 
3.3
Handling of Dropouts
A “dropout” is defined as a subject who has been randomized and discontinues study 
participation prematurely for any reason. Subjects withdrawn from study treatment will not be 
replaced. Refer to Section 5.2.2 in the study protocol for withdrawal of subjects from study.
All efficacy analyses are based on the intent-to-treat population, that comprises all randomized 
subjects, including subjects who withdraw regardless of the reason for withdrawal. See following 
chapters for more details on deriving efficacy endpoints in case of missing data.
3.4
Handling of Missing Data
In order to achieve the goal of a well conducted clinical trial according to ICH Good Clinical 
Practice (ICH-GCP), every effort should be made to collect all data. However, despite best 
efforts, it may be inevitable that missing or incomplete data are reported. All missing or partial 
data will be presented in the subject data listing, as they are recorded on the CRF. Except as 
noted, missing data will not be imputed or carried forward in any statistical analysis.
Adverse event and concomitant medication partial missing start/stop dates will be imputed and 
the imputation rule will be specified in the data specification.
3.5
Interim Analyses and Data Monitoring
3.5.1
Interim Analyses
There is no formal interim analysis for efficacy planned for the primary endpoint SSE-FS.


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
Page: 10 of 50
For the secondary efficacy endpoint of OS, one interim analysis (to be performed at the same 
time as the final SSE-FS analysis) and one final analysis are planned. At the interim OS 
analysis, it is expected that 275 deaths will have occurred (assuming 35.3 months median 
survival in the control arm). 
If SSE-FS is statistically significant at the 0.05 level (2-sided) and rPFS, time to pain progression 
and time to cytotoxic chemotherapy are all statistically significant at the 0.049 level (2-sided), 
then the OS will be formally tested at an overall alpha=0.05 (2-sided). If the analysis of OS after 
275 deaths following treatment with radium-223 dichloride plus abiraterone plus 
prednisone/prednisolone is statistically significantly better compared to control (two-sided p ≤ 
0.005, based on O’Brien-Fleming alpha spending function (1, 2)), then OS will be declared 
positive for the interim analysis, assuming the final event number for OS is 500. The actual 
nominal alpha levels will be calculated based on the actual number of events accrued at the OS 
interim analysis. If the interim OS analysis is not statistically significant, the final analysis for 
OS will be performed when approximately 500 deaths have occurred, corresponding to an 
approximately 70% power to detect a 25% improvement (in OS with Ra-223 Cl2 compared with 
placebo) with a two-sided alpha of 0.05.
If at least one of the secondary endpoints, rPFS, time to pain progression or time to cytotoxic 
chemotherapy, is not statistically significant at the 0.049 level (2-sided), then the OS will be 
formally tested at an overall alpha=0.001 (2-sided). Refer to scenario 2 in section 5.2.2.2.1 for 
details.
3.5.2
Data Monitoring
As described previously in protocol Section 3.1, an IDMC will be instituted for independent 
review of ongoing data from this trial in accordance with a separate IDMC Charter.  The IDMC 
will operate independently of the sponsor and investigators.
An independent data monitoring committee (IDMC) will be established for this study to review 
accumulating efficacy and safety data at regular intervals throughout the study and monitor 
overall study conduct. The IDMC will include experts in oncology, biostatistics, and safety who 
are not participating in this trial and do not have affiliation with the Investigators or the Sponsor
or other significant conflicts of interest. Their main objective will be to protect the interests of 
the subjects in the study and of those still to be entered.  They will do this by monitoring the 
study periodically for safety, study progress, and protocol compliance, as well as assessing the 
risk/benefit of the trial.  IDMC meetings will be held as per separate DMC charter, 
approximately every 6 months throughout the blinded trial phase. Ad hoc meetings will take 
place if needed.
Specific areas of concern for the IDMC are:

Subject safety (unblinded safety data will be reviewed at each meeting and any cases of 
unexpected AEs will be considered)

Accrual factors that may potentially impact on randomization balance


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
Page: 11 of 50

Subject eligibility and adequacy of follow-up 

Protocol compliance (deviations from outcome assessment schedules which may lead to 
biases will be evaluated)
The specific duties of the IDMC as well as statistical monitoring guidelines and procedures are
described in the IDMC Charter.
3.6
Data Rules
Generally, for each date stored in database a set of organizational variables will be derived in 
order to describe the temporal context of that date in the specific study: Phase of treatment (pre, 
during or post study treatment), day relative to the start of study treatment, day relative to the end 
of study treatment.
The baseline for all efficacy endpoints is defined as the last non-missing assessment taken on or 
before the randomization date.
Unless otherwise specified, the baseline for all safety data, is the last non-missing assessment taken 
on or before first treatment date.
4. Analysis Sets
4.1
Assignment of analysis sets
Intent-to-treat analysis set (ITT)
All randomized subjects will be included in the ITT analysis set. The ITT population will be 
used in the analysis of all efficacy endpoints.  Subjects will be included in all ITT analyses 
according to the treatment to which they are randomized.
Safety analysis set (SAF)
All randomized subjects who received at least one dose of any study drug will be included in the 
safety analysis set. This safety population will be used in the analyses of all safety endpoints. 
Subjects will be included in the analyses according to the treatment they received.
Pharmacokinetic analysis set (PKS)
All subjects of Subgroup 1 defined in the protocol with a valid pharmacokinetic profile for non-
compartmental analysis (NCA) will be included in the pharmacokinetic analysis set (PKS).
5. Statistical Methodology
The formal statistical analyses will be both descriptive and inferential. Summaries will be 
provided for each of the treatment group. In addition, descriptive summaries of  population 
characteristics may be provided for the total study population. 


Statistical Analysis Plan
Protocol No.: BAY 88-8223 / 15396
Page: 12 of 50
5.1
Population Characteristics
5.1.1
Disposition of Subjects
The number and percentage of subjects  screened, randomized, and treated  will be presented by 
treatment group and overall.  The number of subjects will also be tabulated by the total number 
of radium 223 injections received. The reasons for subjects discontinued from the treatment will 
be summarized by treatment group. In addition, the number of subjects screened, screen failures,
and included in each analysis population will be displayed by region, country and center. The 
screen failure reasons will be summarized by treatment group.
5.1.2
Demographic and Baseline Characteristics
Descriptive summaries of demographics and baseline characteristics will be presented by 
treatment group and overall for the Safety and ITT populations. Comparability of the treatment 
groups with respect to demographics and baseline characteristics will be assessed using the 
descriptive summaries.
The following demographic data will be summarized:

Sex

Age at screening (years)

Age category (< 65, 65 – 74, 75-84, ≥85 years)

Race and ethnicity

Height (cm)

Weight (kg) at baseline

BMI
The following baseline characteristics will be summarized:

Stage of prostate cancer at diagnosis

Treatment of prostate cancer before enrollment (e.g., surgery, radiation, etc.)

Gleason score at diagnosis of prostate cancer

PSA and total ALP at diagnosis of prostate cancer

PSA and total ALP at randomization

Vital signs:  blood pressure (mm Hg), heart rate (bpm), respiratory rate (rpm), and 
temperature (°C)

ECOG PS

Cancer pain assessment
Categorical summaries of each of three randomization stratification factors: geographical regions 
(Western Europe/North America/Australia vs. Asia vs. rest of world), concurrent use of
denosumab or bisphosphonates  (yes vs. no), and total ALP (< 90 U/L versus ≥ 90 U/L) at 
randomization will also be presented.


Statistical Analysis Plan
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5.1.3
Medical History
Medical history will be summarized by body system for the ITT population by treatment group 
and overall.
5.1.4
Extent of Exposure
Extent of exposure will be summarized for the safety populations by treatment group. 
Duration of treatment will be calculated in days as the date of the last dose of study treatment
(when abiraterone as IMP) – date of the first dose of study treatment + 1. This will be 
summarized using descriptive statistics.
Number of radium 223/placebo injections received will be summarized by treatment group.
Total dose of radium-223 dichloride and abiraterone as IMP will be summarized separately.
5.1.5
Prior and Concomitant Medications
All non-study medications taken during the study will be coded using the World Health 
Organization Drug Dictionary (WHO-DD) 2005 Q3 and the Anatomical Therapeutic Chemical 
(ATC) classification system. Coding will include the drug class and generic drug name.
Non-study medications taken during the study will be categorized as prior medications, 
concomitant medications during the treatment period, and post treatment medications during the 
active follow-up and long-term follow-up.
Prior medications will be defined as a non-study medication with a stop date prior to the first 
dose of study treatment.
Concomitant medications will be defined as:
Non-study medications with a start or stop date on or after the date of the first
dose of study treatment;
Non-study medications that started prior to the first dose of study
treatment and are ongoing during the treatment period;
Non-study medications with partial start dates that indicate that the medication
could be concomitant in relation to the date of the first dose of study
treatment;
Non-study medications with completely missing start dates, unless their stop
dates confirm otherwise (i.e. the stop date is before the first injection of study
treatment).


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Post treatment medications are defined as non-study medications taken after the treatment 
period.
All concomitant medications will be listed, including verbatim descriptions and coded terms, and 
flags for prior medications. Prior, concomitant, and post treatment medications including anti-
cancer therapies will be summarized using frequencies of subjects reporting each drug category 
and generic drug name. For each subject, multiple records of the same concomitant medication 
will be counted once within a drug class and generic drug name.
5.2
Efficacy Analysis
5.2.1
Primary Efficacy Analysis
The primary efficacy endpoint is symptomatic skeletal event-free survival (SSE-FS). It is defined 
as the time from randomization to the earliest occurrence of  the following:
(1) An on-study SSE, which is defined as:
a.
the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms
b. the occurrence of new symptomatic pathological bone fractures (vertebral or non-
vertebral)
c.
the occurrence of spinal cord compression
d. a tumor related orthopedic surgical intervention.
(2) Death from any cause 
The censoring rules for SSE-FS is summarized in Table 1:
Table 1:Symptomatic Skeletal Event Free Survival (SSE-FS) censoring rule.
Situation
End Date 
Censored
Reason for 
Censoring
No post-baseline SSE
assessment and no death
Date of 
Randomization
Yes
No post-baseline 
SSE assessment and 
no death.
Subject had an SSE event
Date of first SSE
No*
N/A
Death without prior SSE 
(<13 weeks between last SSE 
assessment and death) # 
Date of Death
No*
N/A
Death without prior SSE (≥
13 weeks between last SSE 
assessment and death) #
Last SSE assessment 
before the missing 
SSE assessments #
Yes
≥13 weeks between 
last SSE assessment 
and death
Neither SSE nor death at data 
cutoff 
Last SSE assessment Yes
Neither SSE nor 
death
Symptomatic Skeletal Event Free Survival (SSE-FS) = End Date – Date of Randomization +1
*The earliest end date in the table is used in calculating the SSE-FS.
#: use randomization date instead of last SSE assessment date if no post-baseline SSE assessment.
Note: SSE events immediately after missing SSE assessments are still counted as events in the analysis of 
SSE-FS.


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SSE-FS analysis will be performed for the ITT population using a stratified log-rank test 
stratified by the three randomization strata from IxRS: geographical regions (Western 
Europe/North America/Australia vs. Asia vs. rest of world), concurrent use of denosumab or 
bisphosphonates [yes vs. no], and  total ALP < 90 U/L versus total ALP ≥ 90 U/L. The treatment 
variable is binary and will be coded as 1 if the patient is randomized to receive radium-223 
dichloride and 0 if the patient is randomized to receive placebo. The hazard ratio (radium-223 
dichloride/placebo) will be computed together with the two sided 95% CI using a stratified Cox 
regression model with the three randomization factors as strata in the model. 
SSE-FS will also be summarized using the Kaplan-Meier estimates. Median survival time 
together with the 25th and 75th percentiles and associated 95% CI will be presented by treatment 
group. Kaplan-Meier curves will be generated for both treatment groups. 
The contribution of each component of the composite SSE between the arms will be evaluated. 
Descriptive statistics will be presented.
In order to assess the impact of death censoring rule on the analysis of SSE-FS, a sensitivity 
analysis will be performed for SSE-FS by counting all deaths without prior SSE as SSE-FS 
events. 
Sensitivity analyses for SSE-FS will be performed concerning initiation of new systemic 
anticancer therapy or initiation/change of  bone targeted treatment (i.e. 
bisphosphonates/denosumab) separately. In the sensitivity analyses, SSE-FS will be censored at 
the start of new systemic anticancer therapy or initiation/change of  bone targeted treatment if the 
subject received such treatment (see Table 2: for detailed censoring rules).
Another sensitivity analysis will be done by considering the initiation of systemic anticancer 
therapy or initiation/change of bone targeted treatment as a SSE-FS event.
Another supportive analysis for SSE-FS will be performed using a non-stratified log-rank test.
The treatment effect (hazard ratio) will be estimated using the Cox proportional hazards 
regression model without accounting the three stratification factors.
As an exploratory analysis, the stratified Cox proportional hazards regression model may be 
fitted including other baseline covariates considered to be of prognostic importance (see section 
3.2). 
In addition, analyses examining the relationship between body weight (total dose delivered) and 
SSE-FS and the ideal body weight with SSE-FS will be performed. Details regarding the 
subgroup analysis for SSE-FS is specified in Section 5.5.


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Table 2: Censoring rule for SSE-FS sensitivity analysis
Situation
End Date 
Censored
Reason for Censoring
No post-baseline SSE 
assessment and no death
Date of
Randomization
Yes
No  post-baseline  SSE 
assessment and no 
death.
Subject had a SSE event
Date of first SSE
No*
N/A
Death without prior SSE (<13 
weeks last SSE assessment and 
death)#
Date of Death
No*
N/A
New systemic anticancer 
therapy started (or 
initiation/change of  bone 
targeted treatment) prior to on 
study SSE or death
Start date of new 
systemic anticancer 
therapy (or bone 
targeted treatment)
Yes
Start of new systemic 
anticancer therapy (or 
initiation/change of  
bone targeted treatment)
Death without prior SSE (≥13 
weeks between last SSE
assessment and death)#
Last SSE assessment 
before missing SSE
assessment (use 
randomization date if 
no post-baseline SSE 
assessment)#
Yes
≥13 weeks between last 
SSE assessment and 
death
Neither SSE nor death at data 
cutoff 
Last SSE assessment Yes
Neither SSE nor  death
Symptomatic Skeletal Event Free Survival (SSE-FS) = End Date – Date of Randomization +1
*The earliest end date in the above table is used in calculating the SSE-FS.
#: use randomization date instead of last SSE assessment date if no post-baseline SSE assessment.
All the sensitivity analyses and supportive analyses will be done for the ITT population only.
5.2.2
Secondary efficacy Analysis
5.2.2.1
Secondary efficacy endpoints
The secondary efficacy variables are specified below: 

Overall survival (OS)

Time to opiate use for cancer pain

Time to pain progression

Time to cytotoxic chemotherapy

Radiological progression free survival(rPFS)
Overall survival is defined as the time (days) from the date of randomization to the date of 
death due to any cause.  For subjects who are still alive, their OS will be censored at the last 
known alive date or the database cutoff date, whichever occurs first. 


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Time to opiate use for cancer pain is defined as the interval from the date of randomization to 
the date of opiate use.  Subjects who have no opiate use at the time of analysis will be censored 
at the last known date of no opiate use.  Subjects with no on-study assessment or no baseline 
assessment will be censored at the date of randomization.
Analgesic use will be captured via three methods:
analgesic concomitant medication case report form, where the physician records the 
analgesic medication prescribed to manage pain.  
24 hour analgesic consumption case report form, in which all analgesic medication taken 
in the last 24 hours, including dose of medication and number of pills consumed, will be 
recorded. Patients will be asked to bring all of their medication to the clinic visit and 
complete this form with the assistance of the clinician.  
Opiate use case report form, in which the information of opiate pain medication since last 
assessment was collected.
For the time to first opiate use for cancer pain secondary endpoint, the earliest date of the first 
opiate use recorded via any of the following three methods will be used: the 24 hour analgesic 
consumption case report form, analgesic concomitant medication case report form or opiate use 
case report form.
Patients who had opiate analgesics at baseline are not eligible for the analysis of this endpoint.
Time to pain progression is defined as the interval from randomization to the first date a subject 
experiences pain progression based on worst pain score (WPS):
For asymptomatic patients (WPS 0 at baseline), pain progression is defined as an increase of 2 or 
more points in the average (i.e., average of 7-day assessments) “worst pain in 24 hours” score 
from baseline observed at 2 consecutive evaluations ≥4 weeks apart 
OR
initiation of short or long-acting opioid use for pain.
Assessments will occur daily for one week (including the visit date).  An evaluable pain 
assessment interval requires completion of a minimum of 4 out of 7 daily questions. Subjects 
who have not experienced pain progression at the time of analysis will be censored on the last 
date the subject was known to have not progressed.  Subjects with no on-study assessment or no 
baseline assessment will be censored at the date of randomization.  
For mildly symptomatic patients (WPS 1-3 at baseline), pain progression is defined as an 
increase of 2 or more points in the average (i.e., average of 7-day assessments) “worst pain in 24 


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hours” score from baseline observed at 2 consecutive evaluations ≥4 weeks apart and an average 
worst pain score of ≥ 4.
OR
initiation of short or long-acting opioid use for pain.
Assessments will occur daily for one week (including the visit date).  An evaluable pain 
assessment interval requires completion of a minimum of 4 out of 7 daily questions. Subjects 
who have not experienced pain progression at the time of analysis will be censored on the last 
date the subject was known to have not progressed.  Subjects with no on-study assessment or no 
baseline assessment will be censored at the date of randomization.
For both asymptomatic and mildly symptomatic patients, the opioid use component of this 
endpoint will be based on the same source data for time to opiate use endpoint. Patients who had 
opiate analgesics at baseline are not eligible for the analysis of this endpoint.
Time to cytotoxic chemotherapy is defined as the time (days) from the date of randomization to 
the date of the first cytotoxic chemotherapy. Subjects who have not started cytotoxic 
chemotherapy during the study will be censored at the last assessment date.  
Radiological progression-free survival (rPFS) is defined as the time (days) from the date of 
randomization to the date of confirmed radiological progression or death (if death occurs before 
progression).  Subjects without confirmed radiological progression or death at the time of 
analysis will be censored at their last date of radiological tumor assessment (See Table 3 for 
detailed censoring rules). Bone scans and CT/MRIs will be read both locally and by blinded 
independent central assessment.  If there is an inconsistency between local assessment and 
central review, then the assessment will be based on central review. If progression is detected by 
bone scan, a confirmatory scan is required at least 6 weeks later. A single SPECT or MRI (with 
and without contrast media) should be obtained to confirm any suspicious bone scan findings.
The date of confirmed radiological progression will be the date of first observation of 
radiological progression.  
Radiological bone progression is determined if at least one of the following criteria is met:
A subject is considered to have progressed by bone scan if:
o
The first bone scan with ≥2 new lesions compared to baseline is observed <12 weeks 
from randomization and is confirmed by a second bone scan taken ≥6 weeks later 
showing ≥2 additional new lesions (a total of ≥4 new lesions compared to baseline); or
o
The first bone scan with ≥2 new lesions compared to baseline is observed ≥12 weeks 
from randomization and the new lesions are verified on the next bone scan ≥6 weeks later 
(a total of ≥2 new lesions compared to baseline).
If bone scans are repeated, the best scan should be submitted to the core imaging lab as per 
judgment of the site.


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Progression in soft tissue and occurrence of visceral disease will be assessed by CT or MRI 
every 8 weeks then every 12 weeks (± 7 days) based on modified RECIST 1.1 (protocol section 
14.3). CT or MRI scans will be read both locally and by blinded independent central assessment.  
The RECIST will be used to assess soft tissue and visceral disease only.  Bone lesions detected 
by CT or MRI cannot be selected as target or non-target lesions.  Bone lesions will be evaluated 
by bone scans. 
Table 3: Radiological progression free survival censoring rule
Situation
End Date 
Censored
Reason for 
Censoring
No baseline or post-baseline  
radiological assessment
Randomization Date
Yes
No baseline or post-
baseline  tumor
assessment.
Subject had a radiological 
assessment of PD (no more than one 
missed radiological assessment)
Date of first PD
No*
N/A
Subject discontinued from study for 
other than PD or death
Last radiological
assessment without 
PD
Yes
Subject
discontinued from 
study due to a 
reason other than 
PD or death
Death during the study (no more 
than one missed radiological 
assessment) without radiological PD 
assessment before death
Date of Death
No*
N/A
Subject discontinued from study due 
to PD, but no documented PD date
Date of last 
radiological 
assessment
Yes
Subjects 
discontinued from 
study due to PD, but 
no documented date
of PD
Subject still on study at the time of 
data cutoff without PD
Last radiological
assessment  before 
data cutoff
Yes
Subject is still alive 
without PD
Death or PD after more than one  
missed radiological  assessment 
Date of last 
radiological
assessment before 
missed assessment
Yes 
Missed more than 
one tumor 
assessments
New systemic anticancer treatment 
started prior to radiological PD or 
death
Date of last 
radiological 
assessment before 
starting new 
systemic anticancer 
treatment
Yes 
New systemic 
anticancer treatment 
started
Radiological Progression Free Survival (rPFS) = End Date – Date of Randomization +1
*Earliest end dates in the above table are used in calculating the PFS.


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5.2.2.2
Analysis of secondary efficacy endpoints
A hierarchical testing procedure will be followed for the analysis of  secondary endpoints.
All time to event efficacy analysis will be performed for the ITT population using a stratified 
log-rank test accounting for the three randomization stratification factors. The treatment variable 
is binary and will be coded as 1 if the subject was randomized to receive radium-223 dichloride
and 0 if the subject was randomized to receive placebo. The treatment effect (hazard ratio) will 
be estimated using the Cox proportional hazards regression model stratified by the three 
randomization stratification factors. For rPFS, analyses will be done based on both the 
investigator’s and the independent assessments. Analysis based on the independent assessment 
will be considered as the primary analysis for rPFS. Analysis based on the investigator’s 
assessment will be considered as supportive analysis.
Time to event endpoints will also be summarized using the Kaplan-Meier estimates. Median 
survival time together with the 25th and 75th percentiles and associated 95% confidence interval 
(CI) will be presented by treatment group as well as the number and percentage of censored 
observations. A Kaplan-Meier curve will be generated for each treatment group. 
Sensitivity analysis will be conducted for rPFS without considering new systemic anti-cancer 
treatment received in the censoring rules.
Sensitivity analysis will be done for time to pain progression without considering initiation of 
short or long-acting opioid use for pain as event.
Sensitivity analysis will be performed for time to opiate use by only using the analgesic use data 
on the Opiate Use eCRF page. Similarly sensitivity analysis will be performed for time to pain 
progression using pain score data and analgesic use data only based on the Opidate Use eCRF 
page.
Although patients who had opiate analgesics at baseline are excluded from the primary analysis 
of time to pain progression, they will be included in the analysis as a sensitivity analysis. 
For patients who took a weak opiate at baseline, the initiation of any strong opioid would be 
counted as pain progression; For patients who took a strong opioid at baseline, the initiation of 
an additional strong opioid would be counted as pain progression.
The pain score change at week 12 will also be analyzed using an ANCOVA model with baseline 
pain score and study treatment as covariates.
Per protocol, individual subjects may be unblinded per investigators request after they have an 
SSE, allowing the investigator to determine if the subject would be a candidate to receive 
treatment with radium 223 dichloride. This unblinding criteria is considered to be the only 
feasible option to allow patients to have access to Xofigo in the placebo arm, after they have 
experienced an SSE, thereby becoming symptomatic. For all the secondary efficacy endpoints, 
analyses will be done based on the randomized treatment. Further evaluation might be done to 
evaluate the potential impact of unblinding on the analysis of secondary endpoints.


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5.2.2.2.1
Hierachial testing procedure
The overall type I error rate for the primary endpoint and selected secondary endpoints will be 
controlled at 2-sided 0.05 or less using a hierarchical testing procedure as below:
If the primary endpoint SSE-FS is statistically significant at the 0.05 level (2-sided), then the 
alpha level will be split between OS (alpha=0.001) and the secondary endpoints rPFS, TtPP and 
TtCC (alpha=0.049).
The rPFS, TtPP and TtCC will be formally tested at 0.049 using a hierarchical testing procedure 
in this order (Figure 1):
-
rPFS: Radiographic progression-free survival
-
TtPP: Time to pain progression 
-
TtCC: Time to cytotoxic chemotherapy
There are two possible scenarios for testing secondary endpoints rPFS, TtPP, TrCC and OS, 
depending on the analysis results:
Scenario 1:
If  rPFS, TtPP and TtCC are all statistically significant at the 0.049 level (2-sided), then the OS 
will be formally tested at an overall alpha=0.05 (2-sided). OS will be formally tested at the 0.005 
level (2-sided) at the interim OS analysis with 275 deaths or at the 0.048 level (2-sided) at the 
final OS analysis with 500 deaths. To maintain an overall 2-sided significance level of 0.05, 
these levels will be adjusted based on the number of deaths observed at the interim OS analysis.
Figure 1 shows the details of the testing sequence for scenario 1.
Scenario 2:
If at least one of the secondary endpoints, rPFS, TtPP or TtCC, is not statistically significant at 
the 0.049 level (2-sided), then OS will be formally tested at an overall alpha=0.001 (2-sided). OS 
will be formally tested at the 5.3×10-6 level (2-sided) at the interim OS analysis with 275 deaths 
or at the 0.001 level (2-sided) at the final OS analysis with 500 deaths. Figure 2 shows the details 
of the testing sequence for scenario 2.


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Figure 1. Pre-specified testing procedure (scenario 1)
Figure 2. Pre-specified testing procedure (scenario 2)
If SSE-FS is not statistically significant at the 0.05 level (2-sided), then no formal testing will be 
performed for any other endpoints.


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5.2.3
Exploratory efficacy analysis 
5.2.3.1
Exploratory efficacy endpoints
There are multiple exploratory endpoints specified for this study as listed below. 
Time to first on-study SSE is defined as the time (days) from the date of randomization to the 
date of the first on-study SSE.
Percentage change in total ALP from baseline to 12 weeks and the percentage change in total 
ALP from baseline to 24 weeks will be calculated for each subject, based on laboratory data 
collected as of the 12- and 24-week assessments, respectively. The last observation (including 
baseline) carried forward method will be used to impute the missing value at week 12 or week 
24.
Time to ALP progression is defined as the time (days) from the date of randomization to the 
date of first ALP progression.  Alkaline phosphatase progression is defined as 25% increase 
from the baseline value, at least 12 weeks from baseline in subjects with no ALP decline from 
baseline; or 25% increase above the nadir value, which is confirmed by a second value 
obtained 3 or more weeks later in subjects with an initial ALP decline from baseline.
Time to PSA progression is defined as the time (days) from the date of randomization to the 
date of first PSA progression.  Prostate specific antigen progression is defined as 25% increase 
from the baseline value and an increase in absolute value of 2 ng/mL, at least 12 weeks from 
baseline in subjects with no PSA decline from baseline; or 25% increase and an absolute 
increase of 2 ng/mL above the nadir value, which is confirmed by a second value obtained 3 or 
more weeks later in subjects with an initial PSA decline from baseline.  
Alkaline phosphatase response is defined as ≥30% reduction of the blood level, compared to 
the baseline value.  Confirmed ALP response is defined as a ≥30% reduction of the blood level, 
compared to the baseline value, confirmed by a second ALP value 4 or more weeks later. ALP 
responses will be evaluated at week 12 and week 24 after treatment is started.
Prostate specific antigen response is defined as ≥30% reduction of the blood level, compared 
to the baseline value.  A confirmed PSA response is defined as ≥30% reduction of the blood 
level, compared to the baseline value, confirmed by a second PSA value 4 or more weeks later.
PSA responses will be evaluated at week 12 and week 24 after treatment is started.
Radiological progression free survival based on bone scans (bone rPFS) is  defined as the 
time (days) from the date of randomization to the date of confirmed radiological progression 
detected by bone scans or death (if death occurs before progression). Subjects without confirmed 
radiological progression or death at the time of analysis will be censored at their last date of 
radiological tumor assessment.  Bone scans will be read both locally and by blinded independent 
central assessment. If there is an inconsistency between local assessment and central review, then 
the assessment will be based on central review. If progression is detected by the independent 
central assessment, a confirmatory scan is required at least 6 weeks later.  The date of confirmed 


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radiological progression will be the date of first observation of central assessment of radiological 
progression.  Radiological progression is determined if at least one of the following criteria is 
met:

A subject is considered to have progressed by bone scan if:
o
The first bone scan with ≥2 new lesions compared to baseline is observed <12 
weeks from randomization and is confirmed by a second bone scan taken ≥6 
weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions 
compared to baseline); or
o
The first bone scan with ≥2 new lesions compared to baseline is observed ≥12 
weeks from randomization and the new lesions are verified on the next bone scan 
≥6 weeks later (a total of ≥2 new lesions compared to baseline).
If bone scans are repeated the best scan should be submitted to the core imaging lab as per 
judgment of the site.
HRQoL Endpoints: Time to increase in physical symptoms of disease based on the NCCN-
FACT FPSI-17 physical disease related symptoms (FPSI-DRS-P) subscale score measured 
during the treatment period will be assessed using the NCCN-FACT FPSI-17 questionnaire.
The NCCN-FACT FPSI-17 is a validated instrument that was developed to assess symptoms of
prostate cancer, symptoms of treatment of prostate cancer, and health related quality of life of 
prostate cancer patients (3)The instrument was developed in accordance recent FDA guidance 
for development of instruments for ePRO. The instrument contains 17 items, each of which 
utilize a Likert scale with 5 possible responses.  The ten items reflect disease related physical 
symptoms of disease and the responses on the items are be summed to calculate a disease related 
physical symptom subscale score.  One item represents emotion symptom of disease and the 
response to that item is used to calculate a disease related emotional symptom subscale score.  
Four items represent treatment related symptoms and the responses to these items are summed to 
calculate a treatment side effect subscale score.  Finally, two items represent functional well-
being and response to those items are summed calculated a functions/well-being subscale score.
Time to deterioration in HRQoL will be the endpoint to evaluate the HRQoL FPSI-DRS-P 
subscale score.  Deterioration is defined as a 2 point drop in DRS-P score that persists for two 
consecutive assessments at least 4 weeks apart, if two consecutive assessment are available. If 
there is a 2 point drop in the DRS-P score and the next assessment is not available due to death 
then that single 2 point drop would count as a deterioration. The date of the event is the first 
assessment with at least 2 points decrease from the baseline. If no deterioration observed, time to 
deterioration in HRQoL will be censored at the last HRQoL observation.
Time to increase in physical symptoms of disease based on the NCCN-FACT FPSI-17 physical 
disease related symptoms (FPSI-DRS-P) subscale score measured during the period between 
start of treatment and end of active follow-up with clinic visit. 


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5.2.3.2
Analysis of exploratory efficacy endpoints 
Similar to the primary efficacy endpoint, the stratified log-rank test stratified by the three 
randomization strata will be performed for the time to event variables (time to first on-study 
SSE, percentage change in total ALP from baseline, time to ALP progression, time to PSA 
progression and bone rPFS, etc.) based on the ITT population. The censoring rules for bone rPFS 
will be the same as defined for rPFS in Table 33. The treatment effect (hazard ratio) and its 95% 
CI will be estimated using the Cox proportional hazards regression model stratified by the three 
randomization stratification factors. The Kaplan-Meier estimates and plots will also be presented 
for each endpoint.
Sensitivity analysis of Time to total ALP progression will be performed by droping the 12 week 
restriction in the definition.
To assess the potential bias due to missing data , FPSI-DRS-P data will also be analyzed using a 
pattern mixture model. Patients will be ranked based on the percentage of completed HRQoL 
assessments (where the numerator for a patient is the number of assessments and the 
denominator is the number of assessments that the patient should have had if the completed the 
questionnaire at every scheduled visit prior to their death or prior to leaving the study due to 
administrative censoring). The median value of the percentage of completed HRQoL assessment
will be used to categorize patients into “patients with higher degree of missing data”  or “patients 
with lower degree of missing data”. An index variable for the two groups (0=  patient with a 
“high degree of missing data” and 1 = patient with a “lower degree of missing data”) will be 
created. A stratified Cox regression model will be used which contains the treatment variable, the 
index variable, and a term for the interaction between treatment and the index variable. The 
stratification factors for the Cox model will be the stratification factors used at randomization. If 
the interaction term is statistically significant, the analysis will indicate that there might be 
evidence of informative censoring.
CMH test adjusting the three randomization strata will be used for the ALP response and PSA 
response to evaluate difference between treatment group. Response rate difference and its exact 
95% CI will be provided. ANCOVA with randomization strata as covariates will be done for the 
percentage change in total ALP from baseline.
Summary statistics will be provided for the HRQoL scores and subscales. See Section 5.4.2 for 
additional information on the analysis of HRQoL data.
5.2.3.2.1
Exploratory endpoint for labeling purposes
For labeling purposes, analysis for time to increase in physical symptoms of disease based on the 
NCCN-FACT FPSI-17 physical disease related symptoms (FPSI-DRS-P) subscale score 
measured during the treatment period will be included in the multiplicity adjustment for this 
study. This exploratory endpoint will be tested at a two-sided alpha level of 0.05 if the primary 
endpoint and the selected secondary efficacy endpoints specified in section 5.2.2.2.1 all have 
statistically significant results based on the preplanned method for alpha adjustment.


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No multiplicity adjustment will be done for other exploratory endpoints. Further analyses may be 
identified and performed for exploratory purposes.
5.3
Safety Analysis
All safety analyses will be done based on the safety population. No formal statistical test will be 
done for the safety endpoints.
5.3.1
Adverse events
All adverse events (AE) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 19 or higher. The intensity of an AE will be documented using the 
NCI-CTCAE v4.03. 
Each AE recorded on the CRF will be classified as either a pre-treatment AE, a treatment-
emergent AE (TEAE) or a post-treatment AE. 
The treatment period for this study extends from the initiation of treatment until 4 weeks after the 
last administration of abiraterone as IMP and prednisone/prednisolone or 6 months after last 
administration of radium-223/placebo, whichever occurs later unless a new systemic anti-cancer 
therapy is initiated. If a new anti-cancer therapy is initiated before the end of the period defined 
above, the treatment period extends from the initiation of treatment until 4 weeks after the start 
date of the new anti-cancer therapy.
Pre-treatment AEs
Pre-treatment AEs will be defined as AEs that started and either stopped before the first dose of 
study treatment or continued after and did not worsen in intensity(i.e. increase in CTC toxicity 
grade or became serious) during the treatment period. 
Treatment-emergent AEs
All other AE starting or worsening within the treatment period will be considered TEAEs for 
example:

Events that started on or after the first dose and within the treatment period and are not a 
continuation of a pre-treatment event.

Events that started before the first dose and worsened after the first dose or the treatment 
period.
Post-treatment AEs
Post-treatment follow-up AEs will be defined as AEs that started after the treatment period. Note 
that the intention of this study is that only related AEs will be collected after the treatment 
period.
An overall summary of AEs will be provided to present the number and percentage of subjects 
with


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
any pre-treatment AEs, TEAEs, or post-treatment AEs

any study drug related TEAEs

any serious TEAEs, 

any serious related TEAEs

any CTC Grade ≥3 TEAEs

any TEAEs leading to discontinuation

any TEAEs leading to death
TEAEs and post-treatment AEs will be summarized by MedDRA system organ class and 
preferred term. For each subject, multiple occurrences of the same event will be counted once 
within a system organ class and preferred term.
The same summaries will be repeated for related TEAEs, serious TEAEs, serious related TEAEs, 
CTC Grade ≥3 TEAEs, CTC Grade 5 TEAEs, TEAEs leading to discontinuation and TEAEs 
leading to death.
The maximum severity of the TEAEs and post-treatment AEs will be summarized according to 
the NCI-CTCAE toxicity criteria. For each subject, multiple occurrences of the same event will 
be counted once at their maximum severity within a system organ class and preferred term. 
TEAE will also be summarized by NCI-CTCAE toxicity criteria and relationship to study 
medication.
The numbers of TEAEs, and subjects experiencing TEAEs will be presented.
A data listing will be produced for all AEs, TEAEs leading to discontinuation and drug related 
TEAEs. Verbatim descriptions and coded terms will be listed for all AEs.  
5.3.2
Deaths
Deaths reported during the study period will be tabulated by treatment group. A data listing of all 
deaths will be provided.
5.3.3
Clinical Laboratory Data
The following laboratory parameters will be summarized:

Hematology parameters: Hematocrit, Hb, Platelet Counts, RBC, WBC, WBC differential.  

Chemistry  parameters: Na, K, Cl, Ca, ALT, AST, LDH, Total ALP, Creatinine, Blood 
Urea Nitrogen (BUN), Total Bilirubin, and Albumin.

Other parameters: PSA, Testosterone.
Descriptive statistics (number of observations, mean, standard deviation, minimum, median and 
maximum values) will be presented for clinical laboratory tests (hematology and clinical 
biochemistry), their changes from baseline (including baseline value), and their percent changes 
from baseline by treatment group at applicable visits. Graphical presentations may also be 


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generated for each laboratory parameter by visit and treatment group to investigate trends over 
time and outliers in the data.
In addition, changes from baseline will be summarized in shift tables according to severity 
during treatment and baseline CTC grade.
If more than one assessment occurred at any visit (i.e. repeat samples taken), the last valid (non-
missing) value will be used in the summaries. Unscheduled laboratory data will be listed but will 
not be included in the summary tables.
5.3.4
ECG
Changes from baseline at week 4 and at end of treatment (4 weeks post last injection) in ECG 
data during the treatment period will be summarized for each treatment group using shift tables.
5.4
Analysis of Other Endpoints
Other endpoints will be summarized for the ITT population..
5.4.1
ECOG Performance Status
The number and percentage of subjects in each category will be presented. Changes from 
baseline in PS on the ECOG scale will be summarized in shift tables by treatment group.
5.4.2
Quality of Life
Summaries of HRQoL data will be performed for the ITT population and will be based on an as 
observed basis (i.e. no imputation for missing data performed) unless otherwise specified.
5.4.2.1
EQ-5D
EQ-5D questionnaire consists of five ordinal categorical responses and a visual analogue scale 
(VAS).  The responses to the five ordinal questions are used to calculate a utility score and the 
response to the VAS item is used to calculate a self-reported health status score. UK tariffs (i.e. 
weights) and the standard EQ-5D scoring algorithm will be used to calculated the utility scores.
For each treatment group, responses to the ordinal questions at each assessment time point will 
be described with frequency tables.
Summary statistic, including mean and change from baseline, for the utility score and the VAS 
score will be presented by treatment group for each assessment time points.
5.4.2.2
BPI-SF
The BPI-SF (protocol Section 14.9) is a short, self-administered questionnaire with 11 items, 
which was designed to evaluate the intensity of, and the impairment caused by pain. All BPI-SF


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items are scored using rating scales. Four items measure pain intensity (pain now, average pain, 
worst pain, and least pain) using 0 (“no pain”) to 10 (“pain as bad as you can imagine”) numeric 
rating scales, and seven items measure the level of interference with function caused by pain 
(general activity, mood, walking ability, normal work, relations with other people, sleep and 
enjoyment of life) using 0 (no interference) to 10 (complete interference) rating scales.
The items are aggregated into two dimensions, (1) Pain severity index, using the mean of the 
four items on the pain intensity, and (2) Function interference index, using the mean of the seven 
pain interference items.  All four severity items must be completed for aggregating the pain 
severity index. The function interference index is scored as the mean of the item scores 
multiplied by seven, given that more than 50% or four of seven, of the items have been 
completed.
Summary statistic, including mean and change from baseline, for the pain severity and pain 
intensity and the items make up these indices will be provided by visit and treatment. 
5.4.2.3
NCCN-FACT FPSI-17
The NCCN-FACT FPSI-17 (Comprehensive Cancer Network - Functional Assessment of Cancer 
Therapy - Prostate Symptom Index-17) instrument consists of 17 questions relating to four 
domains: Disease-related symptoms subscale – physical (DRS-P), Disease-related symptoms 
subscale – emotional (DRS-E), Treatment side effects subscale (TSE), Function and well-being 
subscale (FWB).
Summary statistic, including mean and change from baseline,  for each domain will be 
summarized using descriptive statistics by study visit and treatment group.
5.4.2.4
Long term safety 
Descriptive summaries will be provide for the long term safety endpoints including new primary
malignancies and hematopoietic reserve for tolerability of subsequent chemotherapy
5.4.2.5
Resource utilization 
Resource utilization will be provided in the data listing.
5.5
Examination of Subgroups
Subgroup analyses will be conducted for the primary efficacy endpoint SSE-FS, rPFS and OS
based on the ITT population. Descriptive statistics and hazard ratio estimates with 95% CI will 
be provided at least for the subgroups listed below, provided there is a sufficient number of 
events in total within the subgroup across the treatment arms. 

ECOG performance status at baseline (0 vs 1)

Extent of Disease (number of bone lesions <6 vs. 6-20 vs. >20 at baseline)

Asymptomatic vs mildly symptomatic 

Ethnicity (collected as Caucasian, Hispanic, Black, Asian and Other)


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
Age group (<65, 65-74, 75-84, >=85)

Body weight and ideal body weight normalized dose quartiles

Randomization stratification factors:
o
geographical regions (Western Europe/North America/Australia vs. Asia vs. rest 
of world) 
o
concurrent use of denosumab or bisphosphonates (combined strata) (Yes vs. No)
o
total ALP < 90 U/L versus total ALP ≥ 90 U/L.

US and EU

Randomization strata concurrent use of denosumab versus bisphosphonates

BMI < 30 and >=30

Number of Radium-223 dichloride injections received (by number of injections - 1- 4, vs. 
5-6)

Gleason Score at the time of diagnosis (<8, >=8, Missing)

Baseline PSA values by median

Received prior Antiandrogens (enzalutamide vs. first generation Antiandrogens vs. none)

Baseline LDH by median

Baseline tumor location (bone only vs. bone with soft tissues or others)
If important effects are found in subgroups, the interaction analyses between the treatment and 
the subgroups may be performed. 
Safety analysis (i.e. AE) will be conducted based on age subgroup, body weight and ideal body 
weight normalized dose quartiles. 
5.6
Pharmacokinetics / pharmacodynamics
Pharmacokinetics of radium-223 dichloride will not be evaluated in this study; however, the PK 
of abiraterone will be investigated in 2 subgroups.  In each subgroup, approximately 40 subjects 
(approximately 20 per treatment arm) will be enrolled. 
Statistical analysis will be done only for Subgroup 1(Non-compartmental analysis).   The 
Subgroup 2 population PK analysis is not part of the analyses described in this SAP. Subgroup 2 
population PK analysis results will be presented in a separate report . For Non-compartmental 
PK analysis see section 5.6.2. 
5.6.1
Biomarkers assessment
Summary statistics for biomarkers and their changes from baseline will be presented by visits 
and treatment. 


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5.6.2
Pharmacokinetics
The concentration-time courses of abiraterone will be tabulated separated by treatment. The 
following statistics will be calculated for each of the sampling points: geometric mean, geometric 
standard deviation (re-transformed standard deviation of the logarithms), and geometric 
coefficient of variation, as well as arithmetic mean, standard deviation, and arithmetic coefficient 
of variation, minimum, median, maximum value and the number of measurements. Means at any 
time will only be calculated if at least 2/3 of the individual data were measured and were above 
the lower limit of quantification (LLOQ). For the calculation of the mean value a data point 
below LLOQ will be substituted by 1 half of this limit. In tables showing mean values, where 
values below LLOQ are included in the calculation of mean values, these means will be marked.
Individual and geometric mean concentration vs time curves of abiraterone (using the actual 
sampling times for individual plots and the planned sampling times for mean plots) will be 
plotted by treatment using both linear and semilogarithmic scale.
Pharmacokinetic characteristics (tmax excluded) will be summarized by the statistics mentioned 
above. Tmax will be described utilizing minimum, maximum and median as well as frequency 
counts.
6. Document history and changes in the planned statistical analysis
SAP dated 20 Sep 2013 v1.0 without attachments submitted to FDA.
SAP Amendment 1 dated 22 September 2014 v2.0 without attachments submitted to FDA.
SAP Amendment 2 dated 21 April 2016 v3.0 without attachments submitted to FDA.
SAP Amendment 3 dated 20 April 2017 v4.0 without attachments submitted to FDA.
SAP Amendment 4 dated 10 July 2017 v5.0 without attachments submitted to FDA. The main 
change in this amendment is to address FDA’s comment on statistical testing procedure in 
Amendment 3.
7. References
1
Lan K.K.G. and DeMets D.L. (1983). Discrete sequential boundaries for clinical trials. 
Biometrika 70;3:659-63
2 O'Brien P.C. and Fleming T.R. (1979). A multiple testing procedure for clinical trials. 
Biometrics 35:459-56
3 Scher HI, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for Patients 
With Progressive Prostate Cancer and Castrate Levels of Testosterone: 
Recommendations of the Prostate Cancer Clinical Trials Working Group.  J Clin Oncol 
2008;26:114-1159 


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8. SAP amendments - amended
Amendment 1 - Table of Changes in the SAP Amendment
Note: This SAP amendment is prepared based on the protocol amendment 1. Only changes with potential impact on the  statistical 
analysis are included in the comparison table below.  All other changes made according to the protocol amendment were considered 
as cosmetic changes. Details for these changes can be found in the amended protocol Section 13.
SAP PAGE
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6
1.3
• Time to increase in physical 
symptoms of disease based on the 
NCCN-FACT FPSI-17 physical disease 
related symptoms (FPSI-DRS-P) 
subscale score measuredAssessment of 
pharmacokinetics (PK) of abiraterone 
Resource utilization

Time to increase in physical symptoms of 
disease based on the NCCN-FACT FPSI-17 
physical disease related symptoms (FPSI-DRS-
P) subscale score measured during period 
between start of treatment and end of active 
follow-up with clinic visits

Assessment of pharmacokinetics (PK) of 
abiraterone 

Resource utilization
Per protocol 
amendment; 
adjust format
8
2.1.1
If based on the investigator assessment, 
the subject does continue to receive 
clinical benefit, administration of study 
drug can be continued.  
If based on the investigator assessment, the subject 
does continue to receive clinical benefit, 
administration of study drug can be continued.  
If a SSE occurs during the first 6 cycles of 
treatment, subjects can complete the full 6 
administrations of radium-223 dichloride / 
placebo and can continue abiraterone acetate 
plus prednisone / prednisolone as long as the 
subject continues to receive clinical benefit 
based on the investigator assessment.
Per protocol 
amendment


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If a SSE occurs after the first 6 cycles of 
treatment, subjects can continue abiraterone 
acetate plus prednisone / prednisolone as long as 
the subject continues to receive clinical benefit 
based on the investigator assessment.
After an on-study SSE, abiraterone acetate will 
be considered standard of care (i.e., non-
investigational medicinal product [non-IMP]) 
and will not be supplied as study medication. 
Thus, after an on-study SSE, abiraterone acetate 
should be prescribed locally and recorded on the 
concomitant medications electronic case report 
form (eCRF) page.
21
4.1 
Pharmacokine
tic analysis set 
(PKS)
All subjects with a valid 
pharmacokinetic profile for non-
compartmental analysis (NCA) will be 
included in the pharmacokinetic 
analysis set (PKS).
All subjects of Subgroup 1 defined in the 
protocol with a valid pharmacokinetic profile for 
non-compartmental analysis (NCA) will be 
included in the pharmacokinetic analysis set (PKS).
Per protocol 
amendment
23
5.1.4
Duration of treatment will be calculated 
in days as the date of the last dose of
study treatment – date of the first dose 
of study treatment + 1. This will be 
summarized using descriptive statistics.
Number of radium 223/placebo 
injections received will be summarized 
by treatment group.
Total dose of radium-223 dichloride 
and abiraterone as IMP will be 
summarized separately.
Duration of treatment will be calculated in days as 
the date of the last dose of study treatment (when 
abiraterone as IMP) – date of the first dose of 
study treatment + 1. This will be summarized using 
descriptive statistics.
Number of radium 223/placebo injections received 
will be summarized by treatment group.
Total dose of radium-223 dichloride and 
abiraterone as IMP will be summarized separately.
Per protocol 
amendment
23
5.1.5
Non-study medications taken during the 
study will be categorized as prior 
medications, concomitant medications, 
Non-study medications taken during the study will 
be categorized as prior medications, concomitant 
medications during the treatment period, and 
Per protocol 
amendment


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and post treatment medications.
post treatment medications during the active 
follow-up and long-term follow-up.
24
5.2.1
In addition the impact of baseline total body 
weight and ideal body weight on SSE-FS will be 
explored.
Per protocol 
amendment
27
5.2.2.1 Table 
5
Situation: Subject discontinued from 
study due to PD, but no documented 
PD date 
Censored: No*
Situation: Subject discontinued from study due to 
PD, but no documented PD date 
Censored: Yes
correction
32
5.2.3.1
Alkaline phosphatase response is 
defined as ≥30% reduction of the blood 
level, compared to the baseline value.  
Confirmed ALP response is defined as 
a ≥30% reduction of the blood level, 
compared to the baseline value, 
confirmed by a second ALP value 4 or 
more weeks later. 
Prostate specific antigen response is 
defined as ≥30% reduction of the blood 
level, compared to the baseline value.  
A confirmed PSA response is defined 
as ≥30% reduction of the blood level, 
compared to the baseline value, 
confirmed by a second PSA value 4 or 
more weeks later. 
Alkaline phosphatase response is defined as ≥30% 
reduction of the blood level, compared to the 
baseline value.  Confirmed ALP response is defined 
as a ≥30% reduction of the blood level, compared 
to the baseline value, confirmed by a second ALP 
value 4 or more weeks later. ALP responses will 
be evaluated at week 12 and week 24 after 
treatment is started.
Prostate specific antigen response is defined as 
≥30% reduction of the blood level, compared to the 
baseline value.  A confirmed PSA response is 
defined as ≥30% reduction of the blood level, 
compared to the baseline value, confirmed by a 
second PSA value 4 or more weeks later. PSA 
responses will be evaluated at week 12 and week 
24 after treatment is started.
Per protocol 
amendment
35
5.3.1
The treatment period for this study 
extends from the initiation of treatment 
until 4 weeks after the last 
administration of abiraterone and 
The treatment period for this study extends from 
the initiation of treatment until 4 weeks after the 
last administration of abiraterone as IMP and 
prednisone/prednisolone or 6 months after last 
Per protocol 
amendment


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prednisone/prednisolone or 6 months 
after last administration of radium-
223/placebo, whichever occurs later.
administration of radium-223/placebo, whichever 
occurs later.
38
5.4.2.2
The items are aggregated into two 
dimensions, (1) Pain severity index, 
using the sum of the four items on the 
pain intensity, and (2) Function 
interference index, using the sum of the 
seven pain
interference items. All four severity 
items must be completed for 
aggregating the pain severity index. 
The function interference index is 
scored as the mean of the item scores 
multiplied by seven, given that more 
than 50% or four of seven, of the items 
have been completed.
The items are aggregated into two dimensions, (1) 
Pain severity index, using the mean of the four 
items on the pain intensity, and (2) Function 
interference index, using the mean of the seven 
pain interference items.  All four severity items 
must be completed for aggregating the pain severity 
index.  The function interference index is scored as 
the mean of the item scores multiplied by seven, 
given that more than 50% or four of seven, of the 
items have been completed.
correction
39
5.6
The population PK analysis is not part 
of the analyses described in this SAP. 
For Non-compartmental
PK analysis see section 5.6.2.
Pharmacokinetics of radium-223 dichloride will 
not be evaluated in this study; however, the PK 
of abiraterone will be investigated in 2 
subgroups.  In each subgroup, 40 subjects 
(approximately 20 per treatment arm) will be 
enrolled. 
Statistical analysis will be done only for 
Subgroup 1(Non-compartmental analysis).   The 
Subgroup 2 population PK analysis is not part of 
the analyses described in this SAP. Subgroup 2 
population PK analysis results will be presented 
in a separate report . For Non-compartmental PK 
analysis see section 5.6.2..  
To clarify


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Amendment 2 - Table of Changes in the SAP Amendment 2
Note: This SAP amendment 2 is mainly for clarifications and some minor corrections. Major changes in this SAP amendment have 
been summarized as follows.
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20
3.2
• Baseline albumin value;
• Baseline hemoglobin value;
• Baseline LDH value;
• Baseline ECOG performance status (0, 1);
• Baseline PSA value;
• Baseline total ALP value;
• Age.
• Baseline albumin value (< or ≥ median);
• Baseline hemoglobin value (< or ≥ median);
• Baseline LDH value (< or ≥ median);
• Baseline ECOG performance status (0, 1);
• Baseline PSA value (< or ≥ median);
• Baseline total ALP value (< or  ≥ 90 U/L);
• Age (<65, ≥65).
Pre-specify the cutoff 
values to be used for 
the baseline 
covariates in 
exploratory analysis
23
5.1.2

PSA and total ALP at randomization
Added a summary of 
baseline 
characteristics at 
randomization
24
5.1.1
In addition, the number of subjects 
screened, and included in each analysis 
population will be displayed by region, 
country and center. 
In addition, the number of subjects screened, 
screen failures, and included in each analysis 
population will be displayed by region, country 
and center. The screen failure reasons will be 
summarized by treatment group
Added a table for 
screen failure reasons.
24
5.1.4
Extent of exposure will be summarized for 
the ITT and safety populations by treatment 
group. 
Extent of exposure will be summarized for the 
safety populations by treatment group. 
ITT includes
randomized patients 
who are not treated, 
and extent of 
exposure does not 
apply to these patients
25
5.1.5
Prior, concomitant, and post treatment 
medications will be summarized using 
frequencies of subjects reporting each drug 
category and generic drug name.
Prior, concomitant, and post treatment 
medications including anti-cancer therapies will 
be summarized using frequencies of subjects 
reporting each drug category and generic drug 
Clarify


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name.
25
5.2.1
The primary efficacy endpoint is 
symptomatic skeletal event-free survival 
(SSE-FS). It is defined as the time from 
randomization to the occurrence of one of 
the following:
The primary efficacy endpoint is symptomatic 
skeletal event-free survival (SSE-FS). It is 
defined as the time from randomization to the 
earliest occurrence of  the following:
Clarify that the 
earliest date will be 
used
26
5.2.1
Table 2
No baseline or post-baseline SSE 
assessment
No post-baseline SSE assessment and no death.
Patients do not need 
baseline SSE 
assessment to have an 
SSE event
26
5.2.1
Table 2
Death before 1st SSE assessment during the 
study
Death without prior SSE (<13 weeks last SSE 
assessment and death)
Clarify
26
5.2.1
Table 2
Missing two or more SSE assessments 
(defined as ≥13 weeks between last SSE 
assessment and death ) before death
Death without prior SSE (≥13 weeks between 
last SSE assessment and death)
Clarify
26
5.2.1
Table 2
No SSE or Death at data cutoff or end of 
follow up
Neither SSE nor Death at data cutoff 
Clarify
27
5.2.1
Table 3
Same changes as Table 2
Clarify
27
5.2.1
In order to assess the impact of death censoring 
rule on the analysis of SSE-FS, a sensitivity 
analysis will be performed for SSE-FS by 
counting all deaths without prior SSE as SSE-
FS events.
Added a sensitivity 
analysis to evaluate 
the impact of 
censoring rules on 
SSE-FS


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29
5.2.2.1

analgesic diary which will be completed 
by subjects on each day that the BPI-SF 
“rate your worst pain experienced in the 
last 24 hours” question is asked.  In the 
analgesic diary, the subject will be 
asked to record the name, dosage and 
number of pills consumed in the last 24 
hours for pain relief.  

Opiate use case report form, in which the 
information of opiate pain medication since 
last assessment was collected.
Added one data 
source from Opiate 
Use page;
ePRO device data can 
not be used for 
analysis due to high
proportion of 
unkwown analgesic 
drug types 
29
5.2.2.1
For the time to first opiate use for cancer 
pain secondary endpoint, the date of the first 
opiate use recorded via any of the following 
three methods: the 24 hour analgesic 
consumption case report form, analgesic 
concomitant medication case report form or 
analgesic diary will be used.
For the time to first opiate use for cancer pain 
secondary endpoint, the earliest date of the first 
opiate use recorded via any of the following 
three methods: the 24 hour analgesic 
consumption case report form, analgesic 
concomitant medication case report form or 
opiate use case report form will be used.
Patients who had opiate analgesicsat baseline 
are not eligible for the analysis of this endpoint.
Same rationale as the 
previous one; Added 
a clarification 
sentence.
30
5.2.2.1
For both asymptomatic and mildly symptomatic 
patients, the opioid use component of this 
endpoint will be based on same source data for 
time to opiate use. For patients who took a weak 
opiate at baseline, the initiation of any strong 
opioid would be counted as pain progression; 
For patients who took a strong opioid at 
baseline, the initiation of an additional strong 
opioid would be counted as pain progression.
Added a clarification 
paragraph
30
5.2.2.1
Subjects who have not started cytotoxic 
chemotherapy during the study will be censored 
at last assessment date.  
Clarify


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32
5.2.2.1
Table 5
N/A
Subjects discontinued from study due to PD, but 
no documented date of PD
Clarified a few 
censoring rules
33
5.2.2.2
N/A
Sensitivity analysis will be performed for time 
to opiate use by only using the analgesic use 
data on the Opiate Use eCRF page. Similary 
sensivitiy analysis will be performed for time to 
pain progression using pain sore data and 
analgesic use data only based on the Opidate 
Use eCRF page.
The pain score change at week 12 will also be 
analyzed using an ANCOVA model with 
baseline pain socre and study treatment as 
covariates.
Added some 
sensitivity analyses
34
5.2.2.2.1
Added a figure for testing procedure for US 
submission to clarify the testing sequency
Clarify
34
5.2.2.2.1
OS will be considered for inclusion in the 
US label if the result is statistically 
significant at the 0.025 level (2-sided).
OS will be considered for inclusion in the US 
label if the result is statistically significant at the 
0.0015 level (2-sided) at the interim OS analysis 
with 275 deaths or at the 0.0245 level (2-sided) 
at the final OS analysis with 500 deaths. To 
maintain an overall 2-sided significance level of 
0.025, these levels will be adjusted based on the 
number of deaths observed at the interim OS 
analysis. 
Clarified the 
significance levels at 
each analysis for 
overall survival.
35
5.2.2.2.2
Added a figure for testing procedure for EU 
submission to clarify the testing sequency
Clarify


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38
5.2.3.2
Sensitivity analysis of Time to bone ALP 
progression will be performed by droping the 12 
week restriction in the definition.
Added a sensitivity 
analysis
38
5.2.3.2
To assess the potential bias due to missing data , 
FPSI-DRS-P data will also be analyzed using a 
pattern mixture model. Patients will be ranked 
based on the percentage of completed HRQoL 
assessments (where the numerator for a patient 
is the number of assessments and the 
denominator is the number of assessments that 
the patient should have had if the completed the 
questionnaire at every scheduled visit prior to 
their death or prior to leaving the study due to 
administrative censoring). The median value of 
the percentage of completed HRQoL assessment 
will be used to categorize patients into “patients 
with higher degree of missing data”  or “patients 
with lower degree of missing data”. An index 
variable for the two groups (0=  patient with a 
“high degree of missing data” and 1 = patient 
with a “lower degree of missing data”) will be 
created. A stratified Cox regression model will 
be used which contains the treatment variable, 
the index variable, and a term for the interaction 
between treatment and the index variable. The 
stratification factors for the Cox model will be 
the stratification factors used at randomization. 
If the interaction term is statistically significant, 
the analysis will indicate that there might be 
evidence of informative censoring.
Moved from previous 
section


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41
5.3.1
The same summaries will be repeated for 
related TEAES, serious TEAEs, serious 
related TEAEs, CTC Grade ≥3 TEAEs, 
TEAEs leading to discontinuation and 
TEAEs leading to death.
The same summaries will be repeated for related 
TEAES, serious TEAEs, serious related TEAEs, 
CTC Grade ≥3 TEAEs, CTC Grade 5 TEAEs, 
TEAEs leading to discontinuation and TEAEs 
leading to death.
Added CTC Grade 5 
TEAEs as a separate 
table
42
5.3.1
A data listing will be produced for all AEs. 
Verbatim descriptions and coded terms will 
be listed for all AEs.  
A data listing will be produced for all AEs, 
TEAEs leading to discontinuation and drug 
related TEAEs. Verbatim descriptions and 
coded terms will be listed for all AEs.  
Added some extra AE 
listings
42
5.3.2
A data listing of all deaths will be provided.
Added a death listing
42
5.5
Subgroup analyses will be conducted for the 
primary efficacy endpoint SSE-FS based on 
the ITT population. Descriptive statistics 
and hazard ratio estimates with 95% CI will 
be provided at least for the subgroups listed 
below, provided there is a sufficient number 
of events in total within the subgroup across 
the treatment arms.  
Subgroup analyses will be conducted for the 
primary efficacy endpoint SSE-FS, rPFS and 
OS based on the ITT population. Descriptive 
statistics and hazard ratio estimates with 95% CI
will be provided at least for the subgroups listed 
below, provided there is a sufficient number of 
events in total within the subgroup across the 
treatment arms.  
Added rPFS and OS 
for subgroup analysis
Amendment 3 - Table of Changes in the SAP Amendment 3
Note: This SAP amendment 3 is mainly focused on statistical testing procedure changes. Some minor corrections and clarifications 
are also included. Major changes in this SAP amendment have been summarized as follows.


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2.1.1 and 
2.2
Deleted
The two sections 
were copied from 
protocol amendment. 
No need to repeat it in 
the SAP.
8
2.2
This study is also powered (~60%) for the 
analysis of OS
This study is also powered (~70%) for the 
analysis of OS.  
Power increased due 
to more alpha is 
assigned to OS testing
8
2.2
If the final analysis of OS after 500 deaths 
reveals that the experimental treatment is 
statistically significantly better than 
treatment with control (p ≤ 0.0245), then the 
OS endpoint will be declared positive for 
the final analysis.
If the final analysis of OS after 500 deaths 
reveals that the experimental treatment is 
statistically significantly better than treatment 
with control (p ≤ 0.048), then the OS endpoint 
will be declared positive for the final analysis.
p-value threshold is 
updated due to more 
alpha assigned to OS 
testing
3.2
Baseline total ALP value (< or >=90 U/L)
Deleted
It was already 
mentioned earlier in 
the same section
3.4
If values are missing at the Baseline (Week 
0) visit,  data  recorded at  screening visit 
will be considered as baseline value. If 
screening record is also missing,  the 
baseline value will be left as missing.
Deleted
Baseline values will 
be defined in section 
3.6 (data rules)
9-10
3.5.1
If the analysis of OS after 275 deaths 
following treatment with radium-223 
dichloride plus abiraterone plus 
prednisone/prednisolone is statistically 
significantly better compared to control (p ≤ 
0.0015, based on O’Brien-Fleming alpha 
spending function (1, 2)), then OS will be 
declared positive for the interim analysis, 
assuming the final event number for OS is 
If the analysis of OS after 275 deaths following 
treatment with radium-223 dichloride plus 
abiraterone plus prednisone/prednisolone is 
statistically significantly better compared to 
control (p ≤ 0.005, based on O’Brien-Fleming 
alpha spending function (1, 2)), then OS will be 
declared positive for the interim analysis, 
assuming the final event number for OS is 500.
p-value threshold is 
updated due to more 
alpha assigned to OS 
testing


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500.
10
3.5.1
If the interim OS analysis is not statistically 
significant, the final  analysis for OS will be 
performed when approximately 500 deaths 
have occurred, corresponding to an 
approximately 60% power to detect a 25% 
improvement (in OS with Ra-223 Cl2
compared with placebo) with a two-sided 
alpha of 0.025.
If the interim OS analysis is not statistically 
significant, the final  analysis for OS will be 
performed when approximately 500 deaths have 
occurred, corresponding to an approximately 
70% power to detect a 25% improvement (in 
OS with Ra-223 Cl2 compared with placebo) 
with a two-sided alpha of 0.05.
Power increased due 
to more alpha is 
assigned to OS testing
11
3.6
The baseline for all efficacy endpoints is 
defined as the last non-missing assessment 
taken on or before the randomization date.
Unless otherwise specified, the baseline for all 
safety data, is the last non-missing assessment 
taken on or before first treatment date.
New texts added to 
clarify the definition 
of baseline for 
efficacy and safety 
endpoints.
3.7
The results of validity review meetings will 
be documented in the Validity Review 
Reports and may comprise decisions and 
details relevant for statistical evaluation. 
Any changes to the statistical analysis 
prompted by the results of the validity 
review meeting will be documented in an 
amendment and, if applicable, in a 
supplement to this SAP.
Deleted
Validity review 
meetings will not 
impact the patients in 
each analysis set 
defined in this SAP 
because there is no 
per-protocol set 
defined for this study.
4.1
Final decisions regarding the assignment of 
subjects to analysis sets will be made during 
the Validity Review Meetings and 
documented in the Validity Review Reports 
Deleted
Validity review 
meetings will not 
impact the patients in 
each analysis set 


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(see SAP Section 3.7).
defined in this SAP 
because there is no 
per-protocol set 
defined for this study.
15
5.2.1
SSE-FS analysis will be performed for the 
ITT population using a stratified log-rank 
test stratified by the three randomization 
strata
SSE-FS analysis will be performed for the ITT 
population using a stratified log-rank test 
stratified by the three randomization strata from 
IxRS
Clarified that the 
stratification data are 
from IxRS instead of 
eCRF pages.
16
5.2.1
Another sensitivity analysis will be done 
considering the initiation of systemic 
anticancer therapy
Another sensitivity analysis will be done by 
considering the initiation of systemic anticancer 
therapy or initiation/change of  bone targeted 
treatment as a SSE-FS event.
Added bone targeted 
treatment to align 
with the wording in 
the censoring rule in 
Table 2
5.2.2.1
For each visit, a patient will be assigned an 
AQA scale rating based on 24 hour 
analgesic consumption case report form.
Table 4 Analgesic Quantification 
Algorithm
deleted
AQA is not required 
for analysis in this 
study because 
patients are not 
allowed to take opiate 
analgesics at baseline
18
5.2.2.1
For patients who took a weak opiate at 
baseline, the initiation of any strong opioid 
would be counted as pain
progression; For patients who took a strong 
opioid at baseline, the initiation of an 
additional strong opioid would be counted 
as pain progression.
Patients who had opiate analgesics at baseline 
are not eligible for the analysis of this endpoint.
Patients who had 
opiate analgesics at 
baseline will be 
excluded from the 
analysis of Time to 
Pain Progression in 
order to be consistent 
with Time to Opiate 
use. The original 
method of handling 
these patients will be 
used as a sensitivity 


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analysis.
20
5.2.2.2
A two-sided type I error rate of 0.025 will 
be will be used for the analysis of each 
secondary endpoint.
A hierarchical testing procedure will be 
followed for the analysis of each secondary 
endpoint.
Statistical testing 
procedure has been 
updated.
21
5.2.2.2
Although patients who had opiate analgesics at 
baseline are excluded from the primary analysis 
of time to pain progression, they will be 
included in the analysis as a sensitivity analysis. 
For patients who took a weak opiate at baseline, 
the initiation of any strong opioid would be 
counted as pain progression; For patients who 
took a strong opioid at baseline, the initiation of 
an additional strong opioid would be counted as 
pain progression.
Sensitivity analysis will be conducted for rPFS 
without considering new systemic anti-cancer 
treatment received in the censoring rules.
Sensitivity analyses 
were added for the 
analysis of rPFS and 
Time to Pain 
Progression
21-22
5.2.2.2.1
All texts in sections 5.2.2.2.1 and 5.2.2.2.2
The overall type I error rate for the  primary 
endpoint and selected secondary endpoints will 
be controlled at 2-sided 0.05 or less using a 
hierarchical testing procedure as below: 
If the primary endpoint SSE-FS is statistically 
significant at the 0.05 level (2-sided), then a 
claim on the secondary endpoints will be made 
in the following order at the same 0.05 level (2-
sided):
-
rPFS
-
Time to pain progression 
Given the importance 
of the rPFS endpoint 
and higher hurdle for 
OS testing, it was 
considered that split 
alpha is not the most 
efficient testing 
procedure, hence a 
sequential testing is 
utilized for OS and 
other secondary 
endpoints. 


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-
Time to cytotoxic 
chemotherapy 
-
OS (interim)
If SSE-FS, rPFS, time to pain progression and 
time to cytotoxic chemotherapy are all 
statistically significant at the 0.05 level (2-
sided), the OS will be formally tested. OS will 
be considered for inclusion in the label if the 
result is statistically significant at the 0.005 
level (2-sided) at the interim OS analysis with 
275 deaths or at the 0.048 level (2-sided) at the 
final OS analysis with 500 deaths. To maintain 
an overall 2-sided significance level of 0.0-5, 
these levels will be adjusted based on the 
number of deaths observed at the interim OS 
analysis. 
Time to opiate use will not be formally tested 
but will be analyzed using the same approach as 
other secondary endpoints.
Time to opiate use 
was removed from 
the testing hierarchy 
because it is 
contained in TTPP 
and will be analyzed 
separately as a 
secondary endpoint.
25
5.2.3.2.1
For labeling purposes, analysis for time to 
increase in physical symptoms of disease 
based on the NCCN-FACT FPSI-17 
physical disease related symptoms (FPSI-
DRS-P) subscale score
measured during the treatment period will 
be included in the multiplicity adjustment 
for this study. This exploratory endpoint 
will be tested at a two-sided alpha level of 
0.05 if all primary and secondary efficacy 
endpoints have statistically significant 
For labeling purposes, analysis for time to 
increase in physical symptoms of disease based 
on the NCCN-FACT FPSI-17 physical disease 
related symptoms (FPSI-DRS-P) subscale score 
measured during the treatment period will be 
included in the multiplicity adjustment for this 
study. This exploratory endpoint will be tested 
at a two-sided alpha level of 0.05 if the primary 
endpoint and the selected secondary efficacy 
endpoints specified in section 5.2.2.2.1 all have 
statistically significant results based on the 
The testing sequence 
was updated based on 
the new statistical 
testing procedure


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results based on the preplanned method for 
alpha adjustment
preplanned method for alpha adjustment.
26
5.3.1
The treatment period for this study extends 
from the initiation of treatment until 4 
weeks after the last administration of 
abiraterone as IMP and 
prednisone/prednisolone or 6 months after 
last administration of radium-223/placebo, 
whichever occurs later.
The treatment period for this study extends from 
the initiation of treatment until 4 weeks after the 
last administration of abiraterone as IMP and 
prednisone/prednisolone or 6 months after last 
administration of radium-223/placebo, 
whichever occurs later unless a new systemic 
anti-cancer therapy is initiated. If a new anti-
cancer therapy is initiated before the end of the 
period defined above, the treatment period 
extends from the initiation of treatment until 4 
weeks after the start date of the new anti-cancer 
therapy.
Treatment period was 
updated based on the 
latest protocol 
amendment
30
5.5

Baseline LDH by median

Baseline tumor location (bone only vs. 
others)
New subgroup 
variables were added
Amendment 4 - Table of Changes in the SAP Amendment 4
Note: This SAP amendment 4 is primarily focused on addressing FDA’s comment on the statistical testing procedure in the 
submitted SAP Amendment 3. The changes have been summarized as follows.
SAP 
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9
2.2
This study is also powered (~70%) for the 
analysis of OS. For the concluding analysis 
of OS, 500 deaths are projected to occur by 
approximately 71.4 months after the first 
subject is randomized, assuming the median 
This study is also powered (~70%) for the 
analysis of OS if OS is tested at a 0.05 level (2-
sided)  For the concluding analysis of OS, 500 
deaths are projected to occur by approximately 
71.4 months after the first subject is 
Due to the changes in 
the statistical testing 
procedure, the power 
and p-value boundary 
for OS analysis are 


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OS for the control arm is 35.3 months and a 
25% improvement for the radium-223 
dichloride arm.  If the final analysis of OS 
after 500 deaths reveals that the 
experimental treatment is statistically 
significantly better than treatment with 
control (two-sided p≤0.048), then the OS 
endpoint will be declared positive for the 
final analysis.
randomized, assuming the median OS for the 
control arm is 35.3 months and a 25% 
improvement for the radium-223 dichloride 
arm.  If the final analysis of OS after 500 deaths 
reveals that the experimental treatment is 
statistically significantly better than treatment 
with control , then the OS endpoint will be 
declared positive for the final analysis.
dependent on the 
analysis results of the 
secondary endpoints. 
10
3.2
A step-wise selection method will be used to 
choose the final statistical model with entry 
alpha level 0.1 and exit alpha level 0.1. The 
stratification factors are always included as 
covariates in the final model. If deemed 
necessary, additional variables may also be 
added in the model selection process. 
To clarify how to 
select the final 
statistical model in 
this exploratory 
analysis.
11
3.5.1
If the analysis of OS after 275 deaths 
following treatment with radium-223 
dichloride plus abiraterone plus 
prednisone/prednisolone is statistically 
significantly better compared to control 
(two-sided p ≤ 0.005, based on O’Brien-
Fleming alpha spending function (1, 2)), 
then OS will be declared positive for the 
interim analysis, assuming the final event 
number for OS is 500. The actual nominal 
alpha levels will be calculated based on the 
actual number of events accrued at the OS 
interim analysis. If the interim OS analysis 
is not statistically significant, the final  
analysis for OS will be performed when 
If SSE-FS is statistically significant at the 0.05 
level (2-sided) and rPFS, time to pain 
progression and time to cytotoxic chemoterhapy 
are all statistically significant at the 0.049 level 
(2-sided), then the OS will be formally tested at 
an overall alpha=0.05 (2-sided). If the analysis 
of OS after 275 deaths following treatment with 
radium-223 dichloride plus abiraterone plus 
prednisone/prednisolone is statistically 
significantly better compared to control (two-
sided p ≤ 0.005, based on O’Brien-Fleming 
alpha spending function (1, 2)), then OS will be 
declared positive for the interim analysis, 
assuming the final event number for OS is 
500. The actual nominal alpha levels will be 
The testing strategy 
of OS is changed 
based on the new 
testing procedure 
described in section 
5.2.2.2.1


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approximately 500 deaths have occurred, 
corresponding to an approximately 70% 
power to detect a 25% improvement (in OS 
with Ra-223 Cl2 compared with placebo) 
with a two-sided alpha of 0.05.
calculated based on the actual number of events 
accrued at the OS interim analysis. If the interim 
OS analysis is not statistically significant, the 
final  analysis for OS will be performed when 
approximately 500 deaths have occurred, 
corresponding to an approximately 70% power 
to detect a 25% improvement (in OS with 
Ra-223 Cl2 compared with placebo) with a two-
sided alpha of 0.05.
If at least one of the secondary endpoints, rPFS, 
time to pain progression or time to cytotoxic 
chemotherapy, is not statistically significant at 
the 0.049 level (2-sided), then the OS will be 
formally tested at an overall alpha=0.001 (2-
sided). Refer to scenario 2 in section 5.2.2.2.1 
for details.
22
5.2.2.2.1
To address FDA’s 
comment on the 
statistical testing 
procedure in SAP 
amendment 3, the 
alpha level will be 
split between OS 
(alpha=0.001) and the 
secondary endpoints 
rPFS, TtPP and TtCC 
(alpha=0.049) when 
the SSE-FS is 
statistically 
significant at the 0.05 
level (2-sided). 


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31
5.5

Received prior Antiandrogens 
including enzalutamide (Yes vs. 
No)

Received prior Antiandrogens  
(enzalutamide vs. first generation 
Antiandrogens vs. none)
Since enzalutamide is 
expected to have 
more impact on 
efficacy analysis than 
other antiandrogens, 
it was separated from 
other antiandrogens 
in subgroup analysis


Supplement Statistical Analysis Plan
BAY 88-8223/15396
Page: 1 of 7:
Reference Number: RD-OI-0119
Supplement Version: 9.0
Title page
A phase III randomized, double-blind, placebo-controlled trial of 
radium-223 dichloride in combination with abiraterone acetate and 
prednisone/prednisolone in the treatment of asymptomatic or mildly 
symptomatic chemotherapy-naïve subjects with bone predominant 
metastatic castration-resistant prostate cancer (CRPC)  
Short title: Evaluation of Radium-223 dichloride in combination with Abiraterone in 
CRPC - ERA 223
Bayer study drug
BAY no. 88-8223 / Radium-223 dichloride / Xofigo
[Study purpose:]
To compare the symptomatic skeletal event-free survival of subjects 
with asymptomatic or mildly symptomatic chemotherapy-naïve bone 
predominant metastatic castration-resistant prostate cancer (CRPC) 
treated with radium-223 dichloride or placebo, in combination with 
abiraterone and prednisone/prednisolone
Clinical study 
phase:
III
Date:
15 October 2018
Study No.:
BAY 88-8223 / 
15396
Version:
1.0
Author:
Confidential
The information provided in this document is strictly confidential and is intended solely 
for the guidance of the clinical investigation.  Reproduction or disclosure of this 
document, whether in part or in full, to parties not associated with the clinical 
investigation or its use for any other purpose without the prior written consent of the 
sponsor is not permitted.
Throughout this document, symbols indicating proprietary names (®, TM) are not displayed.  Hence, the 
appearance of product names without these symbols does not imply that these names are not protected.
This Statistical Analysis Plan is produced on a word-processing system and bears no signatures.
The approval of the Statistical Analysis Plan is documented in a separate Signature Document.
PPD


Statistical Analysis Plan
Protocol No.: < BAY No./Impact No.>
Page: 2 of 7:
Reference Number: RD-OI-0119
Supplement Version: 9.0
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 2
1.
Introduction....................................................................................................................... 3
2.
Study Objectives................................................................................................................ 3
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 4
5.
Analysis Sets ...................................................................................................................... 4
6.
Statistical Methodology .................................................................................................... 4
6.1
Changes in the Definition of Prior and Concomitant Medications.................................. 4
6.2
Efficacy............................................................................................................................ 5
6.2.1
Change in Sensitivity Analyses and Exploratory Analyses for Primary Efficacy 
Endpoint ....................................................................................................................... 5
6.2.2
Changes in Sensitivity Analyses for Secondary Efficacy Endpoints ........................... 5
6.2.3
Changes in Sensitivity Analyses for Exploratory Efficacy Endpoint........................... 6
6.2.4
Changes in Examination of Subgroups ........................................................................ 6
6.3
Exploratory variables and analyses.................................................................................. 6
6.4
Pharmacokinetics............................................................................................................. 7
6.4.1
Changes in Planned PK Analyses................................................................................. 7
6.5
Safety ............................................................................................................................... 7
6.5.1
Adverse Events............................................................................................................. 7
7.
Document history and changes in the planned statistical analysis............................... 7
8.
References .......................................................................................................................... 7
Abbreviations
All abbreviations that are used in the SAP must be defined in this section.
The following is an example of commonly used abbreviations:
AE
Adverse Event
CI
Confidence Interval
CSR
Clinical Study Report
OS
Overall Survival
rPFS
Radiological Progression-free Survival
SSE-FS
Symptomatic Skeletal Event-free Survival
SAP
Statistical Analysis Plan


Statistical Analysis Plan
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Reference Number: RD-OI-0119
Supplement Version: 9.0
1.
Introduction
This Supplemental Statistical Analysis Plan (SAP) describes analyses that were not included 
in the main SAP but may be used for CSR. Changes to planned analyses in the SAP v5.0 are 
also described in this Supplemental SAP.
This Supplemental SAP version 1.0 is a supplement of SAP version 5.0 dated 10th July 2017.  
2.
Study Objectives
The primary objective is to compare, in subjects with asymptomatic or mildly symptomatic 
chemotherapy-naïve bone predominant metastatic CRPC, the clinical benefit of radium-223 
dichloride versus placebo in combination with abiraterone and prednisone/prednisolone, with 
the primary efficacy endpoint being:

Symptomatic skeletal event-free survival (SSE-FS)
.
The secondary objectives of this study are:

OS

Time to opiate use for cancer pain

Time to pain progression

Time to cytotoxic chemotherapy

rPFS

Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy
The exploratory objectives of this study are:

Time to first on-study SSE

Percentage change in total ALP from baseline

Time to ALP progression

Time to PSA progression

ALP response

PSA response

Bone scan-specific rPFS

Time to increase in physical symptoms of disease based on the NCCN-FACT FPSI-17 
physical disease related symptoms (FPSI-DRS-P) subscale score measured during the 
treatment period

Time to increase in physical symptoms of disease based on the NCCN-FACT FPSI-17 
physical disease related symptoms (FPSI-DRS-P) subscale score measured during 
period between start of treatment and end of active follow-up with clinic visits


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
Assessment of pharmacokinetics (PK) of abiraterone 

Resource utilization

Biomarker assessments

An additional explorative objective is to evaluate the impact of baseline total body 
weight (TBW) and ideal body weight (IBW) on SSE-FS and adverse events.
3.
Study Design
Refer to the main SAP v5.0 dated 10th July 2017.
4.
General Statistical Considerations
Refer to the main SAP v5.0 dated 10th July 2017.
5.
Analysis Sets
Refer to the main SAP v5.0 dated 10th July 2017.
6.
Statistical Methodology
Refer to the main SAP v5.0 dated 10th July 2017.
6.1
Changes in the Definition of Prior and Concomitant Medications
Non-study medications taken before and/or during the study will be categorized as prior 
medications, concomitant medications, and post treatment medications. Two modifications 
will be made for the definition. 
The definition of concomitant medications will be updated for the scenarios below:
Old definition: 
Non-study medications that started prior to the first dose of study
treatment and are ongoing during the treatment period;
New Definition:
Non-study medications that started prior to the first dose of study
treatment and are ongoing after the start of study treatment;
The definition of post-treatment medications will be updated as  below:


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Old definition:  Post treatment medications are defined as non-study medications 
taken after the treatment period.
New definition: Post treatment medications are defined as non-study medications 
taken after the last dose of study treatment. 
Detailed classifications of prior/concomitant/post treatment medication are also illustrated in 
Table 6–1:
Table 6–1 Medication Classification
Prior to 
study 
drug
Study 
drug 
started
Treatment 
with study 
drug
Study 
drug 
stopped
Follow 
up
Prior 
Medication?
Concomitant 
Medication?
Post-treatment 
Medication?
C1
Yes
No
No
C2
Yes
Yes
No
C3
No
Yes
Yes
C4
Yes
Yes
Yes
C5
No
No
Yes 
C6
No
Yes 
No 
C7
No
Yes 
No 
C8
No
Yes 
No 
C1= medication started before study drug administration and ended on or before study drug administration
C2= medication started before study drug administration and ended during study drug administration 
C3= medication started on or after study drug administration and ended after study drug administration
C4= medication started before study drug administration and ended after study drug administration 
C5= medication started on or after study drug administration and ended after study drug administration
C6= medication started on or after study drug administration and ended before or on the same date as end of study drug administration
Note: C7and C8 are covered under C6.
6.2
Efficacy
6.2.1
Change in Sensitivity Analyses and Exploratory Analyses for Primary 
Efficacy Endpoint 
The planned sensitivity analyses and exploratory analyses for SSE-FS in the main SAP v5.0 
will not be performed because the primary endpoint was not met.
6.2.2
Changes in Sensitivity Analyses for Secondary Efficacy Endpoints
The sensitivity analysis for time to pain progression by including the subjects with opiate use 
at baseline will not be performed. 


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6.2.3
Changes in Sensitivity Analyses for Exploratory Efficacy Endpoint 
The pattern mixture model for analyzing FPSI-DRS-P data will not be performed. CMH test 
for comparing treatment difference will not be performed for the ALP and PSA response.
6.2.4
Changes in Examination of Subgroups
The list used for subgroup analyses for SSE-FS, rPFS and OS were updated and provided as 
below: 

ECOG performance status at baseline (0 vs 1)

Extent of Disease (number of bone lesions <6 vs. 6-20 vs. >20 but not superscan vs. 
superscan at baseline)

Asymptomatic vs mildly symptomatic 

Race (collected as Caucasian, Hispanic, Black, Asian and Other)

Ethnicity(collected as Hispanic or Latino, not Hispanic or Latino, not reported)

Randomization stratification factors(IxRS data):
o
geographical regions (Western Europe/North America/Australia vs. Asia vs. 
rest of world) 
o
concurrent use of denosumab or bisphosphonates (combined strata) (Yes vs. 
No)
o
total ALP < 90 U/L versus total ALP ≥ 90 U/L.

US vs. EU vs. rest of the world

CRF data: concurrent use of denosumab or bisphosphonates(Y/N)

CRF data: concurrent use of biophosonates (Y/N)

CRF data:  concurrent use of denosumab (Y/N)

BMI < 30 and >=30

Gleason Score at the time of diagnosis (<8, >=8, Missing)

Baseline PSA values by median

Received prior Antiandrogens including enzalutamide(Y/N)

Baseline LDH by median

Baseline tumor location (bone only vs. bone with soft tissues or others)

Prior use of enzalutamide(Y/N)

Piro chemotherapy(<=1 regimen vs. >1 regimen)

Baseline hemoglobin by median

Prior skeletal related event(SRE)(Y/N)

Baseline renal impaired(Normal GFR vs mild decrease in GFR vs. moderate decrease 
in GFR)
6.3
Exploratory variables and analyses
Refer to the main SAP v5.0 dated 17 NOV 2017.


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6.4
Pharmacokinetics
6.4.1
Changes in Planned PK Analyses
The planned summary statistics for concentration and PK parameters of abiraterone by 
treatment will not be performed due to very small number of samples collected. 
6.5
Safety
Refer to the main SAP v5.0 dated 10th July 2017.
6.5.1
Adverse Events
Additional analyses of Adverse Events of Special Interest
Time to fracture is defined as the time (months) from the first dose date to the date of first 
fracture. Subjects without fractures are censored at last visit date during the treatment period. 
Time to fracture will be summarized using Kaplan-Meier estimates.  Median survival time 
together with the 25th and 75th percentiles and associated 95%  Brookmeyer-Crowley 
confidence intervals (CI) will be presented by treatment arm.  Corresponding Kaplan-Meier 
curves will be generated by treatment arm.   
The summary statistics will be also be provided for first fracture occurred after treatment 
started by including:

Timing of first fracture(<6 months, 6-12 months, 12-24 months and >=24 months)

Number of subjects with at least one fracture

Number of subjects with first fracture after last study treatment date

Number of subjects with first fracture before or on last study treatment date

Number of subjects with first fracture before or on last xofigo dose date

Patients who had a fall or dizziness within 7 days before or on the date of fracture

Number of fractures considered as serious AE
7.
Document history and changes in the planned statistical analysis
-
Main SAP v5.0 dated 10th July 2017.
8.
References
Refer to the main SAP v5.0 dated 10th July 2017.