Clinical trial NCT02023697
Conditions: Prostatic Neoplasms
Sponsor: Bayer
Start date: 2014-03-10; Completion date: 2018-08-09
Enrollment: 391 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess different doses and regimens of radium-223 dichloride on the incidence of symptomatic skeletal events. Eligible subjects must have castration resistant prostate cancer with 2 or more skeletal metastases documented within 8 weeks of randomization. Subjects will be randomized to one of 3 treatment arms in a 1:1:1 fashion: a standard regimen of radium-223 dichloride of 50 kBq/kg (55 kBq/kg after implementation of NIST update) injections every month for 6 months, a high dose regimen of 80 kBq/kg (88 kBq/kg after implementation of NIST update)injections every month for 6 months or an extended duration regimen of 50 kBq/kg (55 kBq/kg after implementation of NIST update) injections every month for 12 months. Following the treatment phase, subjects will be followed up every 12 weeks for a minimum of 2 years, at which point they will enter a long term follow-up period during which they are seen every 6 months for up to 7 years after the last dose of radium dichloride. Symptomatic skeletal event and safety endpoints will be assessed at each clinic visit. Pain and analgesic use data will be collected every 4 weeks through Week 48. Additionally, radiological assessments including MRI/CT of the abdomen and pelvis and chest CT, as well as technetium-99 bone scans will be performed at Weeks 8, 16, and 24 and continue every 12 weeks thereafter until disease progression is documented in either the bone or in soft tissue. Radiological imaging will be evaluated by blinded central review.

Detailed description:

Arms: arm 1: One injection to be administered every 4 weeks up to 6 injections. The dose per injection is 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update). arm 2: One injection to be administered every 4 weeks up to 6 injections. The dose per injection is 80 kBq/kg body weight (88 kBq/kg after implementation of NIST update). arm 3: One injection to be administered every 4 weeks up to 12 injections. The dose per injection is 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update).
Interventions: intervention 1: Radium-223 dichloride (Xofigo, BAY88-8223)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_002.pdf: 
 
Document Type: 
Study Protocol 
Official Title: 
A three arm randomized, open-label Phase II study of radium-223 
dichloride 50 kBq/kg (55 kBq/kg after implementation of National 
Institute of Standards and Technology [NIST] update) versus 80 
kBq/kg (88 kBq/kg after implementation of new NIST update and 
versus 50 kBq/kg (55 kBq/kg after implementation of NIST update) 
in an extended dosing schedule in subjects with castration-resistant 
prostate cancer metastatic to the bone 
NCT Number: 
NCT02023697 
Document Date: 
28 MAR 2018 
 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 1 of 291
Cover page for the integrated clinical study protocol
A three arm randomized, open-label Phase II study of radium-223 dichloride 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) versus 80 kBq/kg (88 kBq/kg after 
implementation of NIST update), and versus 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) in an extended dosing schedule in subjects with 
castration-resistant prostate cancer metastatic to the bone
For this study, the protocol and subsequent protocol amendment were released as follows:

Original protocol, Version 1.0, dated 09 AUG 2013

Amendment 1 (global amendment described in Section 13.1) forming integrated 
protocol Version 2.0, dated 19 NOV 2013

Amendment 2 (global amendment described in Section 13.2) forming integrated 
protocol Version 3.0, dated 13 AUG 2015

Amendment 3 (global amendment described in Section 13.3) forming integrated 
protocol Version 4.0, dated 16 MAY 2017

Amendment 4 (global amendment described in Section 13.4) forming integrated 
protocol Version 5.0, dated 28 MAR 2018
This document integrates the original protocol and all global amendments.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 2 of 291
Title page
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 
4 (Section 13.4.1.4).
A three arm randomized, open-label Phase II study of radium-223 dichloride 
50 kBq/kg (55 kBq/kg after implementation of NIST update) versus 80 kBq/kg
(88 kBq/kg after implementation of NIST update), and versus 50 kBq/kg (55 kBq/kg 
after implementation of NIST update) in an extended dosing schedule in subjects with 
castration-resistant prostate cancer metastatic to the bone
Standard dose versus high dose and versus extended standard dose radium-223 dichloride in
castration-resistant prostate cancer metastatic to the bone
Test drug:
BAY 88-8223 / Radium-223 dichloride
Study purpose:
Efficacy, dose finding
Clinical study phase:
II
Date:
28 MAR 2018
EudraCT no.:
2013-003118-42
Version no.: 5.0
Study no.:
16507
Sponsor:
(Non US):  Bayer AG, D-51368 Leverkusen, Germany
(US territory): Bayer HealthCare Pharmaceuticals Inc., 100 
Bayer Boulevard, P.O. Box 915, Whippany, NJ 07981-0915, 
USA
Sponsor’s medical expert:
Rua Cancioneiro de Evora, 255
Building E1, 1st floor
04708-010 São Paulo – SP Brazil
Phone: 
The study will be conducted in compliance with the protocol, ICH-GCP 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


28 MAR2018 
Integrated Clinical Study Protocol 
No. 16507 
Version 5.0 
Page: 3 of291 
Signature of the sponsor's medically responsible person 
The responsible person changed by Amendments 2, 3 and 4. 
The signatory agrees to the content of the final clinical study protocol as presented. 
Name: 
Date: _J J_ 
-=2o ( 
Role: 
Global Clinical Leader, 
PPD
PPD
PPD


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 4 of 291
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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 5 of 291
Synopsis
Title
A three arm randomized, open-label Phase II study of radium-223 dichloride 
50 kBq/kg (55 kBq/kg after implementation of National Institute of Standards 
and Technology [NIST] update) versus 80 kBq/kg (88 kBq/kg after 
implementation of new NIST update and versus 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) in an extended dosing schedule in subjects 
with castration-resistant prostate cancer metastatic to the bone
Title modified by Amendments 1 and 2.
Short title
Standard dose versus high dose and versus extended standard dose radium-223 
dichloride in castration-resistant prostate cancer metastatic to the bone
Clinical study phase
Phase II
Study objectives
The following objectives will be used to compare radium-223 dichloride 
50 kBq/kg (55 kBq/kg after implementation of NIST update) every 28 days for 
up to 6 doses with radium-223 dichloride 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) every 28 days for up to 6 doses in radium-223
dichloride-naïve subjects; and in subjects receiving radium-223 dichloride 
50 kBq/kg (55 kBq/kg after implementation of NIST standard implementation
update) every 28 days up to 6 doses, to compare a regimen of up to a further 
6 doses of radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation 
of NIST update) every 28 days with no further radium-223 dichloride 
treatment.
Co-primary objectives:

To evaluate efficacy as measured by symptomatic skeletal event-free 
survival (SSE-FS) of radium-223 dichloride 50 kBq/kg (55 kBq/kg 
after implementation of NIST update) every 28 days for up to 6 doses 
compared to radium-223 dichloride 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) every 28 days for up to 6 doses in 
subjects with castration-resistant prostate cancer (CRPC) metastatic to 
the bone not previously receiving radium-223 dichloride; and

To evaluate efficacy as measured by SSE-FS of radium-223 
dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST 
update) every 28 days for up to 6 additional doses compared to no 
further radium-223 dichloride treatment in subjects with CRPC 
metastatic to the bone who previously received radium-223 dichloride 
50 kBq/kg (55 kBq/kg after implementation of NIST update) every 
28 days for up to 6 doses, and survived SSE free and are eligible for 
further radium-223 dichloride treatment
Symptomatic skeletal events (SSEs) are defined as:
o
The use of external beam radiotherapy (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


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 6 of 291
Secondary objectives: 

To evaluate safety and tolerability

To evaluate overall survival (OS)

To evaluate pain improvement rate

To evaluate time to pain progression

To evaluate time to first SSE

To evaluate time to radiological progression

To evaluate radiological progression-free survival (rPFS)
Exploratory objectives:

To evaluate quantitated whole body technetium-99 bone scan tumor 
burden area and index, and determine bone tumor response

To explore the impact of subject body size on the efficacy and safety 
of radium-223 dichloride

Time to increase in physical symptoms of disease based on the 
National Comprehensive Cancer Network (NCCN) FACT-P 
Symptom Index-17 (NCCN-FACT FPSI-17) physical disease related 
symptoms subscale score measured up to Week 48 after the start of 
treatment

To evaluate laboratory indicators of efficacy, including:
o
Prostate specific antigen (PSA) response 
o
Time to PSA progression
o
Alkaline phosphatase (ALP) response
o
Time to ALP progression
o
Percentage change in ALP from baseline

To evaluate change in analgesic use as measured by the Analgesic 
Quantification Algorithm (AQA)
Study objectives modified by Amendments 1, 2, and 3. 
Test drug
BAY 88-8223
Name of active ingredient
Radium-223 dichloride
Doses
50 kBq/kg (55 kBq/kg after implementation of NIST update) every 28 days for 
up to 6 doses (Treatment Arm A), 80 kBq/kg (88 kBq/kg after implementation 
of NIST update) every 28 days for up to 6 doses (Treatment Arm B), or 
50 kBq/kg (55 kBq/kg after implementation of NIST update) every 28 days for 
up to 12 doses (Treatment Arm C)
Doses modified by Amendment 2.
Route of administration
Intravenous (IV) injection (slow bolus)
Duration of treatment
Maximum of 6 doses at 28-day intervals (24 weeks) in Treatment Arms A and 
B; maximum of 12 doses at 28-day intervals (48 weeks) in Treatment Arm C


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 7 of 291
Background treatment / 
concomitant medications / 
prohibited therapies
Concomitant best standard of care (BSoC) is permitted according to local 
clinical practice.  Allowed concomitant treatments for prostate cancer include: 
luteinizing-hormone-releasing hormone (LHRH) analogs, surgery, radiation 
therapy, flutamide, bicalutamide, nilutamide, cyproterone acetate, 
ketoconazole, corticosteroids, estrogens, and enzalutamide. Radium-223 
dichloride should not be given concurrently with abiraterone plus
prednisone/prednisolone.
Subjects who have not undergone bilateral orchiectomy are to receive LHRH 
agonists or antagonists or polyestradiol phosphate throughout the study.  
Subjects receiving bone health agents (BHA), such as bisphosphonates or 
denosumab, prior to receiving study drug treatment may be maintained on 
these therapies throughout all or part of the treatment period. Subjects in the 
treatment period can also initiate these therapies at any time. Based on the 
available data on radium-223 dichloride, the option of starting a BHA during 
the follow-up periods should be considered taking into consideration 
applicable guidelines. Treatment with bisphosphonates or denosumab may be 
stopped at the discretion of the investigator.
Cytotoxic chemotherapy, including taxanes, estramustine, and mitoxantrone,
for prostate cancer, other systemic radioisotopes, concomitant hemibody 
EBRT, or other investigational drugs may not be used during the treatment 
period.  If prohibited therapy is considered appropriate BSoC for a subject 
during the treatment period, further radium-223 dichloride administrations 
must be discontinued, and if possible, prohibited treatment should not be given 
until following the end of treatment (EOT) visit, defined as 30 days after the 
last injection of radium-223 dichloride.
Background treatment, concomitant medications, and prohibited therapies 
modified by Amendments 2 and 4.
Indication
For the treatment of subjects with CRPC who have bone metastases
Diagnosis and main criteria for 
inclusion
Eligible subjects must meet all of the inclusion criteria and none of the 
exclusion criteria listed below.
The main criteria for inclusion are:

Histologically or cytologically confirmed adenocarcinoma of the 
prostate

Castration-resistant disease defined as:
a.
Serum testosterone level: ≤50 ng/dL (1.7 nmol/L)
b.
Bilateral orchiectomy or maintenance on androgen ablation 
therapy with LHRH agonist or antagonist,* or polyestradiol 
phosphate
c.
Serum PSA progression defined as 2 subsequent increases in 
PSA over a previous reference value, with a PSA value of 
≥2 ng/mL at the time of the second increase OR
Radiographic evidence of disease progression in bone 
(according to Prostate Cancer Clinical Trials Working 
Group 2 [PCWG2] criteria) with or without PSA progression
*In subjects who were treated with combined androgen blockade (a 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 8 of 291
growth-hormone-releasing hormone analog or orchiectomy in 
combination with continuous anti-androgen) as initial therapy for a 
prolonged period of time, or who have responded to adding a 
peripheral anti-androgen as second line therapy, progressive disease 
should be documented after discontinuing anti-androgen treatment 
(for at least 6 weeks for bicalutamide and at least 4 weeks for 
flutamide and others) to exclude an anti-androgen withdrawal 
response.

Subjects must be ≥18 years of age.

Eastern Cooperative Oncology Group performance status (ECOG PS) 
0 to 2. In case of ECOG PS 2, the PS must be due to metastatic 
prostate cancer to the bone.

Life expectancy ≥6 months

Two or more skeletal metastases (≥2 hot spots) on bone scintigraphy 
within 8 weeks of randomization

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) without 
transfusion or erythropoietin support within 4 weeks prior to 
screening
d.
Total bilirubin level ≤1.5 x institutional upper limit of 
normal (ULN) (< 3 x ULN for subjects with documented
Gilbert’s syndrome)
e.
Aspartate transaminase and alanine transaminase 
2.5 x ULN
f.
Creatinine ≤1.5 x ULN
g.
Estimated glomerular filtration rate ≥30 mL/min/1.73 m2
according to either the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) creatinine equation 
or the Modification of Diet in Renal Disease abbreviated 
formula
h.
Albumin > 25 g/L

Written, signed informed consent.  Subject must be able to understand 
and be willing to sign the written informed consent form (ICF).  A 
signed ICF must be appropriately obtained prior to the conduct of any 
study-specific procedure.

Sexually active males agree to use condoms and/or their female 
partners of reproductive potential to use a method of effective birth 
control during treatment and for 6 months following the completion 
of treatment with radium-223 dichloride.
The main criteria for exclusion are:

History of visceral metastasis, or visceral metastases as assessed by 
computed tomography (CT) / magnetic resonance imaging (MRI) of 
the abdomen and pelvis and / or chest X-ray (in the presence of 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 9 of 291
suspicious lesion[s], a chest CT scan will be performed to confirm 
and characterize the lesion[s]) within the previous 8 weeks of 
randomization

Lymphadenopathy with lymph nodes exceeding 3 cm in short axis 
diameter

Current central nervous system (CNS) metastases.  Subjects with 
neurological symptoms suggestive of CNS metastasis must undergo 
contrast CT scan or MRI of the CNS within 30 days of the start of 
treatment to exclude CNS metastasis.  Imaging of the CNS is 
otherwise not required.

Chronic conditions associated with non-malignant abnormal bone 
growth (e.g., confirmed Paget’s disease of bone)

Blood transfusions or use of erythropoietin within 4 weeks prior to 
screening, during screening, or prior to the start of treatment 

Treatment with an investigational drug within the 4 weeks prior to 
randomization

Treatment with cytotoxic chemotherapy for prostate cancer, including 
taxanes, estramustine, and mitoxantrone, within the previous 4 weeks 
prior to randomization, or planned treatment with these prohibited 
cytotoxic chemotherapy agents for prostate cancer during the 
treatment period or follow-up

Prior treatment with radium-223 dichloride

Prior systemic radiotherapy with strontium-89, samarium-153, 
rhenium-186, or rhenium-188

Prior hemibody EBRT

Use of biologic response modifiers, such as granulocyte macrophage 
colony-stimulating factor or granulocyte colony-stimulating factor, 
within 4 weeks prior to screening

Other malignancy treated within the last 3 years (except treated 
non-melanoma skin cancer or low-grade superficial bladder cancer)

Imminent or established untreated spinal cord compression based on 
clinical findings and / or MRI. Following treatment of spinal cord 
compression, the subject may be eligible if all other eligibility criteria 
are fulfilled.

Any other serious illness or medical condition such as, but not limited 
to:
a.
Any uncontrolled infection
b.
Cardiac failure New York Heart Association Class III or IV
c.
Crohn’s disease or ulcerative colitis
d.
Bone marrow dysplasia
e.
Unmanageable fecal incontinence

Previous assignment to treatment in this study
Main criteria for inclusion modified by Amendments 1 and 2.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 10 of 291
Main criteria for exclusion modified by Amendments 1 and 2.
Study design
International, multicenter, randomized, open-label Phase II study
Methodology
Subjects enrolled into the study will be randomized to one of the 3 treatment 
arms in 1:1:1 fashion: radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) IV every 28 days for up to 6 doses
(Treatment Arm A) or radium-223 dichloride 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) IV every 28 days for up to 6 doses
(Treatment Arm B) or radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) IV every 28 days for up to 12 doses
(Treatment Arm C).
The randomization will be permuted-block, stratified by use of prior 
chemotherapy (≤1 regimen versus > 1 regimen), by total ALP (< 220 U/L 
versus ≥220 U/L), and by average worst pain score (WPS) of the Brief Pain 
Inventory Short Form (BPI-SF) (WPS ≤4 versus WPS > 4).
The treatment period for efficacy purposes begins at the time of 
randomization.  During the treatment period, study medication is administered 
every 28 days (± 7 days) from Dose 1 and may be delivered in an outpatient
setting.  At each visit, prior to receiving radium-223 dichloride, the subject will 
be evaluated for adverse events (AEs) and laboratory abnormalities to 
determine whether it is safe to continue treatment.
Symptomatic skeletal events will be assessed every 28 days through the latter 
of Week 24 or the EOT visit (Week 24 for Treatment Arms A and B, and 
Week 48 for Treatment Arm C) and every 12 weeks thereafter, until an SSE is 
experienced.  Subjects in Treatment Arms A and B who have not experienced 
an SSE will be contacted by telephone at Weeks 28, 32, 40, and 44, evaluated 
for SSE risk, and encouraged to come to the clinic if a risk is identified.
Radiological assessment, including whole body technetium-99 bone scan,
MRI / CT scan of the abdomen and pelvis, and chest X-ray (in the presence of 
suspicious lesion[s], a chest CT scan will be performed to confirm and 
characterize the lesion[s]), will be performed at Week 8, Week 16, Week 24, 
then every 12 weeks for 2 years after the subject’s last dose of radium-223 
dichloride or until radiologic progression.  If progression is detected by bone 
scan, a confirmatory bone scan is required at least 6 weeks later.  Radiological 
assessments will continue until disease progression is experienced in bone 
according to the PCWG2 criteria or in soft tissue according to Response 
Evaluation Criteria in Solid Tumors 1.1 guidelines. Radiographic imaging will 
be evaluated by blinded central review.
Pain endpoints will be based on subject-reported outcome data. Pain data will 
be collected every 4 weeks through Week 48 in all treatment arms using a 
handheld device. Pain will be assessed by means of selected questions from
the BPI-SF daily for 4 days immediately prior to randomization, in order to 
stratify subjects by WPS ≤4 or > 4, and then as follows:

for Treatment Arms A and B, daily for 7 days prior to each scheduled 
dosing visit from Dose 1, Day 1 through Week 24. During the Active 
Follow-up, pain data will be collected for the 7 days prior to Week 36 
and 48 visits, and for 7 days prior to each telephone contact at 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 11 of 291
Weeks 28, 32, 40 and 44.  

for Treatment Arm C, daily for 7 days prior to each scheduled dosing 
visit from Dose 1, Day 1 through Week 48.
Pain will also be assessed by means of the BPI-SF questionnaire every clinic 
visit or telephone contact from Dose 1, Day 1 visit until the Week 48 visit.  In 
treatment Arms A and B only, the BPI-SF questionnaire will also be completed 
on the day of each telephone contact at Weeks 28, 32, 40, and 44.  
The NCCN-FACT FPSI-17 questionnaire will be completed by the subject in 
all treatment arms every clinic visit starting on Dose 1, Day 1 up to Week 48
visit.  In treatment Arms A and B only the NCCN-FACT FPSI-17
questionnaire will also be completed on the day of each telephone contact at 
Weeks 28, 32, 40, and 44.  
Both the pain assessment using the BPI-SF questionnaire and the NCCN-
FACT FPSI-17 questionnaire will be self-administered by the subject using a 
handheld device. 
Analgesic use will be collected throughout the study.  In addition analgesic use 
over the 24-hour period prior to the day of the visit will be collected by the 
study investigator at each visit for all treatment arms from Dose 1, Day 1 until 
the Week 48 visit, and analgesic use over the 24-hour period prior to each 
telephone contact (in Arms A or B) will be collected by the study investigator 
at the telephone contact at Weeks 28, 32, 40, and 44.
The AQA score will be calculated programmatically from the assessments of 
analgesic use in the last 24 hours.
A Joint Safety Review Committee will conduct safety reviews at regular 
intervals. There is no formal interim analysis planned. The main objective of 
these safety reviews is to ensure subject safety and to identify whether any 
protocol modifications are needed.
Following the EOT visit, subjects will enter the active follow-up period and 
will come to the clinic for selected safety and efficacy evaluations every 
12 weeks for at least 2 years following last study treatment. Subjects not 
experiencing an SSE by 2 years following last study treatment will continue 
active follow-up until the subject experiences an SSE or the primary endpoint 
matures, whichever occurs first.  During active follow-up, every effort will be 
made to follow subjects through clinic visits; however, phone contacts will be 
undertaken for subjects unable to come to the clinic.
All study subjects will be eligible for further follow-up either in this study or 
in a separate long-term follow-up study for up to 7 years.  The separate 
long-term follow-up study has been set up to follow subjects who received 
radium-223 dichloride or placebo in the course of Bayer-sponsored clinical 
trials.  The long-term follow-up study has a specific focus on investigator 
reported, radium-223 dichloride-related AEs and serious AEs, all occurrences 
of leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer 
or any other new primary malignancy, cancer treatment (including any 
systemic cytotoxic chemotherapy or radiotherapy for any malignancy; all 
systemic therapies for prostate cancer, including androgen synthesis inhibitors 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 12 of 291
/ androgen-receptor antagonists, systemic radioisotopes, and radiation 
treatment; excluding analgesics), in subjects who receive cytotoxic 
chemotherapy: all occurrences of febrile neutropenia or hemorrhage during 
their chemotherapy treatment and for up to 6 months thereafter, and survival 
for up to 7 years after last dose of radium-223 dichloride or until death. In 
addition, during the long-term follow-up 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.  
During long-term follow-up, subjects, their treating health care professional, or 
caregiver will be contacted every 6 months by telephone.  All subjects who 
transition into this separate long-term follow-up study will require a separate 
signed informed consent.  Subject data collected at other standard-of-care 
visits and / or contacts may be used to satisfy study-required data.
Transition of all subjects into the separate long-term follow-up study will 
begin following the later of primary endpoint completion or 2 years after the 
last radium-223 dichloride treatment is administered to the last treated subject.
Until the transition to the long term follow-up study begins, some subjects may 
begin long-term follow-up in this study.  This study will end when all subjects 
have transitioned into the long-term follow-up study or discontinued from this 
study for another reason (e.g., Consent Withdrawn, Lost to Follow-up).
Methodology modified by Amendment 1, 2, 3, and 4.
Type of control
Active treatment control with standard dose radium-223 dichloride
Number of subjects
Approximately 360 subjects
Primary / Secondary variables
The primary efficacy variable will be SSE-FS.
The safety variables include:

Incidence and severity of treatment-emergent AEs (TEAEs) and 
laboratory abnormalities graded by National Cancer 
Institute-Common Terminology Criteria Adverse Events version 4.03 
and coded by Medical Dictionary for Regulatory Activities

Incidence of serious TEAEs

Incidence of drug-related AEs in the follow-up period
The secondary efficacy variables include:

OS

Time to first SSE

rPFS

Time to radiological progression

Pain improvement rate


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 13 of 291

Time to pain progression
Secondary efficacy variables modified by Amendments 1 and 2.
Plan for statistical analysis
Subjects will be randomized 1:1:1 to:
Treatment Arm A: radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) intravenously every 28 days up to 6 doses
(“standard dose”)
Treatment Arm B: radium-223 dichloride 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) intravenously every 28 days up to 6 doses
(“high dose”)
Treatment Arm C: radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) intravenously every 28 days up to 12 doses 
(“extended dosing”)
The primary efficacy endpoint, SSE-FS, will be analyzed separately in 
2 respective comparisons, as described below.
Both comparisons will be performed at the time of final analysis, after the 
latest of (1) approximately 135 SSE-FS events in subjects included in 
Comparison 1 as defined below; (2) approximately 75 SSE-FS events 
following the 6th dose in subjects included in Comparison 2 as defined below, 
and (3) the last subject has been followed for 30 days from last treatment.  In 
the event the applicable number of events is not reached, the primary endpoint 
analysis will mature 7 years after the last subject has received last treatment.
No alpha adjustment for multiple comparisons will be performed in this 
Phase II study.
Comparison 1: Standard dose versus high dose: SSE-FS from 
randomization in radium-223 dichloride-naïve subjects
Comparison 1 will test the following hypotheses:
The Null Hypothesis (H0)1: In a population of radium-223 dichloride-naïve 
subjects with CRPC metastatic to the bone, population SSE-FS in subjects 
treated with a regimen of up to 6 doses of 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) (high dose) radium-223 dichloride is equal to 
population SSE-FS in subjects treated with a regimen of up to 6 doses of 
50 kBq/kg (55 kBq/kg after implementation of NIST update) (standard dose)
radium-223 dichloride, versus
The Alternative Hypothesis (HA)1: In a population of radium-223 dichloride-
naïve subjects with CRPC metastatic to the bone, population SSE-FS in 
subjects treated with a regimen of up to 6 doses of 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) (high dose) radium-223 dichloride is greater 
than population SSE-FS in subjects treated with a regimen of up to 6 doses of 
50 kBq/kg (55 kBq/kg after implementation of NIST update) (standard dose)
radium-223 dichloride.
Comparison 1 will analyze SSE-FS with the randomization date as the start 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 14 of 291
date. 
Comparison 1 will pool SSE-FS in subjects in Treatment Arm A, with SSE-FS 
truncated at 24 weeks in subjects in Treatment Arm C, and compare this 
pooled value with SSE-FS in Treatment Arm B.  Only intent-to-treat (ITT)
subjects will be included in this ITT analysis.  In this study, extended dosing 
subjects (Treatment Arm C) will receive the same treatment regimen as 
standard dose subjects (Treatment Arm A) for the first 6 doses, with Dose 7 
scheduled to start after 24 weeks.  Accordingly, data from Treatment Arm C 
subjects arising during the first 24 weeks is relevant to this comparison and 
including it increases the analysis' power under the study assumptions.
It will be performed using a log-rank test with a 1-sided alpha of 0.1 stratified 
by the randomization factors (previous chemotherapy [≤1 regimen versus
> 1 regimen], and total ALP [< 220 U/L versus ≥220 U/L]).  The high-dose 
regimen will be declared superior to the standard-dosing regimen if the 1-sided 
p-value from the stratified log rank test is less than 0.1. 
The hazard ratio (high dose / standard dose) will be computed together with 
2-sided 80% and 95% confidence intervals using a stratified Cox regression 
model with treatment as a factor and previous chemotherapy [≤1 regimen 
versus > 1 regimen] and total ALP [< 220 U/L versus ≥220 U/L] as strata in 
the model for the ITT analysis set.  Kaplan-Meier survival distribution tables 
and plots will also be produced for both Treatment Arms A and B.  Additional 
details will be provided in the statistical analysis plan.
Comparison 2: No further radium-223 dichloride treatment versus
extended dosing: SSE-FS analysis from the 6th dose in subjects receiving 
standard-dose regimen
Comparison 2 will test the following hypotheses:
H02: In a population of subjects treated with a regimen of up to 6 doses of 
50 kBq/kg (55 kBq/kg after implementation of NIST update) (standard dose) 
radium-223 dichloride who survived SSE-free and are eligible for further 
radium-223 dichloride treatment at 24 weeks, population SSE-FS beyond the 
6th dose in subjects treated with a regimen of up to an additional 6 doses of 
50 kBq/kg (55 kBq/kg after implementation of NIST update) (extended dose) 
radium-223 dichloride is equal to population SSE-FS beyond the 6th dose in 
subjects receiving no further radium-223 dichloride treatment beyond the 
standard dose regimen, versus
HA2: In a population of subjects treated with a regimen of up to 6 doses of 
50 kBq/kg (55 kBq/kg after implementation of NIST update) (standard dose) 
radium-223 dichloride who survived SSE-free and are eligible for further 
radium-223 dichloride treatment at 24 weeks, population SSE-FS beyond the 
6th dose in subjects treated with a regimen of up to an additional 6 doses of 
50 kBq/kg (55 kBq/kg after implementation of NIST update) (extended dose) 
radium-223 dichloride is greater than population SSE-FS beyond the 6th dose
in subjects receiving no further radium-223 dichloride treatment beyond the 
standard dose regimen.
Comparison 2 will be an analysis of SSE-FS from the 6th dose in subjects 
surviving SSE-free to the 6th dose.  It will compare subjects in Treatment Arm 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 15 of 291
A with subjects in Treatment Arm C.  
Comparison 2 will be performed using a log-rank test with a 1-sided alpha of 
0.1 stratified by the randomization factors (previous chemotherapy 
[≤1 regimen versus > 1 regimen] and total ALP [< 220 U/L versus 
≥220 U/L]).  The extended dosing regimen will be declared superior to the 
standard dosing regimen if the 1-sided p-value from the stratified log rank test 
is less than 0.1.
The following secondary efficacy time-to-event endpoints will have hypothesis 
testing performed with comparisons analogous to those for the primary 
endpoint: OS, time to first SSE, time to radiological progression, and rPFS.  
Other endpoints, including safety and tolerability variables, will be analyzed 
descriptively for each treatment group.
Plan for statistical analysis modified by Amendments 1, 2, and 3.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 16 of 291
Table of contents
Cover page for 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 .....................................................................................................................16
Table of tables .........................................................................................................................20
List of abbreviations ...............................................................................................................21
Definitions of terms.................................................................................................................23
1.
Introduction......................................................................................................................24
1.1
Background.....................................................................................................................24
1.2
Study rationale................................................................................................................27
2.
Study objectives................................................................................................................28
3.
Investigators and other study personnel........................................................................30
4.
Study design......................................................................................................................32
4.1
Design overview.............................................................................................................32
4.2
Primary and secondary variables....................................................................................35
4.3
Interim Analyses and Joint Safety Review Committee..................................................35
4.4
End of study....................................................................................................................36
5.
Study population..............................................................................................................36
5.1
Eligibility........................................................................................................................36
5.1.1
Inclusion criteria..........................................................................................................37
5.1.2
Exclusion criteria ........................................................................................................38
5.2
Withdrawal of subjects from study.................................................................................40
5.2.1
Withdrawal..................................................................................................................40
5.2.1.1
Definitions................................................................................................................41
5.2.1.2
Process for withdrawal of consent ...........................................................................41
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..............................................................................................42
6.3
Treatment assignment.....................................................................................................43
6.4
Dosage and administration .............................................................................................44
6.4.1
Dose calibration ..........................................................................................................44
6.4.2
Dose handling..............................................................................................................45
6.4.3
Dose calculation..........................................................................................................46


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 17 of 291
6.4.4
Dose preparation .........................................................................................................47
6.4.5
Dose administration ....................................................................................................47
6.4.6
Dose adjustments ........................................................................................................48
6.4.7
Dose delays .................................................................................................................48
6.5
Blinding..........................................................................................................................50
6.6
Drug logistics and accountability...................................................................................51
6.7
Treatment compliance ....................................................................................................51
6.8
Post-study therapy ..........................................................................................................51
6.9
Prior and concomitant therapy........................................................................................52
6.9.1
Prior therapy................................................................................................................52
6.9.2
Concomitant medication .............................................................................................53
7.
Procedures and variables................................................................................................54
7.1
Schedule of procedures...................................................................................................54
7.1.1
Tabulated overview.....................................................................................................54
7.1.2
Timing of assessments ................................................................................................63
7.1.2.1
Screening period ......................................................................................................63
7.1.2.2
Randomization.........................................................................................................65
7.1.2.3
Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C)......................................66
7.1.2.4
Doses 2 to 6 (Treatment Arms A and B) .................................................................68
7.1.2.5
Doses 2 to 12 (Treatment Arm C)............................................................................70
7.1.2.6
End of treatment visit...............................................................................................73
7.1.2.7
Active follow-up ......................................................................................................75
7.1.2.8
End of active follow-up ...........................................................................................81
7.1.2.9
Long-term follow-up to 7 years following last dose................................................84
7.2
Population characteristics...............................................................................................87
7.2.1
Demographic...............................................................................................................87
7.2.2
Medical history............................................................................................................88
7.2.3
Disease history and prior treatment for prostate cancer..............................................88
7.2.4
Body size descriptors ..................................................................................................89
7.3
Efficacy...........................................................................................................................89
7.3.1
Efficacy variables........................................................................................................89
7.3.2
Definition of efficacy variables...................................................................................90
7.3.3
Primary endpoint.........................................................................................................90
7.3.4
Secondary endpoints ...................................................................................................90
7.3.4.1
Overall survival........................................................................................................90
7.3.4.2
Time to first symptomatic skeletal event.................................................................90
7.3.4.3
Radiological progression endpoints.........................................................................91
7.3.4.4
Pain endpoints..........................................................................................................91
7.3.5
Exploratory endpoints .................................................................................................93
7.3.5.1
Quantitated bone scan endpoints .............................................................................93
7.3.5.2
Time to increase in physical symptoms of disease based on FPSI-DRS-P .............94
7.3.5.3
Total alkaline phosphatase endpoints ......................................................................94
7.3.5.4
Prostate specific antigen endpoints..........................................................................95
7.3.5.5
Exploratory pain and analgesic use endpoints.........................................................96
7.3.5.6
Additional pain and health related quality of life endpoints....................................99


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 18 of 291
7.4
Pharmacokinetics / pharmacodynamics .........................................................................99
7.5
Safety..............................................................................................................................99
7.5.1
Adverse events ............................................................................................................99
7.5.1.1
Definitions................................................................................................................99
7.5.1.2
Classifications for adverse event assessment.........................................................101
7.5.1.3
Assessments and documentation of adverse events...............................................104
7.5.1.4
Reporting of serious adverse events.......................................................................105
7.5.1.5
Expected adverse events ........................................................................................106
7.5.2
Pregnancies ...............................................................................................................106
7.5.3
Further safety ............................................................................................................107
7.5.3.1
Laboratory evaluations...........................................................................................107
7.5.3.2
Physical examination .............................................................................................107
7.5.3.3
Vital signs ..............................................................................................................107
7.5.3.4
Eastern Cooperative Oncology Group performance status....................................107
7.5.3.5
Body weight...........................................................................................................107
7.6
Other procedures and variables ....................................................................................108
7.7
Appropriateness of procedures / measurements...........................................................108
8.
Statistical methods and determination of sample size................................................108
8.1
General considerations .................................................................................................108
8.2
Analysis sets .................................................................................................................109
8.3
Variables.......................................................................................................................109
8.4
Statistical and analytical plans......................................................................................110
8.4.1
Primary efficacy analysis ..........................................................................................110
8.4.2
Secondary efficacy analysis ......................................................................................112
8.4.2.1
Analyses of pooled standard dose and high dose from randomization..................112
8.4.2.2
Analyses of standard dosing and extended dosing from the 6th dose ...................112
8.4.2.3
Analyses by treatment arm.....................................................................................113
8.4.2.4
Secondary endpoint analysis methods ...................................................................113
8.4.3
Analysis of exploratory variables..............................................................................113
8.4.4
Safety analysis...........................................................................................................113
8.5
Planned interim analyses ..............................................................................................115
8.6
Determination of sample size.......................................................................................115
9.
Data handling and quality assurance...........................................................................116
9.1
Data recording ..............................................................................................................116
9.2
Monitoring....................................................................................................................117
9.3
Data processing ............................................................................................................117
9.4
Audit and inspection.....................................................................................................117
9.5
Archiving......................................................................................................................118
10. Premature termination of the study.............................................................................118
11. Ethical and legal aspects................................................................................................120
11.1
Ethical and legal conduct of the study..........................................................................120
11.2
Subject information and consent ..................................................................................120
11.3
Publication policy.........................................................................................................121
11.4
Compensation for health damage of subjects / insurance ............................................121


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 19 of 291
11.5
Confidentiality..............................................................................................................121
12. Reference list ..................................................................................................................123
13. Protocol amendments ....................................................................................................126
13.1
Amendment 1 ...............................................................................................................126
13.1.1
Overview of changes.................................................................................................127
13.1.2
Changes to the protocol text......................................................................................140
13.2
Amendment 2 ...............................................................................................................198
13.2.1
Overview of changes.................................................................................................200
13.2.2
Changes to the protocol text......................................................................................212
13.3
Amendment 3 ...............................................................................................................252
13.3.1
Overview of changes.................................................................................................252
13.3.2
Changes to the protocol text......................................................................................255
13.4
Amendment 4 ...............................................................................................................275
13.4.1
Overview of changes.................................................................................................276
13.4.1.1
Change 1: ...............................................................................................................276
13.4.1.2
Change 2: ...............................................................................................................276
13.4.1.3
Change 3: ...............................................................................................................277
13.4.1.4
Change 4: ...............................................................................................................277
13.4.1.5
Minor clarifications:...............................................................................................278
13.4.2
Changes to the protocol text......................................................................................278
14. Appendices......................................................................................................................279
14.1
Response Evaluation Criteria in Solid Tumors, version 1.1 ........................................279
14.2
Recommendations of the Prostate Cancer Clinical Trials Working Group for 
assessment of radiological progression ........................................................................282
14.3
Quantitative bone scan response criteria ......................................................................283
14.4
National Cancer Institute - Common Terminology Criteria for Adverse Events, 
Version 4.03 .................................................................................................................284
14.5
Eastern Cooperative Oncology Group performance status ..........................................285
14.6
Calculation for glomerular filtration rate .....................................................................285
14.7
Brief Pain Inventory-Short Form..................................................................................286
14.8
NCCN FACT-P Symptom Index-17 (NCCN-FACT FPSI-17) Questionnaire............289
14.9
Analgesic Quantification Algorithm ............................................................................291


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 20 of 291
Table of tables
Table 6–1 National Cancer Institute Common Terminology Criteria for Adverse Events 
(version 4.03) Grade 3 and 4 values for neutropenia and thrombocytopenia........49
Table 7–1  Schedule of procedures...........................................................................................55
Table 7–2  Changes to follow-up visit assessments..................................................................80
Table 14–1  Response for subjects with target and non-target lesions...................................281
Table 14–2  Response for subjects with non-target lesions only............................................281
Table 14–3  Recommendations of the Prostate Cancer Clinical Trials Working Group 2 for 
assessment of radiological progression................................................................282
Table 14–4  Radiological progression free survival definition per modified Response 
Evaluation Criteria in Solid Tumors, version 1.1, or progression by bone scan as 
adapted by Prostate Cancer Clinical Trials Working Group 2 criteria ................282
Table 14–5  Quantitative bone scan response criteria ............................................................283
Table 14–6  Eastern Cooperative Oncology Group performance status.................................285


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 21 of 291
List of abbreviations
Section modified by Amendment 1 (Section 13.1), 2 (Section 13.2), and 4 (Section 13.4.1.5).
AE
Adverse event
ALP
Alkaline phosphatase
ALSYMPCA
Alpharadin in Symptomatic Prostate Cancer
ALT
Alanine transaminase
ANC
Absolute neutrophil count
AST
Aspartate transaminase
AQA
Analgesic Quantification Algorithm
BHA
Bone health agent
BPI
Brief Pain Inventory
BPI-SF
Brief Pain Inventory Short Form
BSLA
Bone scan lesion area
BSoC
Best standard of care
CBC
Complete blood count
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CNS
Central nervous system
CR
Complete response
CRF
Case report form
CRO
Clinical research organization
CRPC
Castration-resistant prostate cancer
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DK
Decay correction factor
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EBRT
External beam radiotherapy
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
eGFR
Estimated Glomerular Filtration Rate
EOT
End of treatment
ePRO
Electronic patient-reported outcome
EU
European Union
FPSI-DRS-P
FACT-P Symptom Index-17 physical disease related symptoms
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
Granulocyte colony-stimulating factor
GFR
Glomerular filtration rate
GM-CSF
Granulocyte macrophage colony-stimulating factor
GMP
Good Manufacturing Practice
HA
The Alternative Hypothesis
H0
The Null Hypothesis
IB
Investigator’s Brochure


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 22 of 291
ICF
Informed consent form
IDMC
Independent Data Monitoring Committee
IDMS
Isotope Dilution Mass Spectrometry
IEC
Independent ethics committee
IRB
Institutional review board
ITT
Intent-to-treat
IV
Intravenous
IVRS / IWRS
Interactive voice / web response system
JSRC
Joint Safety Review Committee
kBq
KiloBecquerel; SI unit of radioactivity
LDH
Lactate dehydrogenase
LHRH
Luteinizing-hormone-releasing hormone
MBq
Megabecquerel, SI unit of radioactivity
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
mCi
milli-curie
MCV
Mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NCCN-FACT FPSI-17
NCCN-FACT-P Symptom Index-17
NCI
National Cancer Institute
NE
Not evaluable
NIST
National Institute of Standards and Technology
OME
Oral morphine equivalent
OS
Overall survival
PCWG2
Prostate Cancer Clinical Trials Working Group 2
PD
Progressive disease
PR
Partial response
PRD
Patient ready dose
PRO
Patient-reported outcome
PS
Performance status
PSA
Prostate specific antigen
q6
Every 6
q12
Every 12
QoL
Quality of life
RBC
Red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
rPFS
Radiological progression-free survival
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Stable disease
SI
International System of Units
SRE
Skeletal-related event
SSE
Symptomatic skeletal event


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 23 of 291
SSE-FS
Symptomatic skeletal event-free survival
SUSAR
Suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event
U/L
Units/liter
ULN
Upper limit of normal
US
United States
WBC
White blood cell
WHO
World Health Organization
wk
Week
WPS
Worst pain score
Definitions of terms
Radium-223 
dichloride
The investigational product, a bone-targeting 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.
Dose
Doses are given as kBq per kilogram body weight.  The term “dose” is used 
to describe the quantity of radioactivity from radium-223 administered.
PCWG2 
guidance
The Prostate Cancer Clinical Trials Working Group 2 guidance should be 
followed, as described in Section 14.2 (1)


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 24 of 291
1. Introduction
1.1
Background
Section modified by Amendment 1 (Section 13.1).
According to the American Cancer Society estimates for 2013, the number of new prostate 
cancer cases will be 238,590 and the number of deaths from prostate cancer is expected to be 
29,720 in the United States (US).(2)  A recent review of tumor registry-derived data 
estimated the number of prostate cancers cases in Europe to be 417,000, with 92,000
deaths.(3)
Bone metastases are the main cause of disability and death in subjects with 
castration-resistant prostate cancer (CRPC),(4,5) and approximately 90% of men with CRPC
have radiological evidence of bone metastasis.(4)  Although treatment with docetaxel 
chemotherapy is well-established in this population and has been shown to achieve disease 
responses and improve overall survival (OS), the magnitude of the OS benefit is modest.(6)  
It is estimated that approximately 50% of men diagnosed with CRPC are either judged unfit 
to tolerate docetaxel or elect not to receive it.  Consequently, recent drug development efforts 
have attempted to improve on options for patients with CRPC and metastases using multiple 
strategies, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
In the context of CRPC with bone metastasis, the bisphosphonate zoledronic acid,(7) has 
been available for more than 10 years for the treatment of prostate cancer with bone 
metastasis. More recently, denosumab, the monoclonal antibody that targets receptor 
activator of nuclear factor κB ligand, was approved by the Food and Drug Administration 
(FDA) in November 2010 for the prevention of skeletal-related events (SREs) and as an 
alternative to zoledronic acid.(8)  Importantly, while these 2 drugs are able to modify the 
course of patients with metastatic CRPC and bone metastasis, neither agent has been found to 
improve OS in this group of patients.
Over the past 3 years, a variety of new drugs have been approved for the treatment of CRPC, 
including the vaccine Sipuleucel-T in 2010 for asymptomatic or minimally symptomatic 
patients, cabazitaxel also in 2010, abiraterone acetate plus prednisone in 2011, and 
enzalutamide in 2012.  These drugs demonstrated improved OS, and are tolerable, but they 
were approved without respect to the specific clinical manifestations of CRPC.(9,10,11)
Given the reality that more than 90% of patients with CRPC develop bone metastases, and 
the well-known subsequent impact on quality of life (QoL) as well as survival, an agent that 
specifically targets the major complications of bone metastasis, provides a survival benefit, 
and has a good safety profile would represent a relevant treatment option and a major 
therapeutic advance.
Alpha particle-emitting radiopharmaceuticals represent a new class of cancer therapy for the 
treatment of men with CRPC with bone metastases.(12)  Unlike beta emitting 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 25 of 291
radiopharmaceuticals, alpha particle-emitting radiopharmaceuticals have a more localized 
action(13) (a range of 2 to 10 cell diameters) and are much more potent, causing 
double-strand deoxyribonucleic acid (DNA) breaks leading to cell death.(14)
Radium-223 is a calcium mimetic, alpha particle emitting nuclide, which selectively targets 
areas of increased bone turnover.(15)  The half-life of radium-223 is 11.4 days, allowing 
sufficient time for its preparation, distribution, and administration to subjects.(16)  Unlike 
beta particle-emitting radionuclides, which cause single strand DNA breaks, which can be 
repaired, alpha particle-emitting radium-223 causes difficult to repair double-strand DNA 
breaks,(16) resulting in a highly cytotoxic effect in target areas containing bone metastatic 
cancer cells.(15)  Since radium-223 is targeted to bone, its distribution to soft tissue is 
limited.(15)
The results of nonclinical pharmacology studies indicate that radium-223 dichloride delivers 
potent radiation targeted to bone in areas of high metabolic activity and increased bone 
turnover, such as skeletal metastases.  No effects on central nervous system (CNS), 
respiratory, or cardiovascular function were observed in safety pharmacology or toxicology 
studies conducted in rats and dogs.(16)  Radium-223 dichloride is rapidly eliminated from 
blood and distributed to bone.  In mice and dogs, excretion occurred by both feces and urine.  
No histological changes were observed in organs involved in the excretion of radium-223 
dichloride.(17)  In humans, clinical data show that excretion occurs mainly via the feces, with 
minimal urinary excretion and no entero-hepatic recirculation.(18)
In preclinical studies, in single and repeated dose toxicity studies in rats administered 
radium-223 dichloride, the main findings were reduced body weight gain, hematological 
changes, reduced serum alkaline phosphatase (ALP), and microscopic findings in the bone 
marrow (depletion of hematopoietic cells, fibrosis), spleen (secondary extra-medullary 
hematopoiesis), and bone (depletion of osteocytes, osteoblasts, osteoclasts, fibro-osseous 
lesions, disruption / disorganization of the physis / growth line).  With the exception of body
weight decrease, these findings were related to radiation-induced impairment of 
hematopoiesis and a reduction of osteogenesis, and occurred in the dose range of 20 to
80 kBq (0.000541 to 0.00216 mCi) per kilogram body weight.(17)
Dose-limiting myelotoxicity was seen in dogs after single administration of 450 kBq
(0.0122 mCi) radium-223 dichloride per kilogram body weight (9 times the clinically 
recommended standard dose).(17)
Osteosarcomas occurred in rats at extended times (7 to 12 months) after treatment with single 
doses of ≥ 325 kBq/kg and repeated doses of ≥25 kBq/kg (12 doses) or ≥325 kBq/kg 
(4 doses).  However, the relevance of these animal data needs to be interpreted with caution.  
The appearance of osteosarcomas was anticipated based on literature references identifying 
sarcomas in animals treated with ionizing radiation or bone-seeking radionuclides, 
particularly in skeletally immature and growing animals.  Further details on the toxicology 
studies can be found in the Investigator’s Brochure (IB).(16)


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 26 of 291
Nine clinical studies with radium-223 dichloride have been conducted in over 1,300 subjects 
with prostate or breast cancer with bone metastases.(16)
The safety and tolerability of radium-223 dichloride was first investigated in a single 
injection dose ranging study in 31 subjects diagnosed with prostate (n = 21) or breast cancer 
(n = 10).(18)  Thirty-one subjects with breast or prostate cancer received escalating single or 
multiple doses of radium-223 dichloride (single doses of 46, 93, 163, 213, or 250 kBq/kg 
body weight; multiple doses of 5 x 50 kBq/kg at 3-week intervals or 2 x 125 kBq/kg at 
6-week intervals), and subjects were followed for 8 weeks.  Mild and reversible 
myelosuppression with a nadir 2 to 4 weeks after the injection was observed.  Preliminary 
evidence of efficacy was seen with reduction in total serum ALP concentrations and 
improved pain control across all dose levels.
Radium-223 dichloride was subsequently evaluated in a double-blind, placebo-controlled, 
randomized Phase II study.  Subjects diagnosed with CRPC and bone pain needing external 
beam radiotherapy (EBRT) received up to 4 doses of 50 kBq/kg body weight intravenous 
(IV) radium-223 dichloride administered every 4 weeks in the active arm.(16,19)  The 
relative change in bone ALP from baseline to 4 weeks post-last treatment was -66% 
(range: -92% to 125%) for the 33 subjects who received treatment compared with 9% (range: 
-77% to 384%) for the 31 subjects who received placebo.  The results obtained with 
biochemical markers for bone turnover (type I collagen cross-linked C-telopeptide, 
procollagen I N propeptide) and tumor load (prostate specific antigen [PSA]) support the 
presence of a treatment effect during the treatment period and for 1 to 2 months after the end 
of treatment (EOT).  
A Phase II double-blind, randomized, dose-ranging study was performed to assess the 
palliative effect of 4 single dose levels (5, 25, 50, and 100 kBq/kg body weight radium-223 
dichloride) in 100 hormone refractory prostate cancer subjects.  The target population was 
subjects suffering from bone pain (with at least a score 2 on the Brief Pain Inventory [BPI]
average pain) due to multiple bone metastases secondary to prostate cancer. The aims of the 
study were to assess the effect of one injection of radium-223 dichloride on painful bony 
metastases, and to assess tolerability and safety.  A significant dose response for pain index 
was seen at Week 2 (P = 0.035). At Week 8, there were 40%, 63%, 56%, and 71% pain 
responders (reduced pain and stable analgesic consumption) in the 5, 25, 50, and 100 kBq/kg 
groups, respectively.  There was also a significant improvement in the pain and functional 
indexes of the Brief Pain Inventory Short Form (BPI-SF) for all dose groups (P = 0.04, 0.01, 
0.002, and 0.02; Wilcoxon signed rank test).  Furthermore, a decrease in bone ALP in the 
highest dose group was demonstrated (P = 0.0067).  All doses were safe and well tolerated.
A Phase III study was conducted to evaluate the efficacy and safety of radium-223 dichloride.  
ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) was a multinational, 
randomized, double-blind, placebo-controlled study in subjects with symptomatic CRPC with 
bone metastases.(20,21,22)  A total of 922 subjects were randomized 2:1 to receive 6 IV 
doses of either 50 kBq/kg radium-223 dichloride or placebo every 4 weeks.  Subjects were 
followed until 3 years from the first dose of study drug.  The ALSYMPCA study was 
terminated by the Independent Data Monitoring Committee (DMC) based on the results of a 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 27 of 291
pre-planned interim analysis that evaluated OS.  Overall survival was statistically 
significantly longer with radium-223 dichloride (hazard ratio = 0.695, 95% confidence 
interval [0.552% to 0.875%]; 2-sided P = 0.00185) compared to placebo.  Median OS was 
prolonged to 14.0 months with radium-223 dichloride treatment compared to 11.2 months 
with placebo.  Time to first SRE was statistically significantly longer in the radium-223 
dichloride group compared to placebo (median 13.5 months for radium-223 dichloride versus
8.4 months for placebo; P = 0.00046).  Overall, treatment-emergent serious adverse events 
(SAEs) were experienced by fewer subjects (43.2%, 220 / 509) in the radium-223 dichloride 
group than subjects in the placebo group (54.9%, 139 / 253).
A randomized, double-blind, dose-finding, multicenter Phase II study evaluated 
122 randomized CPRC subjects who received 3 injections of radium-223 dichloride at 6-
week intervals.(23) The doses were 25 kBq/kg (n = 41), 50 kBq/kg (n = 39), and 80 kBq/kg 
(n = 42).  Efficacy was evaluated using blood samples to measure PSA and other tumor 
markers, and SREs and pain assessments were recorded.  Safety was evaluated using adverse 
events (AEs), physical examinations, and clinical laboratory tests.  The study met its primary 
endpoint with a statistically significant dose-response relationship in confirmed (≥50%) PSA 
declines for no subjects in the 25 kBq/kg dose group, 2 subjects (6%) in the 50 kBq/kg dose 
group, and 5 subjects (13%) in the 80 kBq/kg dose group (P = 0.0297).  A greater than 
50% decrease in bone ALP levels was identified in 6 subjects (16%), 24 subjects (67%), and 
25 subjects (66%) in the 25, 50, and 80 kBq/kg dose groups, respectively (P < 0.0001).  The 
most common treatment-related AEs occurring up to Week 24 across all dose groups were 
diarrhea (21%), nausea (16%), and anemia (14%).  No difference in incidence of hematologic 
events was seen among the dose groups.  These data suggested that treatment with 80 kBq/kg 
radium-223 dichloride may result in better efficacy as compared with 50 kBq/kg in patients 
with CRPC without a significant increase in toxicity.(23)
Further details of the efficacy and safety of radium-223 dichloride can be found in the IB,(16) 
which contains comprehensive information on the study drug.
1.2
Study rationale
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Clinical experience with radium-223 dichloride, as described above, demonstrates that 
treatment with 6 administrations of radium-223 dichloride at 50 kBq/kg (55 kBq/kg after 
implementation of National Institute of Standards and Technology [NIST] update) every 4
weeks is associated with important clinical benefits, including a significant improvement in 
median OS as compared to placebo in subjects with CRPC and bone metastases, and with a 
favorable safety profile.  Side effects are mild and predominantly gastrointestinal (diarrhea 
and vomiting).  Myelosuppression is minimal with a low incidence of Grade ≥3 neutropenia 
and thrombocytopenia, and no evidence of cumulative bone marrow toxicity.  These 
observations suggest that treatment beyond 6 doses is plausible.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 28 of 291
The dose-response relationships that were observed in the Phase II studies suggest that 
further clinical benefit, in terms of disease control and pain relief, may be achieved with 
higher doses of radium-223 dichloride without a worse safety profile.  
The tolerability of radium-223 dichloride and preliminary evidence of a dose-response 
relationship suggest possible strategies for enhancing the efficacy of radium-223 by 
increasing exposure to radium-223 dichloride.  Two potential strategies to increase total dose 
are: 1) to increase the total number of treatments with the standard 50 kBq/kg (55 kBq/kg 
after implementation of NIST update) dose or 2) to increase the total dose given for each 
treatment, while retaining the 6-dose regimen.
This 3-arm randomized study was designed to explore both treatment strategies by comparing 
the standard dose regimen of radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) every 4 weeks for up to 6 doses to the high dose regimen of 
80 kBq/kg (88 kBq/kg after implementation of NIST update) and, in subjects receiving the 
standard dose regimen, to compare an extended regimen of up to 6 additional doses of
radium-223 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 4 weeks with 
no further radium-223 dichloride treatment.  Efficacy will be evaluated in terms of 
symptomatic skeletal event-free survival (SSE-FS).  Radiological progression-free survival 
and time to progression will be evaluated as secondary objectives. Additional secondary 
objectives include pain improvement rate and time to progression based on subjects’ self-
assessment of pain, change in analgesic use based on subjects’ analgesic use in the last 
24 hours as evaluated by the Analgesic Quantification Algorithm (AQA).
This study will be conducted to provide data regarding the optimal use of radium-223 
dichloride and long-term safety 
.
Long-term safety assessment
The key attribute of radium-223 dichloride is its specific targeting of bone with limited
radiation exposure beyond the intended target.  However, the proximity of the bone marrow 
space to site of action of radium-223 dichloride means that there is potential for 
radiation-induced bone marrow abnormalities.  These abnormalities, including bone marrow 
dysplasia or new primary malignancies, may not become evident until years after the initial 
exposure to radium-223 dichloride; therefore, long-term follow-up is required to detect them.  
For this reason, both acute and long-term safety of radium-223 dichloride will be assessed in 
this study, with the follow-up period extending to up to 7 years after the last dose of 
radium-223 dichloride.
2. Study objectives
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), and 3 (Section 13.3).
The following objectives will be used to compare radium-223 dichloride 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) every 28 days for up to 6 doses with
radium-223 dichloride 80 kBq/kg (88 kBq/kg after implementation of NIST update) every 28 
CCI


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 29 of 291
days for up to 6 doses in radium-223 dichloride-naïve subjects; and, in subjects receiving 
radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) every 28 
days up to 6 doses, to compare a regimen of up to a further 6 doses of radium-223 dichloride 
50 kBq/kg (55 kBq/kg after implementation of NIST update) every 28 days with no further 
radium-223 dichloride treatment.
Co-primary objectives:

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) every 28 days for up to 6 doses 
compared to radium-223 dichloride 80 kBq/kg (88 kBq/kg after implementation of 
NIST update) every 28 days for up to 6 doses in subjects with CRPC metastatic to the 
bone not previously receiving radium-223 dichloride; and

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 50 kBq/kg
(55 kBq/kg after implementation of NIST update) every 28 days for up to 6 additional 
doses compared to no further radium-223 dichloride treatment in subjects with CRPC
metastatic to the bone who previously received radium-223 dichloride 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) every 28 days for up to 6 doses, and 
survived SSE free and are eligible for further radium-223 dichloride treatment.
Symptomatic skeletal events (SSEs) are defined as:
o
The use of external beam radiotherapy (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
Secondary objectives: 

To evaluate safety and tolerability

To evaluate overall survival (OS)

To evaluate pain improvement rate

To evaluate time to pain progression

To evaluate time to first SSE

To evaluate time to radiological progression

To evaluate radiological progression-free survival (rPFS)


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 30 of 291
Exploratory objectives:

To evaluate quantitated whole body technetium-99 bone scan tumor burden area and 
index, and determine bone tumor response

To explore the impact of subject body size on the efficacy and safety of radium-223 
dichloride

Time to increase in physical symptoms of disease based on the National 
Comprehensive Cancer Network (NCCN) FACT-P Symptom Index-17 (NCCN-
FACT FPSI-17) physical disease related symptoms (FPSI-DRS-P) subscale score 
measured up to Week 48 after the start of treatment

To evaluate laboratory indicators of efficacy, including:
o
PSA response
o
Time to PSA progression
o
ALP response
o
Time to ALP progression
o
Percentage change in ALP from baseline

To evaluate change in analgesic use as measured by the AQA.
3. Investigators and other study personnel
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section (13.3), and 
4 (13.4.1.4).
Global Clinical Leader for the study:
Bayer Consumer Care AG
Peter Merian-Strasse 84
CH-4002 Basel
Switzerland
Phone: 
Study Medical Expert for the study:
Rua Cancioneiro de Evora, 255
Building E1, 1st floor
PPD
PPD
PPD


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 31 of 291
04708-010 São Paulo – SP Brazil
Phone: 
Coordinating investigator for the study:
 US
Tel: 
European Principal Investigator for the study:
Italy
Tel: 
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 site, or an appropriately qualified, trained, and delegated 
individual of the investigational site.
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 pages.
Joint Safety Review Committee
A Joint Safety Review Committee (JSRC), which may contain sponsor, investigator, and/or 
independent members, will conduct safety reviews at regular intervals.  There is no formal 
interim analysis planned.  The objective of these safety reviews is to ensure subject safety and 
PPD
PPD
PPD
PPD
PPD


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 32 of 291
to identify whether any protocol modifications are needed.  The JSRC will not evaluate 
efficacy.  Details on the JSRC and its safety review monitoring will be described in a separate 
JSRC charter.
4. Study design
4.1
Design overview
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 4 
(13.4.1.2).
Subjects enrolled into the study will be randomized to one of the 3 treatment arms in a 
1:1:1 fashion: radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST 
update) IV every 28 days for up to 6 doses (Treatment Arm A), or radium-223 dichloride 
80 kBq/kg (88 kBq/kg after implementation of NIST update) IV every 28 days for up to 
6 doses (Treatment Arm B), or radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) IV every 28 days for up to 12 doses (Treatment Arm C).
The randomization will be permuted-block, stratified by use of prior chemotherapy 
(≤1 regimen versus > 1 regimen), by total ALP (< 220 U/L versus ≥220 U/L), and by 
average worst pain score (WPS) of the BPI-SF (WPS ≤4 versus WPS > 4).
The treatment period for efficacy purposes begins at the time of randomization.  During the 
treatment period, study medication is administered every 28 days (± 7 days) from Dose 1 and 
may be delivered in an outpatient setting.  At each visit, prior to receiving radium-223 
dichloride, the subject will be evaluated for AEs and laboratory abnormalities to determine 
whether it is safe to continue treatment.
Symptomatic skeletal events will be assessed every 28 days through the latter of Week 24 or 
the EOT visit (Week 24 for Treatment Arms A and B, and Week 48 for Treatment Arm C)
and every 12 weeks thereafter, until an SSE is experienced.  Subjects in Treatment Arms A 
and B who have not experienced an SSE will be contacted by telephone at Weeks 28, 32, 40, 
and 44, evaluated for SSE risk, and encouraged to come to the clinic if a risk is identified.
Symptomatic skeletal events are defined as:

The use of EBRT to relieve skeletal symptoms

New symptomatic pathological bone fractures (vertebral and non-vertebral)

Tumor-related orthopedic surgical intervention

Spinal cord compression
Radiological assessment, including whole body technetium-99 bone scan, magnetic 
resonance imaging (MRI) / computed tomography (CT) scan of the abdomen and pelvis, and 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 33 of 291
chest X-ray (in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), will be performed at Week 8, Week 16, Week 24,
then every 12 weeks for 2 years after the subject’s last dose of radium-223 dichloride or until 
radiologic progression.  If progression is detected by bone scan, a confirmatory bone scan is 
required at least 6 weeks later.  Radiological assessments will continue until disease
progression is experienced in bone according to the Prostate Cancer Clinical Trials Working 
Group 2 [PCWG2] criteria or in soft tissue according to Response Evaluation Criteria in 
Solid Tumors 1.1 [RECIST 1.1] guidelines, see Section 14.1 and Section 14.2).  
Radiographic imaging will be evaluated by blinded central review.
Pain endpoints will be based on subject-reported outcome data.  Pain will be assessed by 
means of selected questions from the BPI-SF daily for 4 days immediately prior to 
randomization, in order to stratify subjects by WPS ≤4 or > 4, and then daily for 6 days prior 
to Cycle 1, Day 1 or subsequent visits including telephone contacts, as applicable, plus the 
day of the visit or telephone contact, until Week 48.  Pain will also be assessed by means of 
the BPI-SF questionnaire for all treatment arms at each clinic visit or telephone contact from 
Dose 1, Day 1 until the Week 48 visit and for treatment Arms A and B on the day of each 
telephone contact at Weeks 28, 32, 40, and 44.
The NCCN-FACT FPSI-17 questionnaire will be completed by the subject in all treatment 
arms every clinic visit starting on Dose 1, Day 1 up to Week 48 visit and for treatment Arms 
A and B on the day of each telephone contact at Weeks 28, 32, 40, and 44 (see Section 14.8).
Both the pain assessment using the BPI-SF questionnaire and the NCCN-FACT FPSI-17
questionnaire will be self-administered by the subject using a handheld device.
Analgesic use will be collected throughout the study.  In addition analgesic use over the 
24-hour period prior to the day of the visit will be collected by the study investigator at each 
visit for all treatment arms from Dose 1, Day 1 until the Week 48 visit, and analgesic use 
over the 24-hour period prior to each telephone contact (in Arms A and B) will be collected 
by the study investigator at the telephone contact at Week 28, 32, 40, and 44.
The AQA score will be calculated programmatically from the assessments of analgesic use in 
the last 24 hours (see Section 14.9).
Following the EOT visit, subjects will enter the active follow-up period and will come to the 
clinic for selected safety and efficacy evaluations every 12 weeks for at least 2 years 
following last study treatment. Subjects not experiencing an SSE by 2 years following last 
study treatment will continue active follow-up until the subject experiences an SSE or the 
primary endpoint matures, whichever occurs first.  During active follow-up, every effort will 
be made to follow subjects through clinic visits; however, phone contacts will be undertaken 
for subjects unable to come to the clinic.  
Active follow-up period with clinic visits:
Subjects who discontinue study treatment and who did not have an SSE will enter an active 
follow-up period with clinic visits. These subjects will be evaluated every 12 weeks 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 34 of 291
(± 7 days) for pain endpoints, radiological progression, SSEs, survival, treatment-related AEs 
and serious adverse events (SAEs), and the initiation of other anti-cancer therapies for 
prostate cancer, and cytotoxic chemotherapy and radiotherapy for any new malignancy. 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. During this period, 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. In addition, 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.
The active follow-up period with clinic visits extends from the discontinuation of the 
treatment period until the subject experiences an SSE, can no longer travel to the clinic, 
receives further treatment with cytotoxic chemotherapy for prostate cancer, other systemic 
radioisotopes, hemibody EBRT, or other investigational drugs, dies, is lost to follow-up, or 
withdraws informed consent and actively objects to collection of further data. 
Active follow-up period without clinic visits:
Subjects from the treatment period or the active follow-up period with clinic visits who can 
no longer travel to the clinical site will be followed for survival, treatment-related AEs and 
SAEs, SSEs, pain endpoints, and the initiation of other anti-cancer therapies (for prostate
cancer, and cytotoxic chemotherapy and radiotherapy for any new malignancy) with a phone 
call every 12 weeks (± 7 days). 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. During this period, 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. In addition, 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.
The active follow-up period without clinic visits extends from the end of treatment (EOT) 
period or the end of active follow-up with clinic visits until the subject experiences an SSE, 
dies, is lost to follow-up, or withdraws informed consent and actively objects to collection of 
further data.
The maximum duration of the active follow-up is 7 years from the last dose of radium-223 
dichloride received by the subject.
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported radium-223 dichloride-related AEs and SAEs, all occurrences of 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 35 of 291
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new 
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death.  In addition, during the long-term follow-up 
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.  During long-term follow-up, subjects, their treating health care professional, or 
caregiver will be contacted every 6 months by telephone.  All subjects who transition into this 
separate long-term follow-up study will require a separate signed informed consent.  Subject 
data collected at other standard-of-care visits and / or contacts may be used to satisfy study-
required data.
Transition of all subjects into the separate long-term follow-up study will begin following the 
later of primary endpoint completion or 2 years after the last radium-223 dichloride treatment 
is administered to the last treated subject.
Until the transition to the long-term follow-up study begins, some subjects may begin 
long-term follow-up in this study.  This study will end when all subjects have transitioned 
into the long-term follow-up study or discontinued from this study for another reason (e.g., 
Consent Withdrawn, Lost to Follow-up).
4.2
Primary and secondary variables
Section modified by Amendment 1 (13.1).
The primary efficacy variable will be SSE-FS.
Safety and tolerability variables will be the incidence and severity of treatment-emergent AEs 
(TEAEs) including serious TEAEs, and laboratory abnormalities plus drug-related AEs 
during the follow-up period.  The severity of AEs will be graded by the National Cancer 
Institute Common Terminology Criteria Adverse Events (NCI-CTCAE), version 4.03 and 
coded by Medical Dictionary for Regulatory Activities (MedDRA).
Secondary efficacy variables will be OS, time to first SSE, rPFS, time to radiological 
progression, pain improvement rate, time to pain progression, and change in analgesic use.
4.3
Interim Analyses and Joint Safety Review Committee
Section modified by Amendment 1 (13.1).
No formal interim analysis is planned.  A JSRC, which may contain sponsor, investigator, 
and/or independent members, will conduct safety reviews at regular intervals.  The objective 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 36 of 291
of these safety reviews is to ensure subject safety and to identify whether any protocol 
modifications are needed.  The JSRC will not evaluate efficacy.  Details on the JSRC and its 
safety review monitoring will be described in a separate JSRC charter.
4.4
End of study
Section modified by Amendments 1 (13.1), and 3 (Section 13.3).
The final analysis of this study will take place after the primary endpoint cut-off is reached.
The primary endpoint cut-off will be reached at the later of 1) 135 SSE-FS events in subjects 
included in Comparison 1 as defined in Section 8.4 below, and 2) 75 SSE-FS events 
following the 6th dose in subjects included in Comparison 2 as defined in Section 8.4 below, 
and 3) the last subject has been followed for 30 days from last treatment. In the event the 
applicable number of events is not reached, the primary endpoint analysis will mature 7 years 
after the last subject has received last treatment.
Subjects alive at the time of the final analysis will continue to be followed for up to 7 years 
after the last dose of radium-223 dichloride or death for an updated analysis of long-term 
survival and long-term radiation-related safety.
For each participating European Union (EU) country, the end of the study according to the 
EU Clinical Trial Directive will be reached when the last visit of the last subject for all 
centers in the respective country has occurred.
However, as the primary endpoint of this study is event-based, the end of the study as a 
whole will only be reached when this endpoint has been achieved in subjects in all 
participating centers (EU and non-EU).
5. Study population
5.1
Eligibility
Section modified by Amendment 2 (13.2).
Eligibility should be confirmed within 14 (± 7) days prior to randomization.  At Dose 1, 
Day 1, the hematology values need to be confirmed to be within the treatment ranges 
(absolute neutrophil count [ANC] ≥1.5 x 109/L, platelet count ≥100 x 109/L, and 
hemoglobin ≥9.0 g/dL) prior to dosing.
Rescreening of screen failed subjects is only allowed once after prior approval from the 
Bayer-designated medical representative.  Sponsor approval of rescreening for a screen failed 
subject will be provided by written confirmation to the site.  For these subjects who 
underwent screening procedures (i.e., scans and laboratory work) and cannot meet eligibility 
within the screening period (14 ± 7 days) due to logistical circumstances, screening 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 37 of 291
procedures may need to be repeated.  At the time of rescreening, all expired procedures must 
be repeated and be within 14 ± 7 days prior to randomization.  The maximum period allowed 
for screening will be 35 days (14 days screening + 7 day window + 14 days for rescreening).
Rescreening is also permitted where the subject’s eligibility for the study depends upon the 
completion of washout periods as per protocol (e.g., 4 weeks from treatment with an 
investigational drug).
Rescreening is not permitted in cases in which the initial safety laboratory test results do not 
support eligibility.
5.1.1 Inclusion criteria
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Eligible subjects must meet all of the inclusion criteria listed below:

Histologically or cytologically confirmed adenocarcinoma of the prostate

Castration-resistant disease defined as:
a.
Serum testosterone level: ≤50 ng/dL (1.7 nmol/L)
b. Bilateral orchiectomy or maintenance on androgen ablation therapy with 
luteinizing-hormone-releasing hormone (LHRH) agonist or antagonist,* or 
polyestradiol phosphate
c.
Serum PSA progression defined as 2 subsequent increases in PSA over a 
previous reference value, with a PSA value of ≥2 ng/mL at the time of the 
second increase OR
Radiographic evidence of disease progression in bone (according to PCWG2 
criteria) with or without PSA progression
*In subjects who were treated with combined androgen blockade (a 
growth-hormone-releasing hormone analog or orchiectomy in combination with 
continuous anti-androgen) as initial therapy for a prolonged period of time, or who have 
responded to adding a peripheral anti-androgen as second line therapy, progressive 
disease (PD) should be documented after discontinuing anti-androgen treatment (for at 
least 6 weeks for bicalutamide and at least 4 weeks for flutamide and others) to exclude 
an anti-androgen withdrawal response.

Subjects must be ≥18 years of age.

Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2. In case of 
ECOG PS 2, the PS must be due to metastatic prostate cancer to the bone.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 38 of 291

Life expectancy ≥6 months.

Two or more skeletal metastases (≥2 hot spots) on bone scintigraphy within 8 weeks of 
randomization.

Laboratory requirements:
a.
ANC ≥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) without transfusion or 
erythropoietin support within 4 weeks prior to screening
d.
Total bilirubin level ≤1.5 x institutional upper limit of normal (ULN) 
(< 3 x ULN for subjects with documented Gilbert’s syndrome)
e.
Aspartate transaminase (AST) and alanine transaminase (ALT) 2.5 x ULN
f.
Creatinine ≤1.5 x ULN
g.
Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 according to 
either the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
creatinine equation or the Modification of Diet in Renal Disease (MDRD) 
abbreviated formula (see Section 14.6) (24, 25)
h.
Albumin > 25 g/L

Written, signed informed consent.  Subject must be able to understand and be willing to 
sign the written informed consent form (ICF). A signed ICF must be appropriately 
obtained prior to the conduct of any study-specific procedure.

Sexually active males agree to use condoms and/or their female partners of reproductive 
potential to use a method of effective birth control during treatment and for 6 months 
following the completion of treatment with radium-223 dichloride.
5.1.2 Exclusion criteria
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).

History of visceral metastasis, or visceral metastases as assessed by CT / MRI of the 
abdomen and pelvis and / or chest X-ray (in the presence of suspicious lesion[s], a chest 
CT scan will be performed to confirm and characterize the lesion[s]) within the 
previous 8 weeks of randomization

Lymphadenopathy with lymph nodes exceeding 3 cm in short axis diameter


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 39 of 291

Current CNS metastases.  Subjects with neurological symptoms suggestive of CNS 
metastasis must undergo contrast CT scan or MRI of the CNS within 30 days of the 
start of treatment to exclude CNS metastasis.  Imaging of the CNS is otherwise not 
required.

Chronic conditions associated with non-malignant abnormal bone growth (e.g., 
confirmed Paget’s disease of bone)

Blood transfusions or use of erythropoietin within 4 weeks prior to screening, during 
the screening period, or prior to the start of treatment

Treatment with an investigational drug within the 4 weeks prior to randomization

Treatment with cytotoxic chemotherapy for prostate cancer, including taxanes, 
estramustine, and mitoxantrone, within the previous 4 weeks prior to randomization, or 
planned treatment with these prohibited cytotoxic chemotherapy agents for prostate 
cancer during the treatment period or follow-up

Prior treatment with radium-223 dichloride

Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or 
rhenium-188

Prior hemibody EBRT

Use of biologic response modifiers, such as granulocyte macrophage 
colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF), 
within 4 weeks prior to screening

Other malignancy treated within the last 3 years (except treated non-melanoma skin 
cancer or low-grade superficial bladder cancer)

Imminent or established untreated spinal cord compression based on clinical findings 
and / or MRI. Following treatment of spinal cord compression, the subject may be 
eligible if all other eligibility criteria are fulfilled.

Any other serious illness or medical condition such as, but not limited to:

Any uncontrolled infection

Cardiac failure New York Heart Association Class III or IV

Crohn’s disease or ulcerative colitis

Bone marrow dysplasia

Unmanageable fecal incontinence


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 40 of 291

Previous assignment to treatment in this study
5.2
Withdrawal of subjects from study
5.2.1 Withdrawal
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), and 3 (Section 13.3).
Subjects will be discontinued from study treatment for the following reasons:

At their own request or at the request of their legally acceptable representative
At any time during the study and without giving reasons, a subject may decline further
study treatment.  The subject will not suffer any disadvantage as a result.  The subject 
will continue to be followed up for safety and survival unless he completes the 
procedure for withdrawal of consent specified in Section 5.2.1.2.

If, in the investigator's opinion, continuation of the study treatment would be harmful 
to the subject's well-being

A dose delay of more than 4 weeks (maximum of 8 weeks between 2 injections)

If cytotoxic chemotherapy for prostate cancer, including taxanes, estramustine, and 
mitoxantrone, or other systemic radioisotopes are given during the treatment period

If the subject experiences any non-hematological CTCAE Grade 4 adverse event
lasting > 1 week despite adequate treatment regardless of causality.

If the subject experiences Grade 3 neutropenia or Grades 3 or 4 thrombocytopenia 
lasting > 2 weeks or Grade 4 neutropenia lasting > 1 week despite adequate treatment
regardless of causality.  Blood transfusions and biologic response modifiers, such as 
GM-CSF or G-CSF can be used for the treatment of hematological abnormalities 
during the treatment period.
Subjects may be discontinued from study treatment for the following reason:

At the specific request of the sponsor and in liaison with the investigator (e.g.,
obvious non-compliance, safety concerns)
For any subject who prematurely discontinues study treatment, the EOT assessments must be 
completed.  The subject will remain in the study throughout the follow-up period.  Any 
subject who withdraws from the study procedures but does not withdraw consent should enter 
active follow-up without clinic visits for survival assessment (see Section 7.1.2.8.2).  In all 
cases, the reason for discontinuation from study treatment must be recorded in the electronic 
case report form (eCRF) and in the source documentation.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 41 of 291
Subjects will be withdrawn from the study for the following reasons:

Withdrawal of consent
At any time during the study and without giving reasons, a subject or his legally 
acceptable representative may withdraw consent and decline to participate further in 
the study.  The subject will not suffer any disadvantage as a result.

Lost to follow-up

Death
Details for the premature termination of the study as a whole (or components thereof 
[e.g., centers, treatment arms, dose steps]) are provided in Section 10 (Premature termination 
of the study).
For subjects who withdraw from the study prior to the EOT visit, it is recommended that the 
EOT assessments be completed.
5.2.1.1 Definitions
Screening failures are defined as follows:

A subject who fails to satisfy the selection criteria at any time prior to randomization.  
The reason will be documented in the source documentation and the eCRF and the 
subject will discontinue participation in study with no further follow-up required.

A subject who terminates the study at any time prior to randomization.  The process 
for withdrawal of consent from the study must be followed (see Section 5.2.1.2).
Premature discontinuation of study treatment is defined as a subject who discontinues 
study treatment prematurely for any reason, if the subject has been administered at least one 
dose of study drug.
Drop-out is defined as a subject who discontinues study participation prematurely for any 
reason if the subject has already been randomized.
Subjects who pass screening but discontinue from the study prior to Dose 1 will be followed.  
Due diligence must be performed to follow-up for efficacy parameters.
5.2.1.2 Process for withdrawal of consent
In order to ensure complete study data, it is specified in the ICF that the subject agrees to 
complete all procedures and assessments in the treatment and follow-up periods.  Only 
subjects who sign permission to collect follow-up data should be included in this study.  This 
includes data on any follow-up examinations or analyses of images not analyzed at the time 
the subject completes the study.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 42 of 291
The subject or his legally acceptable representative can withdraw this initial permission for 
study procedures and / or follow-up.  In this case, the subject has to expressively inform the 
investigator (study staff is not sufficient) and has to sign the Declaration of Objection to the 
Collection of Study Data after Withdrawal of Consent.  The objection is also valid, if the 
declaration is not in place for any reason, but the investigator documented the objection in the 
source documentation.
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 (IVRS / IWRS) when a subject signs the ICF and is evaluated 
for inclusion into the study.  When the subject is determined eligible for the study treatment, 
this number must be entered into the IVRS / IWRS.  During the IVRS / IWRS update, the 
subject will be randomized to the treatment arm and the shipment for the initial radium-223 
dichloride dose will be automatically processed.
6. Treatments
6.1
Treatments to be administered
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Subjects enrolled into the study will be randomized to one of the 3 treatment arms in a 
1:1:1 fashion:

Treatment Arm A: radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation 
of NIST update) IV every 28 days up to 6 doses (IV bolus)

Treatment Arm B: radium-223 dichloride 80 kBq/kg (88 kBq/kg after implementation 
of NIST update) IV every 28 days up to 6 doses (IV bolus)

Treatment Arm C: radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation 
of NIST update) IV every 28 days up to 12 doses (IV bolus)
The randomization will be permuted-block, stratified by use of prior chemotherapy 
(≤1 regimen versus > 1 regimen), by total ALP (< 220 U/L versus ≥220 U/L) and by 
average WPS of the BPI-SF (WPS ≤4 versus WPS > 4).
6.2
Identity of study treatment
Section modified by Amendment 2 (Section 13.2).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 43 of 291
The alpha particle-emitting radiopharmaceutical, radium-223 dichloride, is a ready-to-use, 
sterile, non-pyrogenic, clear and colorless aqueous solution of radium-223 dichloride for IV 
administration.  Radium-223 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 1,000 kBq/mL (1,100 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.
The product is manufactured by Institute for Energy Technology (IFE), Isotope laboratories 
Instituttveien 18, NO-2007, Kjeller, Norway on behalf of Bayer AS, Kjelsäsveien 172 A, 
N0-0884 Oslo, Norway.  The product is produced according to Good Manufacturing Practice 
(GMP).  The product will be delivered in a glass vial, ready-to-use with a certified activity.  
Radium-223 dichloride is shipped in a lead container and Type A radioactive package 
according to international transportation guidelines for radioactive materials.
The volume per vial is 6 mL, corresponding to 6 MBq (6.6 MBq after implementation of 
NIST update) at the reference day.  Radium-223 dichloride has a shelf life of 28 days from 
production day, when stored at ambient temperature.  The shelf life has been demonstrated 
for temperatures from cold storage (2ºC to 8°C) up to 40°C.  In addition, it has been shown 
that the product quality is not jeopardized upon freezing.  For the US, study drug may be 
forwarded to the country depot in vials, where it will be prepared as a patient ready dose 
([PRD], in a syringe) before being delivered to the site.
All study drugs will be labeled according to the requirements of local law and legislation.  
Label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request.
For all study drugs, a system of numbering in accordance with all requirements of GMP will 
be used, ensuring that each dose of study drug can be traced back to the respective bulkware 
of the ingredients.  Lists linking all numbering levels will be maintained by the sponsor.
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.
6.3
Treatment assignment
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
This study is a randomized, 3-arm open-label Phase II study.
A subject number (a unique identification number) will be assigned via IVRS / IWRS when a 
subject is evaluated for inclusion into the study.  The subjects will then undergo screening 
procedures and will enter the study after successful screening.  Subjects will be randomized 
1:1:1 to receive one of:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 44 of 291

Treatment Arm A:  Radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) intravenously every 28 days for up to 6 doses
(“standard dose”)

Treatment Arm B: Radium-223 dichloride 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) intravenously every 28 days for up to 6 doses (“high
dose”)

Treatment Arm C:  Radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) intravenously every 28 days for up to 12 doses
(“extended dose”)
The randomization will be permuted-block, stratified by use of prior chemotherapy 
(≤1 regimen versus > 1 regimen), by total ALP (< 220 U/L versus ≥220 U/L), and by 
average WPS of the BPI-SF (WPS ≤4 versus WPS > 4).
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 proportion of beta and gamma radiation emitted.  For 
these reasons, the product can be administered in an outpatient setting.  To minimize the risk 
of contamination, the subject and his caregivers will receive instructions regarding hygiene 
precautions to abide by after receiving the radioactive drug according to the investigational 
site radiation protection guidelines.  After each dose, the subject should be given the subject 
information card to carry with him until the next dosing visit.
6.4.1 Dose calibration
Section modified by Amendment 2 (Section 13.2).
Radium-223 dichloride can be measured in a normal dose calibrator instrument.  When 
written approvals for the use of radium-223 dichloride from the Radiation Protection Agency 
for the specific center have been received by the sponsor, a vial of radium-223 for technical 
use will be sent to the study center.
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).  For dial setting, the 
clinical study center will receive a sealed vial containing a radium-223 solution for 
calibration only.  The vial is identical to the vials used for study treatment.  The amount of 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 45 of 291
radium-223 in the vial 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.  If 
calibration was previously performed and documented at a given site, that documentation 
needs to be provided to the sponsor (i.e., recalibration for those sites may not be necessary).  
A similar dose calibration and approval process will be implemented with the country PRD 
depot, as applicable.
As of Amendment 2, NIST has established an updated standardization for radium-223 
dichloride, which indicates that an approximate 10% difference existed between activity 
values obtained using the current standard and the updated standardization.  The current 
NIST standard for radium-223 dichloride (NIST 2010 [31]) will remain in effect for this 
protocol until all Health Authorities for which Bayer holds a marketing application for 
radium-223 dichloride have approved the regulatory variations for Xofigo®, anticipated Q 2 
2016. All sites will be notified by Bayer when regulatory approvals are in place and the 
updated NIST standardization is to be implemented.  Upon notification, and prior to the 
implementation, all sites will need to add a new dial-setting to their dose calibrators for the 
new NIST standardization for radium-223 dichloride (NIST update [32]), which should be 
documented on the appropriate study forms.  This step will be performed so that all sites will 
have the new dial setting (NIST update [32]) in place at the time of implementation.  The 
current dial setting (NIST 2010) will be used until the worldwide global implementation date 
anticipated for Q 2 2016.
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 patients randomized after the new reference standard is in effect will sign a 
revised ICF 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 Dose handling
Ordering of study drug will be done by notifying the IVRS / IWRS from the study site at 
pre-defined lead times before each planned administration.  The next dose may be requested 
in the IVRS / IWRS upon registration of the current dose through the pre-defined lead time 
(maximum number of days in transit for the given country plus a 2-day buffer) prior to the 
next planned dose date.
The radium-223 dichloride vials must be stored inside their lead container in a secure facility.  
The study drug should be used within 28 days of production.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 46 of 291
Radium-223 dichloride is an alpha particle-emitting radiopharmaceutical and should be 
handled by individuals who are qualified by training and experience in the safe handling of 
radionuclides.  One dedicated person and a back-up designee will have responsibility as 
assigned from the principal investigator for handling and storage of radium-223 dichloride.
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 study 
documentation.  For the US sites which have PRDs prepared at the country depot, the 
measurements of the vial activity before and after dose preparation should be checked and 
recorded by the depot staff and a copy of the documentation should be provided to the site for 
each PRD.  All administrations of radium-223 dichloride will be based on the certified 
activity of radium-223 at the reference date.
6.4.3 Dose calculation
Section modified by Amendment 2 (Section 13.2).
The dosage of radium-223 dichloride is 50 kBq/kg (55 kBq/kg after implementation of NIST 
update) body weight (Treatment Arms A and C) or 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) body weight (Treatment Arm B).  The total activity to be 
injected will be calculated volumetrically using the subject’s body weight, the 50 (55 kBq/kg 
after implementation of NIST update) or 80 kBq/kg body (88 kBq/kg after implementation of 
NIST update) weight 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 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/kga
= volume to be injected (mL)
DK x 1,000 kBq/mLb
a 55 kBq/kg after implementation of NIST update 
b 1,100 kBq/mL after implementation of NIST update 
For high dose treatment arm:
Body Weight (kg) x 80 kBq/kgc
= volume to be injected (mL)
DK x 1,000 kBq/mLb
c 88 kBq/kg after implementation of NIST update 
b 1,100 kBq/mL after implementation of NIST update 
Data regarding activity, calculations, and volume to be injected must be recorded in the 
source documentation and on the appropriate eCRF page.  This applies to both doses that are 
prepared at the site and doses that are prepared by an off-site vendor.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 47 of 291
For the US sites which have PRDs prepared at the country depot:

The subject’s weight measured at the dosing visit will be obtained at the site 
approximately 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; a record of this information transfer will be retained at the site.

Documentation by the central PRD depot of the required activity, calculations, and 
volume in the syringe will be retained at the depot with a copy provided to the site.
6.4.4 Dose preparation
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
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).  Staff 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.
A radio pharmacy will prepare a subject ready dose for dispensing to the subject.  In the US, 
Cardinal Health is the radio pharmacy that will dispense the subject ready dose.
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.
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.
6.4.5 Dose administration
The subject should be encouraged to arrive at the clinic well-hydrated on each dosing day.  
Subjects should avoid drinking or eating within 1 hour before and after administration of the 
study drug.  After administration of study drug, the subject should be encouraged to be 
well-hydrated and to drink ad libitum.
Aseptic technique should be used in the administration of radium-223 dichloride.  The 
syringe should be handed over to the 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.  
After administration, the equipment used in connection with the preparation and 
administration of drug is to be treated as radioactive waste and should be disposed of in 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 48 of 291
accordance with hospital procedure for the handling of radioactive material.  For central PRD 
depots, the same principles apply to dose preparation and handling of radioactive material.
6.4.6 Dose adjustments
Every effort will be made to administer the full dosing regimen of radium-223 dichloride.  
Adjustment of dose level is not permitted.
6.4.7 Dose delays
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Study visits during the treatment period should occur at 28-day intervals (within a window of 
± 7 days).  Delays up to 4 weeks are allowed when the subject is recovering from toxicity.  
Adverse events will be followed as clinically indicated (see Section 7.5.1.3).
Dosing delays may be instituted under the following circumstances:
Disease progression:
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, or neurological and 
hematological complications, as well as metastases to other organs, such as liver and lung.
The investigator should delay treatment with cytotoxic chemotherapy for prostate cancer, 
including taxanes, estramustine, and mitoxantrone, other systemic radioisotopes, hemibody 
EBRT, or other investigational drug, if possible, until the follow-up period.  If the 
investigator determines that such treatments must be given while the subject is receiving 
study drug, further study drug administration must be discontinued.  Subjects who are 
discontinued from study drug will be classified as “withdrawn from treatment” and will enter 
the active follow-up period. If the subject is not treated with any of the prohibited anti-cancer 
therapies, the administration of study drug may be continued until completion of 6/12 cycles
if, in the investigator’s opinion, the subject will continue to receive clinical benefit from 
remaining on study treatment.
Myelosuppression:
Treatment-related changes in hematology parameters may occur.  Hematology values will be 
graded according to the NCI-CTCAE, version 4.03 (14 JUN 2010).

If a subject experiences NCI-CTCAE Grades 3 or 4 neutropenia or thrombocytopenia 
(see Table 6–1), the study drug administration should be delayed until recovery to 
Grade 2 (minimum 1.0 x 109/L) or better.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 49 of 291

If a subject experiences sustained CTCAE Grade 3 neutropenia or sustained CTCAE 
Grades 3 or 4 thrombocytopenia (see Table 6–1) lasting > 2 weeks despite adequate 
treatment and regardless of causality, the subject must be discontinued from treatment 
with radium-223 dichloride.

If a subject experiences sustained CTCAE Grade 4 neutropenia (see Table 6–1) 
lasting > 1 week despite adequate treatment and regardless of causality, the subject 
must be discontinued from treatment with radium-223 dichloride.

Blood transfusions are acceptable during the treatment period, but erythropoietin is 
not allowed.  Use of biologic response modifiers, such as GM-CSF or G-CSF, is 
allowed in the management of acute toxicity during the treatment period.  Such drugs 
(and transfusions) cannot be used for 4 weeks prior to screening and during the 
screening period, or prior to the start of treatment.
Table 6–1 National Cancer Institute Common Terminology Criteria for Adverse 
Events (version 4.03) Grade 3 and 4 values for neutropenia and thrombocytopenia
Adverse Event
Grade 3
Grade 4
Neutropenia
(neutrophil count decreased)
< 1,000 to 500/mm3;
< 1.0 to 0.5 x 109/L
< 500/mm3;
< 0.5 x 109/L
Thrombocytopenia
(platelet count decreased)
< 50,000 to 25,000/mm3;
< 50.0 to 25.0 x 109/L
< 25,000/mm3;
< 25.0 x 109/L
Gastrointestinal events:
Diarrhea: Diarrhea should be treated as per local practice.  A further dose of study medication 
should not be given before diarrhea has recovered to CTCAE (version 4.03) Grade 2 or 
lower.
Nausea / vomiting: Nausea or vomiting should be treated as per local practice.  A further dose 
of study medication should not be given before nausea or vomiting has recovered to CTCAE 
(version 4.03) Grade 2 or lower.
Spinal cord compression:
If the subject experiences spinal cord compression during the treatment period, the subject 
should be treated for the event, and may receive further study drug administration if 
adequately recovered.  A dose delay of up to 4 weeks is permitted.
External beam radiotherapy:
No dose delay is needed for EBRT.
Surgical intervention:
If surgery is required, the subject should continue with study treatment, if this is considered 
safe in the treating investigator’s opinion.  The surgeon needs to be notified that the subject 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 50 of 291
has been given radioactive drug and needs to follow the guidelines for radioactive protection.  
The subject should continue with study treatment if it is considered safe in the treating 
investigator’s opinion.
Non-pathological fractures:
For traumatic fractures in weight-bearing bones during the treatment phase, the study drug 
administration should be delayed for 2 to 4 weeks from the time of fracture.
Pathological fractures:
Pathological fractures may occur as the result of either progressive disease or increased 
physical activity associated with significant pain palliation.  Pathologic fractures are to be 
treated in a manner that attempts to maintain the best functional status and QoL.  Study 
treatment may continue as planned.
Any other adverse event:
If a subject experiences any non-hematological CTCAE (version 4.03) Grade 4 adverse event
regardless of causality lasting more than 7 days despite adequate treatment, further study drug 
administration must be discontinued.
Logistical difficulties:
Screening to Dose 1: An additional 14 days will be permitted for the 14-day screening 
window for ‘failed’ quality of investigational product that requires replacement or 
extraordinary logistical issues.  Prior written approval by the sponsor designee is required and 
screening assessments may need to be repeated to be within the 14 (± 7)-day window prior to 
randomization.  The maximum period allowed for screening will be 35 days (14 days 
screening + 7 day window + 14 days for rescreening).
Doses 2 to 6 (or Doses 2 to 12 for Treatment Arm C): An additional 28 days will be 
permitted for Doses 2 to 6 (or Doses 2 to 12 for Treatment Arm C) for ‘failed’ quality of 
investigational product that requires replacement or extraordinary logistical issues.  Prior 
written approval by the sponsor designee is required.
A dose delay of more than 4 weeks (maximum of 8 weeks between 2 injections) will lead to 
study drug discontinuation.
Note: efficacy assessments should be performed as scheduled despite delays in dosing.
6.5
Blinding
This study is an open-label study.  


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 51 of 291
6.6
Drug logistics and accountability
All study drugs at the investigational site will be stored in accordance with Good Clinical 
Practice (GCP) and GMP requirements and the instructions given by the clinical supplies 
department of the sponsor (or its affiliate / clinical research organization [CRO]), and will be 
inaccessible to unauthorized personnel.  Special storage conditions and a complete record of 
batch numbers and expiry dates can be found in the sponsor study file; the site-relevant 
elements of this information will be available in the investigator site file.  Records of the 
study drug received at the site (and at the country PRD depot, when used in the US) will be 
retained as required.  The responsible site personnel will confirm receipt of study drug via the 
IVRS / IWRS and will use the study drug only within the framework of this clinical study 
and in accordance with this protocol.  Receipt, distribution, and destruction of the study drug 
must be properly documented according to the sponsor’s agreed and specified procedures.  
The monitor will review overall drug accountability and destruction per the site 
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 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.
Written instructions on medication destruction will be made available to affected parties as 
applicable.
6.7
Treatment compliance
Subjects will receive treatment with radium-223 dichloride under the supervision of a 
physician licensed in the administration of radioisotopes.  Personnel will check the 
administration volume and total radioactivity injected.  The activity dose (total and per body 
kilogram) along with the volume and the radioactivity measured in the syringe before and 
after the injection will be recorded in the source data and the appropriate eCRF.  The actual 
administered radioactivity must be within the tolerance limits of ± 10% of the calculated 
radioactivity.
6.8
Post-study therapy
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 
4 (Section 13.4.1.2).
Subjects will have an EOT visit 30 (± 7) days following the last dose of study drug, including 
early discontinuation of study drug, and will be followed every 12 weeks for safety and SSE
evaluations.  Every effort will be made to follow subjects through clinic visits; however, 
phone contact will be undertaken for subjects unable to come to the clinic.  The active 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 52 of 291
follow-up period will continue for 2 years after the subject’s last dose of radium-223 
dichloride or until the primary efficacy analysis matures, whichever occurs last.  
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported radium-223 dichloride-related AEs and SAEs, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes, and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death.  In addition, during the long-term follow-up 
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.  During long-term follow-up, subjects, their treating health care professional, or 
caregiver will be contacted every 6 months by telephone.  All subjects who transition into this 
separate long-term follow-up study will require a separate signed informed consent.  Subject 
data collected at other standard-of-care visits and / or contacts may be used to satisfy study-
required data.
Transition of all subjects into the separate long-term follow-up study will begin following the 
later of primary endpoint completion or 2 years after the last radium-223 dichloride treatment 
is administered to the last treated subject.
Until the transition to the long term follow-up study begins, some subjects may begin 
long-term follow-up in this study.  This study will end when all subjects have transitioned 
into the long-term follow-up study or discontinued from this study for another reason (e.g., 
Consent Withdrawn, Lost to Follow-up).
6.9
Prior and concomitant therapy
6.9.1 Prior therapy
Section modified by Amendment 2 (Section 13.2).
Prior hemibody EBRT or systemic radiotherapy with strontium-89, samarium-153, 
rhenium-186, or rhenium-188 is not allowed.  Subjects are not allowed to receive an 
investigational drug or cytotoxic chemotherapy for prostate cancer, including taxanes, 
estramustine, and mitoxantrone, within 4 weeks prior to randomization in this study.  Blood 
transfusions, erythropoietin, or biologic response modifiers, such as GM-CSF or G-CSF, are 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 53 of 291
not allowed within 4 weeks of screening, during the screening period, or prior to the start of 
treatment.
Information about previous treatment both for primary tumor and bone metastases will be 
recorded in the medical record and in the appropriate eCRF.
All other prior medications, including but not limited to pain medications, antibiotics, 
steroids, bisphosphonates, iron therapy, or radiation therapy taken in the 30 days prior to start 
of study treatment will be recorded in the subject’s medical record and in the appropriate 
eCRF.  The generic or trade name, indication, dosage, and start and stop dates must be 
recorded.
6.9.2 Concomitant medication
Section modified by Amendments 2 (Section 13.2) and 4 (Sections 13.4.1.1, 13.4.1.3, and 
13.4.1.5).
During treatment, all concomitant medications, including therapies for prostate cancer, must 
be recorded in the source documentation as well as the appropriate pages of the eCRFs.  The 
generic or trade name, indication, dosage, and start and stop dates must be recorded.
Contrast media will not be captured as concomitant medication unless there is an AE or SAE 
related to administration of contrast media.
Allowed concomitant treatments for prostate cancer include: LHRH analogs, surgery, 
radiation therapy, flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, 
corticosteroids, estrogens, and enzalutamide.  Subjects who have not undergone bilateral 
orchiectomy are to receive LHRH agonists or antagonists or polyestradiol phosphate 
throughout the study.
Radium-223 dichloride should not be given concurrently with abiraterone plus
prednisone/prednisolone.
Subjects receiving bone health agents (BHA), such as bisphosphonates or denosumab, prior 
to receiving study drug treatment may be maintained on these therapies throughout all or part 
of the treatment period.  Subjects in the treatment period can also initiate these therapies at 
any time.  Based on the available data on radium-223 dichloride, the option of starting a BHA 
during the follow up periods should be considered, taking into consideration applicable 
guidelines. Treatment with bisphosphonates or denosumab may be stopped at the discretion 
of the investigator.  
Analgesic use will be followed and any medications taken for pain should be recorded in the 
source documentation and in the appropriate eCRF.  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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 54 of 291
Blood transfusions are allowed during the treatment period, but erythropoietin is not allowed.
Cytotoxic chemotherapy for prostate cancer, including taxanes, estramustine, and 
mitoxantrone, other systemic radioisotopes, hemibody EBRT, and investigational drugs are 
prohibited.
If the investigator determines that a prohibited treatment is required during the treatment 
period, study drug administration must be discontinued.  If possible, the prohibited therapy 
should not be initiated for at least 4 weeks after the last dose of study drug and after 
completion of the EOT assessments.
7. Procedures and variables
7.1
Schedule of procedures
7.1.1 Tabulated overview
A summary of the schedule of procedures is provided in Table 7–1.
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 
4 (Sections 13.4.1.1 and 13.4.1.2).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 55 of 291
Table 7–1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term 
Follow-up (up 
to 7 years 
after last dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 days 
prior to 
random.c
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 24d
Day 1, Week 28d
Day 1, Week 32d
Day 1, Week 36d
Day 1, Week 40d
Day 1, Week 44d
30 days post-last 
dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up to 
7 years post-last 
dose
End of
Long-term 
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Informed 
consent
X
Inclusion / 
exclusion 
criteriaf
X
Xg
Xg
Demographic 
data
X
Medical and 
disease history
X
Height
X
Weighth
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Training on 
daily PRO pain 
collectioni
X
Pain 
assessmentj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Xk
Randomizationl
X
Review daily 
PRO pain input
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Xk
BPI-SFm
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Xk


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 56 of 291
Table 7–1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term 
Follow-up (up 
to 7 years 
after last dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 days 
prior to 
random.c
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 24d
Day 1, Week 28d
Day 1, Week 32d
Day 1, Week 36d
Day 1, Week 40d
Day 1, Week 44d
30 days post-last 
dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up to 
7 years post-last 
dose
End of
Long-term 
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
NCCN FACT-
P Symptom 
Index-17
Questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
24-hour
Analgesic use 
collectiono
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Vital signsp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examinationq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry 
panel and 
CBCr
X
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
PSA
X
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
X
X
X
Testosterone
X
Whole body 
technetium-99 
bone scansu
X
X
X
X
X
X
X
Xu
X
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 57 of 291
Table 7–1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term 
Follow-up (up 
to 7 years 
after last dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 days 
prior to 
random.c
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 24d
Day 1, Week 28d
Day 1, Week 32d
Day 1, Week 36d
Day 1, Week 40d
Day 1, Week 44d
30 days post-last 
dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up to 
7 years post-last 
dose
End of
Long-term 
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Documentation 
of bone 
metastasesw
X
MRI / CT scan 
abdomen and 
pelvis, chest 
X-rayu
X
X
X
X
X
X
X
Xv
X
X
IVRS / IWRSx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Radium-223 
dichloride 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oral hydrationy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject contact 
cardz
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject and 
family 
instructionsaa
X
X
X
Record SSEs
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xcc
Xcc
Record 
concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 58 of 291
Table 7–1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term 
Follow-up (up 
to 7 years 
after last dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 days 
prior to 
random.c
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 24d
Day 1, Week 28d
Day 1, Week 32d
Day 1, Week 36d
Day 1, Week 40d
Day 1, Week 44d
30 days post-last 
dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up to 
7 years post-last 
dose
End of
Long-term 
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Record limited 
concomitant 
medicationdd
X
X
Record therapy 
for prostate 
cancer other 
than 
radium-223 
dichloride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xee
X
X
X
X
X
Record 
chemotherapy 
for other 
malignancies
X
X
X
X
X
X
Record new 
primary 
malignancies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record AEs 
and SAEsff
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 59 of 291
Table 7–1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term 
Follow-up (up 
to 7 years 
after last dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 days 
prior to 
random.c
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 0d
Day 1, Week 4d
Day 1, Week 8d
Day 1, Week 12d
Day 1, Week 16d
Day 1, Week 20d
Day 1, Week 24d
Day 1, Week 28d
Day 1, Week 32d
Day 1, Week 36d
Day 1, Week 40d
Day 1, Week 44d
30 days post-last 
dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up to 
7 years post-last 
dose
End of
Long-term 
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Record 
radium-223 
dichloride 
related AEs 
and SAEsgg
X
X
X
X
Xhh
Xhh
Record 
SSE-related 
AEs and 
SAEsgg
X
X
Survival status
X
X
X
X
Abbreviations: AE = adverse event; BPI-SF = Brief Pain Inventory Short Form; CBC = complete blood count; CT = computed tomography; ECOG = Eastern 
Cooperative Oncology Group; EOT = end of treatment; ICF = informed consent form; IVRS / IWRS = interactive voice / web response system; MRI = magnetic 
resonance imaging; NCCN = National Comprehensive Cancer Network; PCWG2 = Prostate Cancer Clinical Trials Working Group 2; PRO = Patient-reported 
outcome; PS = performance status; PSA = prostate specific antigen; q6 = every 6; q12 = every 12; RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; SSE = symptomatic skeletal event; US = United States; wk = week; WPS = worst pain score.
a Once a subject switches from active follow-up with clinical visits to active follow-up without clinical visits, the subject will not be allowed to switch back.  A 
subject with a possible SSE may, and is encouraged to, return to the clinic at any time to assess for the presence of an SSE.
b. Subjects, their treating health care professional, or caregiver will be contacted every 6 months by telephone.  Once a separate, extended safety follow-up 
protocol, for the inclusion of subjects who received radium-223 dichloride in the course of Bayer sponsored clinical studies, has been implemented, the study 
subjects surviving after the end of the 2 years of active follow-up will be transitioned to this separate, extended safety follow-up protocol and the current study 
will be terminated at the time the last study subject is transitioned. Subject data collected at other standard-of-care visits and / or contacts may be used to 
satisfy study-required data.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 60 of 291
c. The maximum period for rescreening screen failed subjects is 35 days (14 days screening + 7-day window + 14 days for rescreening) from signing the ICF to 
randomization.  Rescreening of a subject requires prior approval of the Bayer-designated medical representative (see Section 5.1).  Eligibility should be 
confirmed within 14 ± 7 days of randomization.
d. The subject should return to the clinic in advance of the scheduled dose visit such that results of the laboratory assessment are available within 72 hours prior 
to dosing (each dose period is 28 ± 7 days after the prior dose of radium-223 dichloride).
e. Subjects who can no longer travel to the clinical site or who receive further anticancer therapy will only be followed up by telephone (active follow-up without 
clinic visits).  Symptomatic skeletal events will not be collected over the phone.
f. The study record or subject’s clinical record must clearly show that informed consent was obtained prior to any other study procedures being performed.  
Eligibility should be confirmed during the screening period and reconfirmed prior to dosing at Dose 1, Day 1.
g. Reconfirmation of eligibility and registration in the IVRS / IWRS: hematology results obtained within 72 hours of Dose 1, Day 1 should be reviewed and it should 
be confirmed that the values are still within the treatment ranges (absolute neutrophil count ≥1.5 x 109/L, platelet count ≥100 x 109/L, and hemoglobin ≥9.0 
g/dL).  
h. Body weight should be obtained without shoes, using a calibrated electronic physician (column) scale with digital display, measurement units 0.1 kg.  The same 
scale should be used for a given subject throughout the study.  At all sites (in US and outside US), weight is to be taken only once for each dose.  For non-
US sites the weight should be performed within 72 hours prior to dosing.  For US sites, subject weight for the dose day should be obtained at the site within 3 
to 5 days prior to the dose visit.  This weight must be reported to the country PRD depot to allow adequate time for PRD preparation and delivery 
(approximately 2 days).  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.  Please note this is applicable to all dosing visits.  Body weight can be obtained at the local healthcare provider on a calibrated scale and 
the results sent by fax to the Principal Investigator with advanced notice and agreement from the Covance Medical Monitor for each subject.  No other 
procedures can be done at the local healthcare provider.
i When a subject is determined to be eligible, the subject will be trained on daily PRO pain data collection using a handheld device.  The subject will then 
complete the pain assessment daily for 4 days prior to randomization and then daily for one week (6 days prior to Cycle 1, Day 1 or subsequent visits, as 
applicable, plus the morning of the visit).
j. Pain will be assessed during the screening period daily for 4 days prior to randomization and daily for one week (6 days prior to Cycle 1, Day 1 or subsequent 
visits, as applicable, plus the day of the visit).  Subjects will complete the daily pain assessment using a handheld device.  The daily PRO pain input results 
should be reviewed at the visit to check for completeness.
k For Treatment Arms A and B only, pain data will be collected daily using the handheld device for one week (6 days prior to the applicable visit, plus the morning 
of the visit) prior to Week 36 and 48 visits, and daily for one week (6 days prior to the applicable phone call, plus the morning of the phone call) prior to each 
telephone contact at Weeks 28, 32, 40 and 44.  For Treatment Arms A and B only the BPI-SF and the NCCN FACT-P Symptom Index-17 (NCCN-FACT 
FPSI-17) questionnaires will be completed on the day of the Week 36 and 48 visits and on the day of each telephone contact at Weeks 28, 32, 40 and 44.  
Twenty-four (24) hour analgesic use will be collected by the study investigator at Week 36 and 48 Visits and at each telephone contact (in Arms A and B) at 
Weeks 28 (±7 days), 32 (±7 days), 40 (±7 days), and 44 (±7 days).
l. The randomization will be permuted-block, stratified by the use of prior chemotherapy (≤1 regimen versus > 1 regimen), by total alkaline phosphatase 
(< 220 U/L versus ≥220 U/L), and by average WPS of the BPI-SF (WPS ≤4 versus WPS > 4).  Treatment group assignment will occur when the subject is 
randomized via IVRS / IWRS; this randomization step at up to 28 days prior to Dose 1.  Randomization triggers an order for study drug (durations vary based 
on country specific ordering lead times; US depot requires additional step).
m. The BPI-SF questionnaire will be completed at each clinic visit from Dose 1, Day 1 until the Week 48 visit and for Treatment Arms A and B only, on the day of 
each telephone contact at Weeks 28, 32, 40 and 44.  For further details, see Section 14.7.
n. Prior to randomization, the subject will use the hand-held device to complete selected questions from the BPI-SF questionnaire, Question 3, worst pain in the 
last 24 hours will be completed for at least 4 days during a period of no more than 1 week prior to randomization. The average of the 4 days will be used as 
the randomization stratification value. 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 61 of 291
o. Twenty-four (24)-hour analgesic use will be collected and it will be assessed by the study investigator until the Week 48 visit.  Twenty-four (24)-hour analgesic 
use will also be collected by the study investigator at each telephone contact (in Arms A and B) or visit at Weeks 28, 32, 40, and 44. 
p. Systolic / diastolic blood pressure, respiratory rate, body temperature, and heart rate will be measured after the subject has rested for at least 5 minutes.
q. After a complete physical examination at screening, subsequent physical examinations may be 'brief,' but should include any systems with symptoms.  All 
physical examinations will be performed by a physician according to the standard of care.
r. Complete blood count, including hematocrit, hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, white blood cell count, platelet count, and differential blood count reported as absolute count or percentage for neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils will be collected.  Chemistry panel including serum creatinine, sodium, potassium, chloride, calcium, 
phosphorous, magnesium, total bilirubin, total alkaline phosphatase, aspartate transaminase, alanine transaminase, lactate dehydrogenase (screening only), 
and albumin (screening only).
s. Laboratory assessments should be performed within 72 hours of the visit and the results assessed and documented prior to dosing.
t. The PSA result for each dosing visit may be assessed post-dose.
u. Radiological / progression (according to PCWG2 criteria) will be assessed by means of whole body technetium-99 bone scan, chest X-ray (in the presence of 
suspicious lesion[s], a chest CT scan will be performed to confirm and characterize the lesion[s]), and MRI / CT scan of the abdomen and pelvis.  Baseline 
tumor assessment should be performed within 14 (± 7) days of randomization.  If standard of care bone scan and / or MRI / CT scan of the abdomen and 
pelvis and chest X-ray within 8 weeks of randomization are available, they do not need to be repeated at baseline.  If they are not available, they should be 
performed within 14 days ± 7 days of randomization (i.e., during the screening period).  Subsequent tumor assessment should be performed at Week 8, 
Week 16, Week 24 and every 12 weeks thereafter for up to 2 years after the subject’s last dose of radium-223 dichloride or until radiological progression 
(according to PCWG2 criteria or RECIST guidelines), or death, whichever comes first.  If progression is detected by bone scan, a confirmatory bone scan is 
required at least 6 weeks later.  All images should be obtained with the same technique (e.g., CT or MRI) as those obtained at screening.  Schedule 
deviations of ± 2 weeks for imaging / tumor evaluations are allowed.
v. Imaging is not required at the EOT visit if the subject discontinued due to radiological progression or the last tumor evaluation is not older than 4 weeks.
w. Bone imaging should be within 8 weeks of randomization.  If no prior documentation is available, a whole body technetium-99 bone scan will be obtained at 
screening (within 14 ± 7 days of randomization).
x. The IVRS / IWRS will be used to register requests for eligibility / study drug doses.  Once the subject eligibility is approved and registered in the IVRS / IWRS, 
including entry of required demographic and stratification information, the initial drug shipment may be prepared.  Additional IVRS / IWRS transactions for 
dose orders may be required; follow the country-specific guidance in the IVRS / IWRS manual.  The latest order date for the next dose is no later than the 
pre-defined lead time (number of days from order received to delivery to site in the country) prior to the planned dosing date.  The planned date for the next
dose must be specified, when the dose is requested in the IVRS / IWRS.  At Doses 1 through 5, the site should order the next dose in the IVRS / IWRS, as 
soon as the current visit’s dose is registered in the IVRS / IWRS.  The latest order date for the next dose is no later than the pre-defined lead time (number of 
days from order received to delivery to site in the country) prior to the planned dosing date.  For subject visit registrations in the IVRS / IWRS, see the IVRS / 
IWRS manual.
y. The subject should be encouraged to arrive at the clinic well-hydrated on each dosing day and to drink ad libitum after each dose of radium-223 dichloride.  The 
subject should avoid drinking or eating within 1 hour before and after administration of the study drug.
z. The subject contact card is to be provided at each dosing visit for the subject to carry with him until the next visit.
aa. Subject and family instructions should be reviewed with the subject during screening through Dose 1, Day 1.
bb. Subjects identified with possible SSEs will be asked to come to the clinic for an SSE evaluation.  An SSE risk questionnaire will be developed.  Symptomatic 
skeletal events will not be identified over the telephone.
cc. If a subject has an SSE in the active follow-up period, he will continue active follow-up for 2 years following last study treatment.  At Weeks 28, 32, 40, and 44, 
subjects in Treatment Arms A and B will receive telephone contacts assessing for possible SSE risks.  Subjects exhibiting symptoms indicative of possible 
SSEs will be encouraged to visit the clinic early to assess SSE


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 62 of 291
status.  Symptomatic skeletal events will not be determined over the phone. 
dd. Except for complete analgesic use information recorded through Week 48, limited concomitant medication, including narcotic pain medication, will be recorded 
during the active follow-up with clinic visits period.  Contrast agents will only be captured as concomitant medication if there is an AE or SAE related to 
administration of contrast media. 
ee. Subjects who receive further anticancer therapy during the active follow-up period will have an end of active follow-up with clinic visits and will enter the active 
follow-up without clinic visits (telephone follow-up).  Subjects who receive further anticancer therapy after 2 years from last study treatment will enter long-
term follow-up. Radium-223 dichloride should not be given concurrently with abiraterone plus prednisone/prednisolone.
ff. All AEs and SAEs will be assessed and recorded from the time the ICF is signed until 30 days after the last dose of study medication.  All AEs should be 
assessed and documented prior to each dose of radium-223 dichloride.
gg. Any AEs and SAEs occurring beyond 30 days after the last treatment must be documented and reported if considered to be related to study medication or if 
related to an SSE.  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. In addition, during follow-up 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.
hh. Any SAEs 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. In addition, during follow-up 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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 63 of 291
7.1.2 Timing of assessments
7.1.2.1 Screening period
Section modified by Amendments 1 (13.1) and 2 (Section 13.2).
The subject should come to the clinic for screening, preferably in the morning.  The 
following documentation should be collected and assessments should be performed during 
the screening period:
Within 14 (± 7) days prior to randomization:

Signing of the ICF prior to any study specific procedures (enrollment in the study is 
defined as the signing of the ICF)

Confirmation of eligibility criteria

Documentation of demographic data, including age, gender, race, and ethnicity

Height and weight (Note: Body weight should be obtained without shoes, using a 
calibrated electronic physician [column] scale with digital display, measurement units 
0.1 kg.  The same scale should be used for a given subject throughout the study, if 
possible.)

ECOG PS

Documentation of medical history

Documentation of disease history, including prior and current anticancer treatments

Laboratory assessments
o
Complete blood count (CBC), including hematocrit, hemoglobin, red blood 
cell (RBC) count, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), 
white blood cell (WBC) count, platelet count, and differential blood count 
reported as absolute count or percentage for neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin, total ALP, AST, ALT, 
lactate dehydrogenase (LDH), and albumin 

PSA

Testosterone


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 64 of 291

Vital signs (systolic / diastolic blood pressure, respiratory rate, body temperature, and 
heart rate will be measured after the subject has rested for at least 5 minutes)

Complete physical examination

Review of subject and family instructions

Recording of 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)
o
Tumor-related orthopedic surgical intervention
o
Spinal cord compression

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in the 
presence of suspicious lesion[s], a chest CT scan will be performed to confirm and 
characterize the lesion[s]), and whole body technetium-99 bone scan will be 
performed within 14 ± 7 days prior to randomization (i.e., during the screening 
period).  If MRI / CT scan of the abdomen and pelvis, and chest X-ray performed 
within 8 weeks of randomization are available, they do not need to be repeated at 
baseline.

Documentation of bone metastases
o
If standard of care bone scan within 8 weeks of randomization is available, the 
scan does not need to be repeated at baseline.  If this scan is not available, the 
scan should be performed within 14 ± 7 days prior to randomization (i.e.,
during the screening period).  

Recording of AEs from the time the subject signs the ICF

Recording of concomitant medications

When a subject is determined to be eligible, the subject will be trained on daily 
Patient-reported outcome (PRO) pain data collection using a handheld device.  
Eligible subjects will then complete the pain assessment daily
o
for the 4 days immediately prior to randomization. The average of the daily
WPS over the 4-day period will be used for stratification (WPS ≤4 versus 
WPS > 4); 4 days of daily WPS data must be taken before randomization can 
occur. 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 65 of 291
o
for 6 full days prior to the dosing visit plus the morning of the day of the 
dosing visit prior to Dose 1, Day 1.

At all sites (in US and outside US), weight is to be taken only once for each dose.
o
For non-US sites, the weight should be performed within 72 hours prior to 
dosing.
o
For US sites using the central PRD depot ONLY, subject weight for Dose 1, 
Day 1 should be obtained at the site within 3 to 5 days prior to the dose visit.  
This weight must be reported to the country PRD depot to allow adequate time 
for PRD preparation and delivery (approximately 2 days).  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.
The IVRS / IWRS will be used to register requests for eligibility / study drug doses.  Once 
the subject eligibility is approved and registered in the IVRS / IWRS, including entry of 
required demographic and stratification information, the initial drug shipment may be 
prepared.  Additional IxRS transactions for dose orders may be required; follow the country-
specific guidance in the manual.  The latest order date for the next dose is no later than the 
pre-defined lead time (number of days from order received to delivery to site in the country) 
prior to the planned dosing date.  The planned date for the next dose must be specified, when 
the dose is requested in the IVRS / IWRS.  At Doses 1 through 5, the site should order the 
next dose in the IVRS / IWRS, as soon as the current visit’s dose is registered in the IVRS / 
IWRS.  For subject visit registrations in the IVRS / IWRS, see the IVRS / IWRS manual.
7.1.2.2 Randomization
Section modified by Amendment 2 (Section 13.2).
The treatment period for efficacy purposes begins at the time of randomization.  Subjects will 
be randomized to either: radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation 
of NIST update) IV every 28 days for up to 6 doses or radium-223 dichloride 80 kBq/kg 
(88 kBq/kg after implementation of NIST update) IV every 28 days up to 6 doses or 
radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) IV every 
28 days up to 12 doses.  The randomization will be permuted-block, stratified by the use of 
prior chemotherapy (≤1 regimen versus > 1 regimen), by total ALP (< 220 U/L versus 
≥220 U/L), and by the average of the daily WPS of the screening BPI-SF (WPS ≤4 versus 
WPS > 4). Treatment group assignment will occur when the subject is randomized via IVRS 
/ IWRS; this randomization step at up to 28 days prior to Dose 1.  Randomization steps
triggers an order for study drug (durations vary based on country specific ordering lead times; 
US depot requires additional step).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 66 of 291
7.1.2.3 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C)
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
On Day 1 of study therapy, the subject should return to the clinic, preferably in the morning 
and the following assessments will be performed prior to dosing, except where specified 
otherwise:

Reconfirmation of eligibility: hematology results obtained within 72 hours prior to
Dose 1, Day 1 should be reviewed and it should be confirmed that the values are still 
within the treatment ranges (absolute neutrophil count ≥1.5 x 109/L, platelet 
count ≥100 x 109/L, and hemoglobin ≥9.0 g/dL).

BPI-SF questionnaire using a handheld device (should be self-administered at the 
beginning of the visit and should be checked for completion at the visit; see Section 
14.7).

NCCN-FACT FPSI-17 questionnaire, using a handheld device, is also 
self-administered at the beginning of the visit and should be checked for completion 
at the visit prior to treatment (see Section 14.8).

Registration in the IVRS / IWRS

ECOG PS

Laboratory assessments (should be performed within 72 hours prior to the visit and 
the results assessed and documented prior to treatment)
o
CBC, including hematocrit, hemoglobin, RBC count, MCV, MCH, MCHC, 
WBC count, platelet count, and differential blood count reported as absolute 
count or percentage for neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin, total ALP, AST, and ALT

PSA (result may be assessed post-dose)

At all sites (in US and outside US), weight is to be taken only once for each dose.
o
For non-US sites, the weight should be performed within 72 hours prior to 
dosing.
o
For US sites using the central PRD depot ONLY, subject weight for Dose 1, 
Day 1 should be obtained at the site within 3 to 5 days prior to the dose visit.  
This weight must be reported to the country PRD depot to allow adequate time 
for PRD preparation and delivery (approximately 2 days).  All efforts should 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 67 of 291
be made to measure weight at the same visit with the pre-dose laboratory 
assessments in order to avoid 2 pre-dose clinic visits.

Vital signs (systolic / diastolic blood pressure, respiratory rate, body temperature, and 
heart rate will be measured after the subject has rested for at least 5 minutes)

Brief physical examination (see description in Section 7.5.3.2)

Review of subject and family instructions (can be done at any time during the visit)

Review of the daily pain PRO input results at the visit to check for completeness

Analgesic use evaluation: Analgesic use will be collected and it will be assessed by 
the study investigator.

Recording of 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)
o
Tumor-related orthopedic surgical intervention
o
Spinal cord compression

Recording of AEs; all AEs should be assessed and documented prior to the 
radium-223 dichloride dose

Recording of concomitant medications

Recording of therapy for prostate cancer other than radium-223 dichloride

Recording of new primary malignancies

Administration of radium-223 dichloride

Providing the subjects with the subject contact card to carry with him until the next 
visit (can be done at any time during the visit)

Subjects will complete the pain assessment daily for 6 days prior to the dosing visit 
plus the morning of the dosing visit prior to Dose 1, Day 1.
The subject should be encouraged to arrive at the clinic well-hydrated and to drink ad libitum 
prior to and after the radium-223 dichloride dose.  Subjects should avoid drinking or eating 
within 1 hour before and after administration of the study drug.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 68 of 291
Dose 2 should be ordered as soon as Dose 1 is registered in the IVRS / IWRS.  The planned 
date for the next dose must be specified, when the dose is requested in the IVRS / IWRS.  
The order date for the next dose cannot be earlier than the pre-defined country lead time, see 
IVRS / IWRS manual.
7.1.2.4 Doses 2 to 6 (Treatment Arms A and B)
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
The subject should return to the clinic at each dose visit during the treatment period, 
preferably in the morning, and the following assessments are required to be performed prior 
to dosing, except where specified otherwise (each dose period is 28 ± 7 days after the prior 
dose of radium-223 dichloride):

BPI-SF questionnaire using a handheld device (should be self-administered at the 
beginning of each visit and should be checked for completion at the visit; see 
Section 14.7)

NCCN-FACT FPSI-17 questionnaire, using a handheld device, is also 
self-administered at the beginning of the visit and should be checked for completion 
at the visit prior to treatment (see Section 14.8)

ECOG PS

Laboratory assessments (should be performed within 72 hours prior to the visit and 
the results assessed and documented prior to treatment at each treatment visit)
o
CBC, including hematocrit, hemoglobin, RBC count, MCV, MCH, MCHC, 
WBC count, platelet count, and differential blood count reported as absolute 
count or percentage for neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin, total ALP, AST, and ALT 

PSA (result may be assessed post-dose)

At all sites (in US and outside US), weight is to be taken only once for each dose.
o
For non-US sites, the weight should be performed within 72 hours prior to 
dosing.
o
For US sites using the central PRD depot ONLY, subject weight for the next 
dose, Day 1 should be obtained at the site within 3 to 5 days prior to the dose 
visit.  This weight must be reported to the country PRD depot to allow 
adequate time for PRD preparation and delivery (approximately 2 days).  All 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 69 of 291
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.

Vital signs (systolic / diastolic blood pressure, respiratory rate, body temperature, and 
heart rate will be measured after the subject has rested for at least 5 minutes)

Brief physical examination (see description in Section 7.5.3.2)

Review of the daily PRO pain input results at the visit to check for completeness

Analgesic use evaluation: Analgesic use will be collected and it will be assessed by 
the study investigator.

Recording of 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)
o
Tumor-related orthopedic surgical intervention
o
Spinal cord compression

Recording of AEs; all AEs should be assessed and documented prior to each dose of 
radium-223 dichloride

Recording of therapy for prostate cancer other than radium-223 dichloride

Recording of concomitant medications

Recording of new primary malignancies

Administration of radium-223 dichloride

Providing the subjects with the subject contact card to carry with him until the next 
visit (can be done at any time during the visit)

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in the 
presence of suspicious lesion[s], a chest CT scan will be performed to confirm and 
characterize the lesion[s]), and whole body technetium-99 bone scan will be 
performed at Week 8, Week 16, Week 24, then every 12 weeks for 2 years after the 
subject’s last dose of radium-223 dichloride or until radiologic progression.
o
Bone scans will be assessed by adapted PCWG2 criteria (30).  Per adapted 
PCWG2 criteria, confirmation of bone progression by a 2nd scan ≥6 weeks 
later is required in all cases. A SPECT or MRI (with and without contrast 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 70 of 291
media) should be obtained to clarify any suspicious bone scan findings. The 
date of confirmed radiological progression will be the date of first observation 
of radiological progression. The subject should remain on study treatment in 
the interim unless the investigator determines that there is immediate need to 
initiate cytotoxic chemotherapy.
o
All images should be obtained with the same technique (e.g., MRI or CT scan) 
as those obtained at screening
o
For radiologic progression confirmed during the treatment period and 
continued radium-223 dichloride therapy: If radium-223 dichloride treatment 
is continued beyond the date of confirmed radiologic disease progression 
(according to PCWG2 criteria), the MRI / CT scan of the abdomen and pelvis, 
chest X-ray, and whole body technetium-99 bone scan may be discontinued, 
but all other visit assessments should continue.  See Section 7.1.2.7.2.
o
For disease progression confirmed during the treatment period and premature 
discontinuation of radium-223 dichloride therapy: If the subject discontinues 
treatment prematurely for radiologically confirmed progression (according to 
PCWG2 criteria) or because the subject begins a new therapy with cytotoxic 
chemotherapy for prostate cancer, including taxanes, estramustine, and 
mitoxantrone, other systemic radioisotopes, hemibody EBRT, or an 
investigational drug, the subject should have all assessments as required per 
the EOT visit (Section 7.1.2.6) except that the imaging requirements should 
follow the guidance in Table 7–2.

Subjects will complete the pain assessment daily for 6 days prior to the dosing visit 
plus the morning of the dosing visit.

The subject should be encouraged to arrive at the clinic well-hydrated on each dosing 
day and to drink ad libitum prior to and after each radium-223 dichloride dose.  
Subjects should avoid drinking or eating within 1 hour before and after administration 
of the study drug.
At Doses 2 through 5, subsequent doses should be ordered as soon as the current visit’s dose 
is registered in the IVRS / IWRS.  The planned date for the next dose must be specified, 
when the dose is requested in the IVRS / IWRS.  The order date for the next dose cannot be 
earlier than the pre-defined country lead time.
7.1.2.5 Doses 2 to 12 (Treatment Arm C)
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
The subject should return to the clinic at each dose visit during the treatment period, 
preferably in the morning, and the following assessments are required to be performed prior 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 71 of 291
to dosing, except where specified otherwise (each dose period is 28 ± 7 days after the prior 
dose of radium-223 dichloride):

BPI-SF questionnaire using a handheld device (should be self-administered at the 
beginning of each visit through Week 48 and should be checked for completion at the 
visit; see Section 14.7)

NCCN-FACT FPSI-17 questionnaire, using a handheld device, is also 
self-administered at the beginning of the visit and should be checked for completion 
at the visit prior to treatment (see Section 14.8).

ECOG PS

Laboratory assessments (should be performed within 72 hours prior to the visit and 
the results assessed and documented prior to treatment at each treatment visit)
o
CBC, including hematocrit, hemoglobin, RBC count, MCV, MCH, MCHC, 
WBC count, platelet count, and differential blood count reported as absolute 
count or percentage for neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin, total ALP, AST, and ALT 

PSA (result may be assessed post-dose)

At all sites (in US and outside US), weight is to be taken only once for each dose.
o
For non-US sites, the weight should be performed within 72 hours prior to 
dosing.
o
For US sites using the central PRD depot ONLY, subject weight for the next 
dose, Day 1 should be obtained at the site within 3 to 5 days prior to the dose 
visit.  This weight must be reported to the country PRD depot to allow 
adequate time for PRD preparation and delivery (approximately 2 days).  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.

Vital signs (systolic / diastolic blood pressure, respiratory rate, body temperature, and 
heart rate will be measured after the subject has rested for at least 5 minutes)

Brief physical examination (see description in Section 7.5.3.2)

Review of the daily PRO pain input results at the visit to check for completeness
through Week 48


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 72 of 291

Analgesic use evaluation through Week 48: Analgesic use will be collected and it will 
be assessed by the study investigator.

Recording of 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)
o
Tumor-related orthopedic surgical intervention
o
Spinal cord compression

Recording of AEs; all AEs should be assessed and documented prior to each dose of 
radium-223 dichloride

Recording of therapy for prostate cancer other than radium-223 dichloride

Recording of concomitant medications

Recording of new primary malignancies

Administration of radium-223 dichloride

Providing the subjects with the subject contact card to carry with him until the next 
visit (can be done at any time during the visit)

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in the 
presence of suspicious lesion[s], a chest CT scan will be performed to confirm and 
characterize the lesion[s]), and whole body technetium-99 bone scan will be 
performed at Week 8, Week 16, Week 24, then every 12 weeks for 2 years after the 
subject’s last dose of radium-223 dichloride or until radiologic progression.
o
Bone scans will be assessed by adapted PCWG2 criteria (30).  Per adapted 
PCWG2 criteria, confirmation of bone progression by a 2nd scan ≥6 weeks 
later is required in all cases.  A SPECT or MRI (with and without contrast 
media) should be obtained to clarify any suspicious bone scan findings.  The 
date of confirmed radiological progression will be the date of first observation 
of radiological progression.  The subject should remain on study treatment in 
the interim unless the investigator determines that there is immediate need to 
initiate cytotoxic chemotherapy.
o
All images should be obtained with the same technique (e.g., MRI or CT scan) 
as those obtained at screening


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 73 of 291
o
For radiologic progression confirmed during the treatment period and 
continued radium-223 dichloride therapy: If radium-223 dichloride treatment 
is continued beyond the date of confirmed radiologic disease progression 
(according to PCWG2 criteria), the MRI / CT scan of the abdomen and pelvis, 
chest X-ray, and whole body technetium-99 bone scan may be discontinued, 
but all other visit assessments should continue.  See Section 7.1.2.7.2.
o
For disease progression confirmed during the treatment period and premature 
discontinuation of radium-223 dichloride therapy: If the subject discontinues 
treatment prematurely for radiologically confirmed progression or because the 
subject begins a new therapy with cytotoxic chemotherapy for prostate cancer, 
including taxanes, estramustine, and mitoxantrone, other systemic 
radioisotopes, hemibody EBRT, or investigational drugs, the subject should 
have all assessments as required per the EOT visit (Section 7.1.2.6) except that 
the imaging requirements should follow the guidance in Table 7–2.

Subjects will complete the pain assessment daily for 6 days prior to the dosing visit 
plus the morning of the dosing visit.

The subject should be encouraged to arrive at the clinic well-hydrated on each dosing 
day and to drink ad libitum prior to and after each radium-223 dichloride dose.  
Subjects should avoid drinking or eating within 1 hour before and after administration 
of the study drug.
At Doses 2 through 11, subsequent doses should be ordered as soon as the current visit’s dose 
is registered in the IVRS / IWRS.  The planned date for the next dose must be specified, 
when the dose is requested in the IVRS / IWRS.  The order date for the next dose cannot be 
earlier than the pre-defined lead time.
7.1.2.6 End of treatment visit
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
The subject should return to the clinic 30 (± 7) days following the last study treatment or the 
time of premature discontinuation from study treatment, preferably in the morning, and the 
following assessments should be performed:

BPI-SF questionnaire using a handheld device (should be self-administered at the 
beginning of the visit and should be checked for completion at the visit; see 
Section 14.7)

NCCN-FACT FPSI-17 questionnaire, using a handheld device, is also 
self-administered at the beginning of the visit and should be checked for completion 
at the visit prior to treatment (see Section 14.8).

ECOG PS


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 74 of 291

Laboratory assessments (should be performed within 72 hours prior to the visit and 
the results assessed and documented on the visit date)
o
CBC, including hematocrit, hemoglobin, RBC count, MCV, MCH, MCHC, 
WBC count, platelet count, and differential blood count reported as absolute 
count or percentage for neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin, total ALP, AST, and ALT 

PSA

Weight

Vital signs (systolic / diastolic blood pressure, respiratory rate, body temperature, and 
heart rate will be measured after the subject has rested for at least 5 minutes)

Brief physical examination (see description in Section 7.5.3.2)

Review of the daily PRO pain input results at the visit to check for completeness) 

Analgesic use evaluation: Analgesic use will be collected and it will be assessed by 
the study investigator

Recording of 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)
o
Tumor-related orthopedic surgical intervention
o
Spinal cord compression

Recording of AEs and SAEs for 30 days after the last treatment

Recording of concomitant medications

Recording of therapy for prostate cancer other than radium-223 dichloride

Recording of new primary malignancies

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in the 
presence of suspicious lesion[s], a chest CT scan will be performed to confirm and 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 75 of 291
characterize the lesion[s]), and whole body technetium-99 bone scan on the EOT visit, 
if the last tumor evaluation is older than 4 weeks
o
Per adapted PCWG2 criteria (30), confirmation of bone progression by a 2nd
scan ≥6 weeks later is required in all cases.  A SPECT or MRI (with and 
without contrast media) should be obtained to clarify any suspicious bone scan 
findings.  The date of confirmed radiological progression will be the date of 
first observation of radiological progression.
o
All images should be obtained with the same technique (e.g., MRI or CT scan) 
as those obtained at screening
o
For premature discontinuation due to radiological soft tissue progression per 
modified RECIST 1.1 criteria, the confirmation MRI / CT scan of the 
abdomen and pelvis and chest X-ray (in the presence of suspicious lesion[s], a 
chest CT scan will be performed to confirm and characterize the lesion[s]) 
should be completed within the window required per PCWG2 guidance.  In 
case of unequivocal soft tissue progression, a confirmatory scan is not 
mandatory and it will be performed at the investigator’s discretion.
o
For premature discontinuation due to radiological bone progression that has 
been noted on imaging but not confirmed, the confirmation bone scan should 
be completed within the window required per PCWG2 guidance.
o
For premature discontinuation after confirmed radiological progression per 
PCWG2 guidance, the MRI / CT scan of the abdomen and pelvis, chest X-ray,
and the whole body technetium-99 bone scan do not need to be repeated.

Subjects will complete the pain assessment daily for the 6 days prior to plus the 
morning of the Week 28 telephone contact (Treatment Arms A and B only).
In case the 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, 
information on new primary malignancies, including acute myeloid leukemia, and 
hematological conditions, such as myelodysplastic syndrome, aplastic anemia, myelofibrosis, 
as well as any anticancer therapies, will be discussed and captured in the eCRFs.  In these 
cases, the active follow-up with clinic visits will not take place and the subject will go 
directly into the active follow-up without clinic visits.  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.
7.1.2.7 Active follow-up
Section modified by Amendment 1 (Section 13.1).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 76 of 291
The active follow-up has 2 distinct periods: the active follow-up with clinic visits and the 
active follow-up without clinic visits.  Once a subject switches from active follow-up with 
clinical visits to active follow-up without clinical visits, the subject will not be allowed to 
switch back. However, in the event an SSE is identified at an unscheduled clinic visit in an
active follow-up subject, an unscheduled-visit SSE should be recorded regardless of whether 
the subject is receiving clinic visits or telephone-only follow-up.
7.1.2.7.1 Active follow-up with clinic visits
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 4 
(Section 13.4.1.2).
The subject should return to the clinic every 12 weeks (± 14 days) following the EOT visit
until the subject experiences a symptomatic skeletal event or until the primary efficacy 
analysis matures, whichever occurs first.  Active follow-up will continue for 2 years in this 
study and not more than 7 years total including the long term follow-up study (if the subject 
has signed the ICF).
To the extent possible, subjects discontinuing treatment prematurely should nonetheless 
complete the Week 8, 16, 24, 36, and 48 clinic visits and any applicable tumor assessments 
scheduled with respect to treatment start. Similarly, subjects in Treatment Arms A and B 
should receive Week 28, 32, 40, and 44 telephone contacts at the regularly scheduled time 
with respect to treatment start.
In addition to the visits at Weeks 36 and 48 (from the start of treatment) the subjects in 
Treatment Arms A and B will receive telephone contacts at Weeks 28, 32, 40, and 44 (from 
the start of treatment) to assess for possible SSE risks and will continue PRO data collection. 
Pain data, 24-hour analgesic use, BPI and NCCN-FACT FPSI-17 questionnaires will also be 
collected as detailed below.
The following assessments will be performed during the clinic visits:

BPI-SF questionnaire (should be administered at the beginning of the Week 36 and 
48 visits and should be checked for completion at the visit; see Section 14.7). 
(Treatment Arms A and B only).

NCCN-FACT FPSI-17 questionnaire is also administered at the beginning of the visit 
and should be checked for completion at the visit prior to treatment (see Section 14.8).  
(Treatment Arms A and B only).

ECOG PS

Laboratory assessments (should be performed within 72 hours prior to the visit and 
the results assessed and documented on the visit date)


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 77 of 291
o
CBC, including hematocrit, hemoglobin, RBC count, MCV, MCH, MCHC, 
WBC count, platelet count, and differential blood count reported as absolute 
count or percentage for neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin, total ALP, AST, and ALT 

PSA

Vital signs (systolic / diastolic blood pressure, respiratory rate, body temperature, and 
heart rate will be measured after the subject has rested for at least 5 minutes)

Brief physical examination (see description in Section 7.5.3.2)

Review of the daily PRO pain input results at the Week 36 and 48 visits to check for 
completeness (Treatment Arms A and B only)

Analgesic use evaluation at the Week 36 and 48 visits: Analgesic use will be collected 
and it will be assessed by the study investigator (Treatment Arms A and B only).

Recording of 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)
o
Tumor-related orthopedic surgical intervention
o
Spinal cord compression

All AEs and SAEs have to be reported if considered to be related to study medication 
as well as any events considered to be related to an SSE.  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.

In addition, during the long-term follow-up 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.

Recording of limited concomitant medication, including narcotic pain medication

Recording of therapy for prostate cancer

Recording of new primary malignancies


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 78 of 291

Recording of cytotoxic chemotherapy and radiotherapy for any new primary 
malignancy

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in the 
presence of suspicious lesion[s], a chest CT scan will be performed to confirm and 
characterize the lesion[s]), and whole body technetium-99 bone scan performed every 
12 weeks until the end of active follow-up period, radiological progression (according 
to PCWG2 criteria), or death, whichever occurs first
o
Per adapted PCWG2 criteria (30), confirmation of bone progression by a 2nd
scan ≥6 weeks later is required in all cases.  A SPECT or MRI (with and 
without contrast media) should be obtained to clarify any suspicious bone scan 
findings.  The date of confirmed radiological progression will be the date of 
first observation of radiological progression.
o
All images should be obtained with the same technique (e.g., MRI or CT scan) 
as those obtained at screening

After the Week 36 visit, subjects will complete the pain assessment daily for the 7 
days prior to the Week 40 telephone contact.
Telephone contact for SSE risks and PRO pain and analgesic use data collection at
Weeks 28 (±7 days), 32 (±7 days), 40 (±7 days), and 44 (±7 days), subjects in Treatment 
Arms A and B only
The subjects will receive telephone contacts at Weeks 28, 32, 40, and 44 assessing for 
possible SSE risks.  Subjects exhibiting symptoms indicative of possible SSEs will be 
encouraged to visit the clinic early to assess SSE status.  Symptomatic skeletal events will not 
be determined over the phone. 
In the intervals between the visits, the subjects will continue to be followed for PRO pain 
data collection and analgesic use data collection as follows:

Pain will be assessed daily for 6 days prior to the visit plus the morning of each 
telephone contact at Weeks 28, 32, 40, and 44 and the daily PRO pain input data will 
be reviewed for completeness at the telephone contact.

24-hour analgesic use will be collected by the study investigator at each telephone 
contact at Weeks 28, 32, 40, and 44.

The BPI-SF questionnaire will be completed on the day of each telephone contact 
(should be completed prior to the contact and should be checked for completion at the 
contact; see Section 14.7)

NCCN-FACT FPSI-17 questionnaire will be completed on the day of each telephone 
contact (should be completed prior to the contact and should be checked for 
completion at the telephone contact; (see Section 14.8).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 79 of 291
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 radium-223 
dichloride.  In any case the date of death information will also be collected in the 
end-of-follow-up page of the eCRF.
If a subject discontinues due to an AE or another reason other than progression, every effort 
should be made to follow-up for tumor assessment every 12 weeks for MRI / CT scan of the 
abdomen and pelvis, chest X-ray (in the presence of suspicious lesion[s], a chest CT scan will 
be performed to confirm and characterize the lesion[s]), and whole body technetium-99 bone 
scan until disease progression or the start of a new anticancer treatment.
If a subject is no longer able to travel to the clinic due to deteriorating status, the subject will 
enter the active follow-up without visits and will be followed by telephone.
If a subject has an SSE in the active follow-up period, he will continue the active follow-up 
period for 2 years from last study treatment.  If a subject becomes unable to travel to the 
clinic after 2 years after his last treatment, he will enter long-term follow-up.
7.1.2.7.2 Active follow-up without scheduled clinic visits
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 
4 (Section 13.4.1.2).
This period starts when subjects can no longer travel to the clinic or if the subject receives 
further treatment with any of the following anticancer therapies during the follow-up period:
cytotoxic chemotherapy for prostate cancer, including taxanes, estramustine, and 
mitoxantrone, other systemic radioisotopes (samarium-153, strontium-89, rhenium-186, or 
rhenium-188), hemibody EBRT, or other investigational drugs.  Subjects who cannot travel 
to the clinic will be contacted by telephone every 12 weeks (± 14 days) for 2 years following 
the last study treatment to determine the following:

Survival status

Recording of therapy for prostate cancer

All AEs and SAEs occurring beyond 30 days after the last treatment have to be 
documented and reported if considered to be related to study medication.  
Concomitant medication associated with these events will not 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.

Recording of new primary malignancies

Recording of cytotoxic chemotherapy and radiotherapy for any new primary 
malignancy


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 80 of 291

All occurrences of hematological conditions such as myelodysplastic syndrome, 
aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary 
malignancy, such as acute myeloid leukemia, must be reported as SAEs at any time 
and regardless of the investigator’s causality assessment.

In addition, during the long-term follow-up 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.
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.
Table 7–2  Changes to follow-up visit assessments
Subject Status
Changes to Assessments
Assessments to Continue
Active Assessment Follow-up
Achieves radiologic progression 
Discontinue MRI / CT scan 
abdomen and pelvis, chest 
X-ray, and whole body 
technetium-99 bone scan
All active follow-up 
assessments, including safety 
and laboratory assessments; 
reporting AEs / SAEs related to 
study medicationa or an SSE
and documenting new primary 
malignancies through survival
Begins new anticancer therapy 
for prostate cancer due to 
radiological disease progression
Perform end of active follow-up 
with clinic visits and discontinue 
further active follow-up with 
clinic visits
Change contacts to active 
follow-up without scheduled 
clinic visits (telephone follow-
up) a
If subject starts treatment with 
bisphosphonates, denosumab, 
and other supportive therapies
Continue MRI / CT scan 
abdomen and pelvis, chest 
X-ray, and whole body 
technetium-99 bone scan
All active follow-up 
assessments, including safety 
and laboratory assessments; 
reporting AEs / SAEs related to 
study medicationa or an SSE
and documenting new primary 
malignancies through survival
Can no longer travel
Discontinue all scans and active 
follow-up with clinic visits
Change contacts to active 
follow-up without scheduled 
clinic visits (telephone follow-
up) a
Abbreviations: AE = adverse event; CT = computed tomography; MRI = magnetic resonance imaging; 
SAE = serious adverse event; SSE = symptomatic skeletal event
a. In addition, during the long-term follow-up 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.
Only subjects who withdraw consent from the study will be required to follow the procedures 
outlined in Section 5.2.1.2 (i.e., sign the Declaration of Objection to the Collection of Study 
Data after Withdrawal of Consent for the active assessment follow-up period).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 81 of 291
7.1.2.8 End of active follow-up
7.1.2.8.1 End of active follow-up with clinic visits
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 4 
(Section 13.4.1.2).
The subject should return to the clinic for the end of follow-up with clinic visits, preferably in 
the morning, and the following assessments will be performed:

ECOG PS

Laboratory assessments (should be performed within 72 hours prior to the visit and 
the results assessed and documented on the visit date)
o
CBC, including hematocrit, hemoglobin, RBC count, MCV, MCH, MCHC, 
WBC count, platelet count, and differential blood count reported as absolute 
count or percentage for neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin, total ALP, AST, and ALT

PSA

Vital signs (systolic / diastolic blood pressure, respiratory rate, body temperature, and 
heart rate will be measured after the subject has rested for at least 5 minutes)

Brief physical examination (see description in Section 7.5.3.2)

Recording of SSE assessment
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

All AEs and SAEs have to be reported if considered to be related study medication as 
well as any events considered to be related to an SSE.  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 regardless 
of the investigator’s causality assessment. In addition, during the long-term follow-up 
all bone fractures and bone associated events (e.g., osteoporosis) need to be reported


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 82 of 291
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment.

Documentation of limited concomitant medication, including narcotic pain 
medication

Documentation of therapy for prostate cancer

Documentation of new primary malignancies

Recording of cytotoxic chemotherapy and radiotherapy for any new primary 
malignancy

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in the 
presence of suspicious lesion[s], a chest CT scan will be performed to confirm and 
characterize the lesion[s]), and whole body technetium-99 bone scan
o
Per adapted PCWG2 criteria (30), confirmation of bone progression by a 2nd
scan ≥6 weeks later is required in all cases.  A SPECT or MRI (with and 
without contrast media) should be obtained to clarify any suspicious bone scan 
findings.  The date of confirmed radiological progression will be the date of 
first observation of radiological progression.
o
All images should be obtained with the same technique (e.g., MRI or CT scan) 
as those obtained at screening
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 radium-223 
dichloride.  In any case the date of death information will also be collected in the 
end-of-follow-up page of the eCRF.
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported radium-223 dichloride-related AEs and SAEs, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new 
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death. In addition, during the long-term follow-up 
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 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 83 of 291
assessment.  During long-term follow-up, subjects, their treating health care professional, or 
caregiver will be contacted every 6 months by telephone.  All subjects who transition into this 
separate long-term follow-up study will require a separate signed informed consent.  Subject 
data collected at other standard-of-care visits and / or contacts may be used to satisfy study-
required data.
Transition of all subjects into the separate long-term follow-up study will begin following the 
later of primary endpoint completion or 2 years after the last radium-223 dichloride treatment 
is administered to the last treated subject.
Until the transition to the long term follow-up study begins, some subjects may begin 
long-term follow-up in this study.  This study will end when all subjects have transitioned 
into the long-term follow-up study or discontinued from this study for another reason (e.g., 
Consent Withdrawn, Lost to Follow-up).
7.1.2.8.2 End of active follow-up without scheduled clinic visits
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 4 
(Section 13.4.1.2).
The active follow-up period without clinic visits will continue for 2 years after the subject’s 
last dose of radium-223 dichloride.  The end of active follow-up procedures for subjects who 
are in the active follow-up period without clinic visits will include the following:

Survival status

Documentation of therapy for prostate cancer

All AEs and SAEs occurring beyond 30 days after the last treatment have to be 
documented and reported if considered to be related to study medication.  
Concomitant medication associated with these events will not 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.

Documentation of new primary malignancies

Documentation of cytotoxic chemotherapy and radiotherapy for any new primary 
malignancy

All occurrences of hematological conditions such as myelodysplastic syndrome, 
aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary 
malignancy, such as acute myeloid leukemia, must be reported as SAEs regardless of 
the investigator’s causality assessment.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 84 of 291

In addition, during the long-term follow-up 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.
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.
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported radium-223 dichloride-related AEs and SAEs, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new 
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death. In addition, during the long-term follow-up 
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.  During long-term follow-up, subjects, their treating health care professional, or 
caregiver will be contacted every 6 months by telephone.  All subjects who transition into this 
separate long-term follow-up study will require a separate signed informed consent.  Subject 
data collected at other standard-of-care visits and / or contacts may be used to satisfy study-
required data.
Transition of all subjects into the separate long-term follow-up study will begin following the 
later of primary endpoint completion or 2 years after the last radium-223 dichloride treatment 
is administered to the last treated subject.
Until the transition to the long term follow-up study begins, some subjects may begin 
long-term follow-up in this study.  This study will end when all subjects have transitioned 
into the long-term follow-up study or discontinued from this study for another reason (e.g., 
Consent Withdrawn, Lost to Follow-up).
7.1.2.9 Long-term follow-up to 7 years following last dose
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), 3 (Section 13.3), and 4 
(Section 13.4.1.2).
This period starts when subjects have completed the active follow-up period and ends 7 years 
after the last dose of radium-223 dichloride or when the subject dies.  All study subjects will 
be eligible for further follow-up either in this study or in a separate long-term follow-up study 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 85 of 291
for up to 7 years.  The separate long-term follow-up study has been set up to follow subjects 
who received radium-223 dichloride or placebo in the course of Bayer-sponsored clinical 
trials.  The long-term follow-up study has a specific focus on investigator reported 
radium-223 dichloride-related AEs and SAEs, all occurrences of leukemia, myelodysplastic 
syndrome, aplastic anemia, primary bone cancer or any other new primary malignancy, 
cancer treatment (including any systemic cytotoxic chemotherapy or radiotherapy for any 
malignancy; all systemic anti-cancer therapy for prostate cancer, including androgen 
synthesis inhibitors / androgen-receptor antagonists, systemic radioisotopes and radiation 
treatment; excluding analgesics), in subjects who receive cytotoxic chemotherapy: all 
occurrences of febrile neutropenia or hemorrhage during their chemotherapy treatment and 
for up to 6 months thereafter, and survival for up to 7 years after last dose of radium-223 
dichloride or until death.  In addition, during the long-term follow-up 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.  During long-
term follow-up, subjects, their treating health care professional, or caregiver will be contacted 
every 6 months by telephone.  All subjects who transition into this separate long-term follow-
up study will require a separate signed informed consent.  Subject data collected at other 
standard-of-care visits and / or contacts may be used to satisfy study-required data.
Transition of all subjects into the separate long-term follow-up study will begin following the 
later of primary endpoint completion or 2 years after the last radium-223 dichloride treatment 
is administered to the last treated subject.
Until the transition to the long term follow-up study begins, some subjects may begin 
long-term follow-up in this study.  This study will end when all subjects have transitioned 
into the long-term follow-up study or discontinued from this study for another reason (e.g., 
Consent Withdrawn, Lost to Follow-up).
7.1.2.9.1 Long-term follow-up (via telephone follow-up)
Section modified by Amendments 1 (Section 13.1), 3 (Section 13.3), and 4 (Section 13.4.1.2).
Subjects, their treating health care professional, or caregiver will be contacted by telephone 
every 6 months (± 14 days) for 7 years following the last study treatment or until death to 
determine the following:

Survival status

Recording of prostate cancer therapies

All radium-223 dichloride/placebo related AEs

All SAEs occurring during this period have to be documented and reported if 
considered to be related to study medication.  Concomitant treatment associated with 
these events will not be collected unless it is cancer medication / treatment (including 
any systemic cytotoxic chemotherapy or radiotherapy for any malignancy; all 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 86 of 291
systemic anti-cancer therapy for prostate cancer, including androgen synthesis 
inhibitors / androgen-receptor antagonists, systemic radioisotopes and radiation 
treatment; excluding analgesics).  If a subject is unable to provide required details for 
events of interest, this information will need to be obtained from the primary provider.

Recording of new primary malignancies

Recording of cytotoxic chemotherapy and radiotherapy for any new primary 
malignancy

All occurrences of hematological conditions such as myelodysplastic syndrome, 
aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary 
malignancy, such as acute myeloid leukemia, must be reported as SAEs at any time 
and regardless of the investigator’s causality assessment

In addition, during the long-term follow-up 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 subjects who receive cytotoxic chemotherapy: all occurrences of febrile 
neutropenia or hemorrhage during their chemotherapy treatment and for up to 
6 months thereafter.
Subject data collected at other standard-of-care visits and / or contacts may be used to satisfy 
study-required data.
Since this information will be collected over the telephone from the subject, their treating 
health care professional, or caregiver, 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.
Training for conducting the follow-up contacts will be provided to clinical site personnel 
including, but not limited to, use of a telephone script. Subject data collected at other 
standard-of-care visits and / or contacts may be used to satisfy study-required data.
7.1.2.9.2 End of long-term follow-up
Section modified by Amendments 1 (Section 13.1), 3 (Section 13.3) and 4 (Section 13.4.1.2).
The end of study procedures for subjects who are in the long-term follow-up period will 
include the following:

Survival status

Recording of prostate cancer therapies


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 87 of 291

All SAEs have to be documented and reported if considered to be related to study 
medication.  Concomitant treatment associated with these events will not be collected
unless it is cancer medication / treatment (including any systemic cytotoxic 
chemotherapy or radiotherapy for any malignancy; all systemic anti-cancer therapy 
for prostate cancer, including androgen synthesis inhibitors / androgen-receptor 
antagonists, systemic radioisotopes and radiation treatment; excluding analgesics).  If 
a subject is unable to provide required details for events of interest, this information 
will need to be obtained from the primary provider.

Recording of new primary malignancies

Recording of cytotoxic chemotherapy and radiotherapy for any new primary 
malignancy

All occurrences of hematological conditions such as myelodysplastic syndrome, 
aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary 
malignancy, such as acute myeloid leukemia, must be reported as SAEs at any time 
and regardless of the investigator’s causality assessment.

In addition, during the long-term follow-up 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 subjects who receive cytotoxic chemotherapy: all occurrences of febrile 
neutropenia or hemorrhage during their chemotherapy treatment and for up to 6 
months thereafter.
Subject data collected at other standard-of-care visits and / or contacts may be used to satisfy 
study-required data.
Since this information will be collected over the telephone from the subject, their treating 
health care professional, or caregiver, 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.
7.2
Population characteristics
7.2.1 Demographic
Demographic data to include age (reported as date of birth), gender, race, and ethnicity will 
be collected at the time of enrollment.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 88 of 291
7.2.2 Medical history
Section modified by Amendment 2 (Section 13.2).
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 ICF

Considered relevant to the study up to 6 months prior to screening:  history of 
fractures, trauma, osteomyelitis, joint and dental infections, cellulitis, edema, arthritis, 
metabolic bone disease, or limitation of function; history of orthopedic (e.g., presence 
and location of prosthetic implants) and non-orthopedic (e.g., ileal conduit) surgery 
that might affect the results of bone scintigraphy; history of recent scintigraphy, 
especially with 131I, 67Ga, or 111In.
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 7.5.1.1.
7.2.3 Disease history and prior treatment for prostate cancer
History of prostate cancer will be collected separately from the general medical history.  This 
includes but is not limited to:

Date of diagnosis

Staging (performed at diagnosis)

Relapse history

Disease status at study entry

Prior diagnostic and therapeutic procedures

Prior prostate cancer treatments (any therapy that is ongoing should be reported as 
concomitant medication)


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 89 of 291
7.2.4 Body size descriptors
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Body size descriptors will be calculated from subject height and weight at the applicable 
baselines.  Details will be described in the statistical analysis plan (SAP).
7.3
Efficacy
7.3.1 Efficacy variables
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
The complete list of variables to be analyzed for this study will be provided in the SAP.
The primary efficacy variable is SSE-FS.
The secondary efficacy variables are:

OS

Time to first SSE

rPFS

Time to radiological progression

Pain improvement rate

Time to pain progression
The exploratory efficacy variables include:

Bone scan lesion area (BSLA)

Bone scan time point response rate 

Bone scan best overall response rate 

Increase in analgesic use rate

Time to increase in pain management

Pain improvement without increase in analgesic use rate

Time to pain progression or increase in analgesic use

Change in last 24-hour analgesic use score

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 up to 
48 weeks after the start of treatment.

Total ALP response rate 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 90 of 291

Time to total ALP progression 

Percentage change in total ALP 

PSA response rate 

Time to PSA progression 

Palliative pain procedure use
7.3.2 Definition of efficacy variables
Section modified by Amendments 1 (Section 13.1) and 3 (Section 13.3).
In this study, time-to-event endpoints are defined with respect to 2 distinct start dates, 
randomization date and the date of 6th dose. Response and progression endpoints are defined 
with respect to 2 corresponding baselines, the screening (or pre-treatment) baseline and 6th 
dose date baseline. Details on definitions of starting points and baselines will be provided in 
the SAP or in the imaging charter or other central reviewer documentation.
Additional details on endpoints will be provided in the SAP.
7.3.3 Primary endpoint
Symptomatic skeletal event-free survival
Symptomatic skeletal event-free survival is defined as the time in days from the applicable 
start date to the first SSE or death, whichever occurs first, on or following the start date.
Subjects not experiencing death or an SSE as of database cut-off will be censored at the last 
assessment for SSEs. 
7.3.4 Secondary endpoints
7.3.4.1 Overall survival 
Overall survival is defined the time in days from the applicable start date to the date of death 
due to any cause.  Subjects who are still alive or who are lost to survival follow-up as of 
database cut-off date will be censored at the last known alive date on or prior to database 
cut-off date.
7.3.4.2 Time to first symptomatic skeletal event
Time to first SSE is defined as the time in days from the applicable start date to the first SSE
on or following the start date.  Subjects not experiencing an SSE as of database cut-off, 
whether or not surviving, will be censored at the last assessment for SSEs.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 91 of 291
7.3.4.3 Radiological progression endpoints
Section modified by Amendments 1 (Section 13.1 and 3 (Section 13.3).
Radiological progression is radiological progression of soft-tissue disease or radiological
progression of bone disease, whichever occurs first.  Assessment of radiological progression 
will be made by independent central review.
Radiological progression of soft tissue disease is determined according to RECIST 1.1 based 
on MRI or CT scans (see Section 14.1).  Radiological progression of osseous disease is 
determined according to adapted PCWG2 criteria based on whole body technetium-99 bone 
scans (30) (see Section 14.2).  Radiological bone 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).
Further details will be defined in the imaging charter and / or related central review 
documentation, and / or the SAP.
7.3.4.3.1 Radiological progression free survival 
Radiological progression free survival is defined as the time in days from the applicable start 
date to the date of subsequent radiological disease progression or death from any cause (if 
death occurs before such progression).  Subjects not experiencing death or radiological 
disease progression as of database cut-off will be censored at the last radiological disease 
progression assessment.
7.3.4.3.2 Time to radiological progression
Time to radiological progression is defined as the time in days from the applicable start date 
to the date of subsequent radiological progression.  Subjects without radiological progression 
as of database cut-off date, whether or not surviving, will be censored at the last radiological 
progression assessment.
7.3.4.4 Pain endpoints
Section modified by Amendment 1 (Section 13.1) and 2 (Section 13.2).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 92 of 291
The WPS is defined for each subject at baseline and at each applicable 4-week assessment 
date, as the mean of the “worst pain score” values in the last 24 hours from the preceding 7 
days before each applicable visit or telephone contact per the BPI-SF recorded in the 
subject’s reported outcome pain data.
Pain endpoints are defined with respect to each applicable baseline and start date.
The screening baseline for pain endpoints will be based on the pre-Dose 1, 7-day pain 
assessment (Day 7 will be done on the morning of the day of Dose 1, Day 1 of the protocol)
Additional details on pain endpoints will be provided in the SAP.
7.3.4.4.1 Pain improvement rate
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Pain improvement is defined for each baseline in subjects evaluable for pain improvement at 
that baseline, i.e., subjects entering the study with a WPS of at least 4 at the respective 
baseline assessment. Pain improvement with respect to each baseline is defined in each
applicable evaluable subject at each applicable post-baseline assessment time point as a 30% 
and 2-point decrease in WPS over 2 consecutive measurements conducted at least 4 weeks 
apart.
Pain improvement rate is defined for each baseline and applicable post-baseline assessment 
time point as the number of subjects with pain improvement at the time point, divided by the 
total number of subjects evaluable for pain improvement with respect to the applicable 
baseline.
7.3.4.4.2 Time to pain progression
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Pain progression is defined for each baseline in subjects evaluable for pain progression at the 
applicable baseline, i.e., subjects with a WPS of ≤7 at the respective baseline assessment. 
Pain assessments will occur daily for one week, beginning a week prior to each visit and 
including the day of the visit.  An evaluable pain assessment interval requires completion of a 
minimum of 4 out of 7 daily questions. Pain progression is defined as the occurrence of a 
pain increase with respect to the applicable baseline.
A pain increase is defined as follows:

For asymptomatic subjects (WPS 0 to < 1 at baseline), pain increase 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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 93 of 291

For mildly symptomatic subjects (WPS 1-3 at baseline), pain increase 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 worst pain score of ≥4”.

For symptomatic subjects with WPS > 3 and ≤7 at baseline), pain increase 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.
The time to pain progression is defined for each applicable baseline for applicable subjects as 
the time (in days) from the respective baseline until occurrence of the first post-baseline pain 
progression event. Subjects without pain progression as of the last applicable post-baseline
assessment, whether or not surviving, will be censored at the last applicable post-baseline
assessment.  Subjects with insufficient applicable baseline assessment(s) or without adequate
post-baseline assessment(s) will be censored at the applicable baseline date.  Additional 
censoring and other details will be described in the SAP.
7.3.5 Exploratory endpoints
Additional exploratory endpoints may be defined in the SAP.
7.3.5.1 Quantitated bone scan endpoints
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Further details will be defined in the imaging charter and /or related central review 
documentation, and / or the SAP.
7.3.5.1.1 Bone scan lesion area
Bone scan lesion area is defined for each subject at the screening baseline and each 
subsequent radiological assessment time point, as the sum of the pixel areas (cm2) of the set 
of technetium-99 bone scan imaging pixels identified as bone lesion based on central review.
7.3.5.1.2 Bone scan time point response rate
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Bone scan time point response will be determined based on central review. For each 
applicable subject, at each applicable time point following each respective baseline, the time
point BSLA will be compared to the respective baseline BSLA. The bone scan time point 
response with respect to the baseline will be assessed as described in Section 14.3.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 94 of 291
7.3.5.1.3 Bone scan best overall response rate
Bone scan best overall response is defined for each applicable subject, with respect to each 
applicable baseline, as the best bone scan time point response (ordered as responder, stable 
disease, PD, unable to evaluate) to the respective baseline observed following the baseline 
and during the course of the study. Responder and stable disease responses will only be 
reported if observed prior to PD. No confirmation of responder or PD status will occur.
The bone scan best overall response rate is defined for each applicable treatment group, with 
respect to each applicable baseline, as the number of subjects with respective bone scan best 
overall response of responders, divided by the total number of subjects in the treatment 
group.
7.3.5.2 Time to increase in physical symptoms of disease based on FPSI-DRS-P
Section modified by Amendments 1 (Section 13.1) and 3 (Section 13.3).
Time to increase in physical symptoms of disease based on the NCCN-FACT FPSI-17 
physical disease related symptoms (FPSI-DRS-P) subscale score measured up to Week 48 
after start of treatment will be assessed using the NCCN-FACT FPSI-17 questionnaire 
(Section 14.8).
The NCCN-FACT FPSI-17 is a validated instrument that was developed to assess symptoms 
of prostate cancer, symptoms caused by the treatment of prostate cancer, and the health 
related quality of life of prostate cancer patients.(26)  The instrument was developed in 
accordance with recent FDA guidance for the development of instruments for electronic
patient-reported outcome (ePRO).  The instrument contains 17 items, each of which utilizes 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 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, two items 
represent functional well-being and the responses to those items are summed to calculate a 
functional/well-being subscale score.
The NCCN-FACT FPSI-17 will be self-administered by the subject via an ePRO device. 
Time to increase in physical symptoms of disease based on (FPSI-DRS-P) will be calculated 
with respect to baseline value collected prior to first dosing, based only on assessments 
through Week 48. Details, including definition of an increase, will be provided in the SAP.
7.3.5.3 Total alkaline phosphatase endpoints
Total ALP endpoints are determined based on the total ALP laboratory assessments collected 
as described in the assessment schedule.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 95 of 291
A subject is evaluable for ALP endpoints if the subject had a non-missing total ALP 
assessment at the applicable baseline.
7.3.5.3.1 Total alkaline phosphatase response rate
Section modified as of Amendment 3 (Section 13.3).
Total ALP response is defined with respect to each applicable baseline, as a ≥30% reduction 
of the blood total-ALP level compared to the baseline value, confirmed by a second 
consecutive ALP value 4 or more weeks later but within 9 weeks, among evaluable subjects. 
The total ALP response rate is defined for each applicable treatment group, with respect to 
each applicable baseline, as the number of subjects with total ALP response with respect to 
the baseline, divided by the total number of subjects evaluable for the respective total ALP 
response in the treatment group.
7.3.5.3.2 Time to total alkaline phosphatase progression
Section modified by Amendment 3 (Section 13.3).
Total ALP progression is defined with respect to each applicable baseline, as a 25% 
increase from 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 
consecutive value obtained 3 or more weeks later but within 9 weeks in subjects with an 
initial ALP decline from the baseline.
The time to total ALP progression is defined as the time in days from the applicable start date 
to the date of first total ALP progression following the start date.  Subjects not experiencing 
total ALP progression as of database cut-off, whether or not surviving, will be censored at the 
last total ALP lab assessment.
7.3.5.3.3 Percentage change in total alkaline phosphatase at 12 and 24 weeks
The percentage change in total ALP from screening baseline to 12 weeks and the percentage 
change in total ALP from screening baseline to 24 weeks will be calculated for each 
applicable evaluable subject, based on lab data collected as of the 12 and 24-week 
assessments, respectively.
7.3.5.4 Prostate specific antigen endpoints
Prostate specific antigen endpoints are determined based on the PSA laboratory assessments
collected as described in the assessment schedule.
A subject is evaluable for PSA endpoints if the subject had a non-missing PSA laboratory 
assessment at the applicable baseline.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 96 of 291
7.3.5.4.1 Prostate specific antigen response rate
Section modified by Amendment 3 (Section 13.3).
Prostate specific antigen response is defined in each evaluable subject with respect to each 
applicable baseline as a ≥30% reduction of the blood PSA level, compared to the baseline 
value, confirmed by a second subsequent PSA value with a ≥30% reduction from the 
applicable baseline approximately 4 or more weeks later but within 9 weeks.
Prostate specific antigen response rate is defined for each applicable treatment group with 
respect to each applicable baseline, as the number of subjects with PSA response with respect 
to the baseline, divided by the total number of subjects evaluable for the respective PSA 
response in the treatment group.
7.3.5.4.2 Time to prostate specific antigen progression 
Section modified by Amendment 3 (Section 13.3).
Prostate specific antigen progression is defined with respect to each applicable baseline, as a 
25% increase from baseline value and an increase in absolute value of 2 ng/mL, at least 
12 weeks from the applicable 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 consecutive value obtained 3 or more weeks later but within 9 weeks 
in subjects with an initial PSA decline from the baseline.
The time to PSA progression is defined as the time in days from the respective start date to 
the date of first subsequent PSA progression.  Subjects without PSA progression as of 
database cut-off, whether or not surviving, will be censored at the last PSA lab assessment.
7.3.5.5 Exploratory pain and analgesic use endpoints
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
For purposes of determining exploratory increase in analgesic use, pain improvement without 
an increase in analgesic use, and pain progression without an increase in analgesic use, a 
daily analgesic use score will be calculated programmatically for each subject for each day, 
based on the subject’s complete case report form (CRF) data on analgesic use.  Analgesic use 
data will be coded using the World Health Organization (WHO) drug dictionary.  Oral 
morphine equivalents (OMEs) will be calculated.  Each day’s analgesic use in OME units 
will be calculated using the applicable CRF-reported dates and date ranges.  The AQA will be 
applied to obtain a daily analgesic use score.  Details will be described in the SAP.
An increase in analgesic use is defined for each baseline in evaluable subjects, i.e., subjects 
with a valid AQA analgesic use score at the applicable baseline, as follows:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 97 of 291
For subjects not on opioids at the applicable baseline, initiation of short or long-acting opioid 
use for pain will constitute an increase in analgesic use.  For subjects being treated with 
≤600 OME (oral morphine equivalents) of opioids at the applicable baseline, an increase by 
1 point in the daily AQA score and increase ≥50% in daily OMEs will constitute an increase 
in analgesic use.  For subjects being treated at the highest AQA level (> 600 OME/day) at the 
applicable baseline, an increase ≥50% in daily OMEs from that baseline will constitute an 
increase in analgesic use. 
Additional details on analgesic use endpoints, including details on the applicable baselines, 
evaluability for daily analgesic use increase, calculation of daily analgesic use score(s) 
applicable to each baseline and post-baseline time point, and definition of baseline values and 
“increase” in daily analgesic use for purposes of these endpoints, will be provided in the 
SAP.
7.3.5.5.1 Increase in analgesic use rate
Section modified by Amendment 2 (Section 13.2).
Increase in analgesic use rate is defined for each applicable baseline as the number of 
subjects with an increase in analgesic use from that baseline divided by the number of 
subjects evaluable for analgesic use at that baseline.
7.3.5.5.2 Time to Increase in analgesic use
Section modified by Amendment 2 (Section 13.2).
Time to increase in analgesic use is defined for each applicable baseline for applicable 
subjects as the time (in days) from the respective baseline until occurrence of the first 
post-baseline increase in analgesic use pain progression event.  Subjects without increase in 
analgesic use as of the last applicable post-baseline assessment, whether or not surviving, will 
be censored at the last applicable post-baseline assessment.  Subjects with insufficient 
applicable baseline assessment(s) or without adequate post-baseline assessment(s) will be 
censored at the applicable baseline date.  Additional censoring and other details will be 
described in the SAP.
7.3.5.5.3 Pain improvement rate without increase in analgesic use
Section modified by Amendment 2 (Section 13.2).
Pain improvement without increase in analgesic use is defined for each baseline in subjects 
evaluable for both pain improvement and increase in analgesic use at that baseline, as defined 
in Section 7.3.4.4.1 and Section 7.3.5.5.1 respectively, at the applicable baseline assessment.  
Pain improvement without increase in analgesic use is defined in each applicable evaluable 
subject at each applicable post-baseline assessment time point with respect to each baseline, 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 98 of 291
as a 30% and 2-point decrease in WPS over 2 consecutive measurements conducted at least 
4 weeks apart, without an increase in analgesic use. 
Pain improvement without increase in analgesic use rate is defined for each baseline and 
applicable post-baseline assessment time point as the number of subjects with pain 
improvement without increase in analgesic use at the time point, divided by the total number 
of subjects evaluable for pain improvement without increase in analgesic use with respect to 
the applicable baseline.
7.3.5.5.4 Time to pain progression or increase in analgesic use
Section modified by Amendment 2 (Section 13.2).
Time to pain progression is defined for each baseline in subjects evaluable for both pain 
progression and increase in analgesic use, as defined in Section 7.3.4.4.2 and 
Section 7.3.5.5.1, respectively, at the applicable baseline assessment.
The time to pain progression or increase in analgesic use is defined for each applicable 
baseline for applicable subjects as the time (in days) from the respective baseline until 
occurrence of the first post-baseline pain progression (pain increase) event or increase in 
analgesic use event, whichever occurs first.  Subjects with neither pain progression nor an 
increase in analgesic use as of the last applicable post-baseline assessment, whether or not 
surviving, will be censored at the last applicable post-baseline assessment.  Subjects not 
evaluable for both pain progression and increase in analgesic use, and subjects without 
adequate post-baseline assessment(s), will be censored at the applicable baseline date.  
Additional censoring and other details will be described in the SAP. 
Change in the last 24-hour analgesic use score
Change in the last 24-hour analgesic use score is calculated based on the subject’s analgesic 
use in the last 24 hours CRF data. 
For each subject, each analgesic medication from analgesic use in the last 24 hour’s data 
taken at applicable clinic visits (and in Arms A and B, at telephone contacts) will be coded 
using the WHO drug dictionary and OMEs will be calculated from the coded data.
For each subject and applicable visit or telephone contact, analgesic use in the last 24 hours 
will be scored using the AQA (see Section 14.9) based on the coded medications and 
corresponding OME quantities. 
Details on coding and scoring will described in the SAP. 
For each subject, for each applicable baseline and post-baseline time point, the subject’s 
change in the last 24-hour analgesic use is defined as the difference between the subject’s last 
24 hour AQA score at the post-baseline time point and at the applicable baseline.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 99 of 291
7.3.5.6 Additional pain and health related quality of life endpoints
Section modified by Amendments 1 (Section 13.1) and 3 (Section 13.3).
Subject-reported outcome data not described above, palliative pain relief procedure data, 
additional BPI-SF data collected at clinic visits, and pain data collected will be evaluated as 
described in the SAP.
7.4
Pharmacokinetics / pharmacodynamics
No pharmacokinetic or pharmacodynamics assessments will be performed for this study.
7.5
Safety
Section modified by Amendment 1 (Section 13.1).
The investigator(s) and the sponsor’s representative will review the safety data throughout the 
course of the study.  The following safety variables will be evaluated:

Adverse events: AEs will be collected and recorded on an ongoing basis throughout 
the study as described in Section 7.5.1.

Laboratory assessments: The following laboratory assessments with reference ranges, 
including investigator determinations, will be recorded in the source documentation 
and the eCRF:
o
CBC, including hematocrit, hemoglobin, RBC count, MCV, MCH, MCHC, 
WBC count, platelet count, and differential blood count reported as absolute 
count or percentage for neutrophils, lymphocytes, monocytes, eosinophils, and 
basophils
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin, total ALP, AST, ALT, 
LDH (screening only), and albumin (screening only)
7.5.1 Adverse events
7.5.1.1 Definitions
Definition of 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 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 100 of 291
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).
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal symptoms, diseases, laboratory, or vital sign findings.

Conditions that started before signing of ICF and for which no symptoms or treatment 
are present until signing of ICF are recorded as medical history (e.g., seasonal allergy 
without acute complaints).

Conditions that started before signing of ICF and for which symptoms or treatment are 
present after signing of ICF, at unchanged intensity, are recorded as medical history
(e.g., allergic pollinosis).

Conditions that started or deteriorated after signing of informed consent will be 
documented as AEs.
Definition of serious adverse event (SAE)
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – g):
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 inpatient hospitalization or prolongation of existing hospitalization
A hospitalization or prolongation of hospitalization will not be regarded as an 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 an SAE 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 101 of 291
dependent on clinical judgment.  In addition, where local regulatory authorities 
specifically require a more stringent definition, the local regulation takes precedence.
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
g. Is an occurrence of leukemia, myelodysplastic syndrome, aplastic anemia, and 
primary bone cancer or any other new primary malignancy (regardless of the 
investigator’s causality assessment)
If disease progression leads to signs and symptoms that meet the criteria for seriousness (e.g., 
hospitalization), the associated signs and symptoms should be reported as SAEs, not the 
underlying cause (i.e., “progressive disease” should not be recorded as an SAE).  In this case 
disease progression should be mentioned on the SAE form as an “alternative explanation.”
An isolated laboratory abnormality that meets the criteria for CTCAE Grade 4 classification 
is not reportable as an SAE, unless the investigator assesses that the event meets standard 
International Conference of Harmonisation criteria for an SAE.  All laboratory abnormalities, 
including CTCAE Grade 4 abnormalities, will be documented on the laboratory eCRF 
(including values reported from central laboratories).
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 is classified according to the grades specified by the NCI-CTCAE, 
version 4.03 (see Section 14.4).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 102 of 291
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:
1. The existence of a clear alternative explanation, e.g., mechanical bleeding at surgical 
site.
or
2. 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 subjects response after 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 pharmacokinetics of the study treatment: 
The pharmacokinetic properties (absorption, distribution, metabolism, and excretion) of 
the study treatment, coupled with the individual subject’s pharmacodynamics should be 
considered.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 103 of 291
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
- Dose increased
- 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
- Fatal
- Unknown


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 104 of 291
7.5.1.3 Assessments and documentation of adverse events
Section modified by Amendments 2 (Section 13.2) and 4 (Section 13.4.1.2).
All AEs occurring from the time the subject signs the ICF until 30 days after the last dose of 
study medication must be recorded on the eCRF.  Treatment-emergent AEs and all SAEs that 
occur during the treatment period and up to 30 days after the last administration of 
radium-223 dichloride must be reported on the appropriate eCRF.
A laboratory test abnormality should be reported as an AE if it is considered clinically 
relevant (e.g., causing the subject to withdraw from the study), requires treatment, causes 
apparent clinical manifestations, or is judged as relevant by the investigator.  Laboratory 
abnormalities that are not considered clinically significant do not need to be entered as an 
AE. Laboratory abnormalities related to the disease under study (e.g., PSA, testosterone) do 
not need to be recorded as AEs. 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, possibly alternative factors (co-
morbidities, co-medications), therapeutic action taken, result of therapeutic action, and 
ultimate outcome of the AE.  The investigator’s assessment of AEs and laboratory results 
with grades and causality assessments must be documented and retained in the source 
documentation.
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 beyond 30 days after the last treatment have to be reported if 
considered to be related to study medication or if related to an SSE (during active follow-up 
with clinic visits only).  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.  In 
subjects who receive cytotoxic chemotherapy, all occurrences of febrile neutropenia or 
hemorrhage during their chemotherapy treatment must be reported as SAEs at any time and 
for up to 6 months thereafter. In addition, during the long-term follow-up 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.  If a 
subject is unable to provide required details for events of interest, this information may need 
to be obtained from the primary provider.
Adverse events may be reported spontaneously by the subject or elicited through open 
(non-leading) questioning during each visit during the treatment period and for 30 days after 
the last dose.  As far as possible, all AEs must be described by their duration (start and stop 
date), severity (graded according to the CTCAE, version 4.03), relationship to treatment, and 
according to the need of other specific therapy. All information will be recorded in the 
source documentation and AE eCRF.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 105 of 291
Subjects who sign the ICF and are randomized but who discontinue prior to receiving the first 
dose will not be followed for safety.
7.5.1.4 Reporting of serious adverse events
Section modified by Amendment 4 (Section 13.4.1.2).
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 (e.g., 
hospitalization), the associated signs and symptoms should be reported as SAEs, not the 
underlying cause (i.e., “progressive disease” should not be recorded as an SAE).  In this case, 
disease progression should be mentioned on the SAE form as an “alternative explanation.”
Reporting of additional malignancies
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, 
regardless of the investigator's causality assessment.
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 recipient 
detailed in the 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.
Serious AEs occurring after the protocol-defined observation period will be processed by the 
sponsor according to all applicable regulations.
In addition, during the long-term follow-up 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.
Any CTCAE Grade 4 screening laboratory abnormality that is part of the disease profile 
should not be reported as an SAE, specifically when they are allowed or not excluded by the 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 106 of 291
protocol inclusion / exclusion criteria.  If an investigator is in doubt about the applicable 
reporting obligations, he / she should consult with the study monitor for the sponsor.
Notification of the independent ethics committees / independent review boards
Notification of the independent ethics committees (IECs) / institutional review boards (IRBs)
about all relevant events (e.g., SAEs, suspected, unexpected, serious adverse reactions 
[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 site
The sponsor will inform all investigational sites about reported relevant events (e.g.,
SUSARs) according to all applicable regulations.  The sponsor will send SUSARs to a site 
once the site initiation visit has occurred and will stop sending SUSARs to a site once the last 
subject EOT visit for that site (30 days after last dose) occurs.
7.5.1.5 Expected adverse events
For this study, the applicable reference document is the most current version of the IB.  
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 sites.
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 an SAE, although a pregnancy per se is not considered an SAE.  
Bayer usually does not gather information of drug exposure via the father; however, if those 
cases are reported, all efforts should be made to obtain similar information on course and 
outcome, subject to the partner’s consent.
For all reports, the forms provided are to be used.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 107 of 291
7.5.3 Further safety
7.5.3.1 Laboratory evaluations
Section modified by Amendment 1 (Section 13.1).
Blood samples will be collected by a member of the investigator’s team per the schedule of 
assessments.  The same local laboratory should be used throughout the study for a given 
subject.  The following laboratory assessments will be recorded with reference ranges:

CBC, including hematocrit, hemoglobin, RBC count, MCV, MCH, MCHC, WBC 
count, platelet count, and differential blood count reported as absolute count or 
percentage for neutrophils, lymphocytes, monocytes, eosinophils, and basophils

Chemistry panel, including serum creatinine, sodium, potassium, chloride, calcium, 
phosphorous, magnesium, total bilirubin, total ALP, AST, ALT, LDH (screening 
only), and albumin (screening only)
7.5.3.2 Physical examination
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by a physician at the investigational site.  A complete physical examination will be performed 
at the screening visit; a brief physical examination will be performed at all other visits.  Brief 
physical examinations will include systems of primary relevance and those systems 
associated with symptoms.  Full and brief physical examinations will be performed according 
to the standard of care.
7.5.3.3 Vital signs
Systolic / diastolic blood pressure, respiratory rate, body temperature, and heart rate will be 
measured after the subject has rested for at least 5 minutes.
7.5.3.4 Eastern Cooperative Oncology Group performance status
A screening ECOG PS of 0 to 2 must be confirmed and documented.  The ECOG PS is 
defined in Section 14.5.
7.5.3.5 Body weight
Section modified by Amendment 2 (Section 13.2).
Body weight will be measured without shoes, using a calibrated electronic physician 
(column) scale with digital display, measurement units 0.1 kg.  The same scale should be 
used for a given subject throughout the study.  At all sites (in US and outside US), weight is 
to be taken only once for each dose.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 108 of 291

For non-US sites, the weight should be performed within 72 hours prior to dosing.

For US sites using the central PRD depot ONLY, subject weight for the dose day 
should be obtained at the site within 3 to 5 days prior to the dose visit.  This weight 
must be reported to the country PRD depot to allow adequate time for PRD 
preparation and delivery (approximately 2 days).  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.  Body weight can be obtained at the local healthcare 
provider on a calibrated scale and the results sent by fax to the Principal Investigator
with advanced notice and agreement from the Covance Medical Monitor for each 
subject.  No other procedures can be done at the local healthcare provider.
7.6
Other procedures and variables
Not applicable.
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 II studies of oncology drugs.
Tumor progression will be assessed by MRI / CT scan of the abdomen and pelvis, chest 
X-ray, and whole body technetium-99 bone scan and it will be evaluated according to the 
PCWG2 criteria (see Section 14.2).  All images should be obtained with the same technique 
(e.g., MRI or CT) as those obtained at screening.
8. Statistical methods and determination of sample size
8.1
General considerations
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
Subjects will be randomized in a 1:1:1 ratio to one of:

Treatment Arm A: Radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) intravenously every 28 days up to 6 doses (“standard 
dose”)

Treatment Arm B: Radium-223 dichloride 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) intravenously every 28 days up to 6 doses (“high
dose”)

Treatment Arm C:  Radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) intravenously every 28 days up to 12 doses
(“extended dosing”)


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 109 of 291
Randomization will be stratified by: 

Prior chemotherapy (≤1 regimen versus > 1 regimen)

Total ALP (< 220 U/L versus ≥220 U/L).

Average WPS of the BPI-SF (WPS ≤4 versus WPS > 4)
Analysis of the primary variables will be performed for each subgroup for individual 
stratification factors.  Statistical analyses will be performed using SAS; the version used will 
be specified in the SAP.
8.2
Analysis sets
Section modified by Amendments 2 (Section 13.2) and 3 (Section 13.3).
The following 3 analysis sets will be defined:
Intent-to-treat (ITT): All randomized subjects.  The ITT analysis set 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 were randomized.
Week 24 (W24): All ITT subjects in Arm A (standard dose) and Arm C (extended dosing) 
treated with radium-223 dichloride and eligible for further treatment at W 24(i.e., 7th 
injection).  Week 24 applies to subjects who received the 6th injection without any dose 
delays. As dose delays are allowed per protocol, 6th injection can occur after Week 24 for 
subjects who had dose delays. Hence, this population is defined based on the number of 
injections not based on the timing.  The W24 dataset will be used for the analysis of efficacy 
endpoints related to Comparison 2 and associated evaluations.  Subjects will be included in 
W24 analyses according to the treatment to which they were randomized.  
Safety: All randomized subjects who have received at least one study drug administration.  
This safety analysis set will be used in the analyses of all safety endpoints.  Subjects will be 
included in the analyses according to the treatment they received.
8.3
Variables
Efficacy variables are listed in Section 7.3.1.  Definitions for each efficacy variable are given 
in Section 7.3.2.  
The primary efficacy variable is SSE-FS.
The safety variables are defined in Section 7.5 and listed in Section 8.4.4.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 110 of 291
8.4
Statistical and analytical plans
8.4.1 Primary efficacy analysis
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), and 3 (Section 13.3).
Decision rules and adjustment of alpha for primary endpoints
The primary efficacy endpoints, SSE-FS, will be analyzed separately in 2 respective 
comparisons, as described below.
Both comparisons will be performed at the time of final analysis, after the latest of 
(1) approximately 135 SSE-FS events in subjects included in Comparison 1 as defined below; 
(2) approximately 75 SSE-FS events following the 6th dose in subjects included in 
Comparison 2 as defined below; and (3) the last subject has been followed for 30 days from 
last treatment. In the event the applicable number of events is not reached, the primary 
endpoint analysis will mature 7 years after the last subject has received last treatment.
No alpha adjustment for multiple comparisons will be performed in this Phase II study. 
Comparison 1: Standard dose versus high dose: SSE-FS from randomization in radium-
223 dichloride-naïve subjects
Comparison 1 will test the following hypotheses:
The Null Hypothesis (H0)1: In a population of radium-223 dichloride-naïve subjects with 
CRPC metastatic to the bone, population SSE-FS in subjects treated with a regimen of up to 6 
doses of 80 kBq/kg (88 kBq/kg after implementation of NIST update) (high dose) radium-
223 dichloride is equal to population SSE-FS in subjects treated with a regimen of up to 6 
doses of 50 kBq/kg (55 kBq/kg after implementation of NIST update) (standard dose) 
radium-223 dichloride, versus
The Alternative Hypothesis (HA)1: In a population of radium-223 dichloride-naïve subjects 
with CRPC metastatic to the bone, population SSE-FS in subjects treated with a regimen of 
up to 6 doses of 80 kBq/kg (88 kBq/kg after implementation of NIST update) (high dose) 
radium-223 dichloride is greater than population SSE-FS in subjects treated with a regimen 
of up to 6 doses of 50 kBq/kg (55 kBq/kg after implementation of NIST update) (standard 
dose) radium-223 dichloride.
Comparison 1 will analyze SSE-FS with randomization date as start date.
Comparison 1 will pool SSE-FS in subjects in Treatment Arm A, with SSE-FS truncated at 
24 weeks in subjects in Treatment Arm C, and compare this pooled value with SSE-FS in 
Treatment Arm B.  Only ITT subjects will be included in this ITT analysis.  In this study, 
extended dosing subjects (Treatment Arm C) will receive the same treatment regimen as 
standard dose subjects (Treatment Arm A) for the first 6 doses, with Dose 7 scheduled to start 
after 24 weeks.  Accordingly, data from Treatment Arm C subjects arising during the first 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 111 of 291
24 weeks is relevant to this comparison and including it increases the analysis power under 
the study assumptions.
It will be performed using a log-rank test with a 1-sided alpha of 0.1 stratified by the 
randomization factors (previous chemotherapy [≤1 regimen versus > 1 regimen] and total 
ALP [< 220 U/L versus ≥220 U/L]).  The high-dose regimen will be declared superior to the 
standard-dosing regimen if the 1-sided p-value from the stratified log-rank test is less than 
0.1. 
The hazard ratio (high dose / standard dose) will be computed together with 2-sided 80% and 
95% confidence intervals using a stratified Cox regression model with treatment as a factor 
and previous chemotherapy (≤1 regimen versus > 1 regimen) and total ALP (< 220 U/L 
versus ≥220 U/L) as strata in the model for the ITT population.  Kaplan-Meier survival 
distribution tables and plots will also be produced for both Treatment Arms A and B. 
Additional details will be provided in the SAP.
Comparison 2: No further radium-223 dichloride treatment versus extended dosing: 
SSE-FS analysis from the 6th dose in subjects receiving standard-dose regimen
Comparison 2 will test the following hypotheses:
H02: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg
(55 kBq/kg after implementation of NIST standard update) (standard dose) radium-223 
dichloride who survived SSE-free and are eligible for further radium-223 dichloride 
treatment at 24 weeks, population SSE-FS beyond the 6th dose in subjects treated with a 
regimen of up to an additional 6 doses of 50 kBq/kg (55 kBq/kg after implementation of
NIST update) (extended dose) radium-223 dichloride is equal to population SSE-FS beyond 
the 6th dose in subjects receiving no further radium-223 dichloride treatment beyond the 
standard dose regimen, versus
HA2: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) (standard dose) radium-223 dichloride who 
survived SSE-free and are eligible for further radium-223 dichloride treatment at 24 weeks, 
population SSE-FS beyond the 6th dose in subjects treated with a regimen of up to an 
additional 6 doses of  50 kBq/kg (55 kBq/kg after implementation of NIST update) (extended 
dose) radium-223 dichloride is greater than population SSE-FS beyond the 6th dose in 
subjects receiving no further radium-223 dichloride treatment beyond the standard dose 
regimen.
Comparison 2 will be an analysis of SSE-FS from the 6th dose, in subjects surviving SSE-
free to the 6th dose.  It will compare subjects in Treatment Arm A with subjects in Treatment 
Arm C. 
Comparison 2 will be performed using a log-rank test with a 1-sided alpha of 0.1 stratified by 
the randomization factors (previous chemotherapy [≤1 regimen versus > 1 regimen] and total 
ALP [< 220 U/L versus ≥220 U/L]).  The extended dosing regimen will be declared superior 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 112 of 291
to the standard dosing regimen if the 1-sided p-value from the stratified log-rank test is less 
than 0.1.
8.4.2 Secondary efficacy analysis 
Selected secondary variables will be tested. No multiple testing procedures to control overall 
alpha level will be performed in this Phase II study. All testing will be one-sided with a 
significance level of 0.10. Further details will be specified in the SAP. 
Secondary efficacy analyses will be grouped as follows:
8.4.2.1 Analyses of pooled standard dose and high dose from randomization
Section modified by Amendment 1 (Section 13.1).
For the following secondary endpoint analyses, subjects will be classified into 2 treatment 
groups: (1) the “standard dose” treatment group, consisting of ITT subjects in Treatment 
Arm A pooled with subjects in Treatment Arm C, and (2) the “high dose” treatment group, 
ITT subjects in Treatment Arm B. For these analyses, the start date will be randomization, 
and the screening (or pre-treatment) baseline will be used. Only data truncated at 24 weeks 
will be included for Treatment Arm C subjects. 
The following secondary efficacy time-to-event endpoints will have hypothesis testing 
performed to compare these treatment groups: OS, time to first SSE, time to radiological 
progression, and rPFS.
Other endpoints will be analyzed descriptively for each treatment group. 
Other endpoints and analyses for these treatment groups may be defined in the SAP.
8.4.2.2 Analyses of standard dosing and extended dosing from the 6th dose
Section modified by Amendment 3 (Section 13.3).
For the following secondary endpoint analyses, subjects will be classified into 2 treatment 
groups: (1) the “standard dose” treatment group, consisting of applicable ITT subjects in 
Treatment Arm A, and (2) the “extended dosing” treatment group, consisting of applicable 
ITT subjects in Treatment Arm C. For these analyses except for rPFS, the 6th dose date will 
be used as the reference date. For rPFS, randomization date will be used as the reference 
date.
For secondary endpoint time-to-event analyses for these treatment groups, subjects included 
will have survived to the 6th dose without having experienced the applicable event, and will 
have completed and / or not been discontinued from treatment.  Details defining these 
analyses will be provided in the SAP. 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 113 of 291
The following secondary efficacy time-to-event endpoints will have hypothesis testing 
performed to compare these treatment groups: OS, time to first SSE, and rPFS.  
Other endpoints will be analyzed descriptively for each treatment group. 
Other endpoints and analyses for these treatment groups may be defined in the SAP.
8.4.2.3 Analyses by treatment arm
Selected descriptive efficacy analyses and listings will be provided by randomized treatment 
arm. Details will be provided in the SAP. 
8.4.2.4 Secondary endpoint analysis methods
All secondary endpoint hypothesis tests will be performed using a stratified log-rank test: For 
each log-rank test, the factors from the randomization will be used for stratification.  
For time to event endpoints, Kaplan-Meier survival distribution tables and plots with 95% 
confidence intervals will be produced for each applicable treatment group.
Rates will be calculated with 95% confidence intervals for each treatment group. 
8.4.3 Analysis of exploratory variables
Section modified by Amendment 1 (Section 13.1).
Analyses of exploratory variables will be defined in the SAP. 
An exploratory analysis will be performed estimating and modeling SSE-FS efficacy in 
Treatment Arm B (high dose) versus Treatment Arm C (extended dosing). Analyses will be 
further described in the SAP. No formal comparison testing between Treatment Arm B and 
Treatment Arm C will be performed.
An exploratory analysis of the impact of baseline body size descriptors on the efficacy and 
safety of radium-223 dichloride will also be performed with respect to each applicable 
baseline.  Details regarding the baseline body size descriptor definitions, analysis 
specifications, and applicable baseline definitions will be provided in the SAP.
8.4.4 Safety analysis 
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
No formal interim analysis for safety is planned. A JSRC will review the safety data 
periodically.  Details on the JSRC are described in Section 3.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 114 of 291
The safety endpoints include:

Incidence and severity of TEAEs and laboratory abnormalities graded by 
NCI-CTCAE 4.03 and coded by MedDRA

Incidence of serious TEAEs

Incidence of drug-related AEs in the follow-up period
Safety data evaluated will also include laboratory data, vital signs, and physical examination 
results.
Safety variables will be analyzed using frequency tables and descriptive statistics, or through 
listings.
The following safety analyses will be performed as follows:
1. Treatment-emergent safety events
The treatment period for safety purposes for this study extends from the initiation of 
treatment until 30 days after the last administration of radium-223 dichloride. Events 
starting or worsening within the treatment period will be considered treatment-
emergent.
For the analysis of treatment-emergent safety events, subjects will be grouped by 
treatment arm as treated.
2. Safety events emerging during the standard-regimen treatment period
For this analysis, subjects will be classified into 2 groupings, 50 kBq/kg (55 kBq/kg 
after implementation of NIST update) subjects (Treatment Arms A and C, pooled), 
and 80 kBq/kg (88 kBq/kg after implementation of NIST update) subjects (Treatment 
Arm B), as treated. It will be performed for selected safety endpoints for events 
emerging from start of treatment through the later of 24 weeks from treatment start or 
30 days following completion of 6 doses of radium-223 dichloride treatment.
3. Safety events emerging following the standard-regimen treatment period
This analysis will be performed in each treatment arm for events following the later of 
24 weeks from treatment start or 30 days following completion of 6 doses of 
radium-223 dichloride treatment.  It will be performed for selected safety endpoints 
collected during active follow-up after end of treatment through primary endpoint 
completion. This analysis will be performed by treatment group as treated.
4. Safety events emerging during long-term follow-up following primary endpoint 
completion.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 115 of 291
Safety events emerging following primary endpoint completion and any events 
emerging during long-term follow-up, will be reported in a separate document(s) from 
the study Clinical Study Report.
Further details describing these analyses will be provided in the SAP.
8.5
Planned interim analyses
No formal interim analysis is planned, and no alpha adjustment to efficacy analyses for an 
interim analysis is required.
8.6
Determination of sample size
Section modified by Amendments 1 (Section 13.1), 2 (Section 13.2), and 3 (Section 13.3).
The sample size is calculated to have the indicated power, separately and with no 
multiple-testing adjustment, to detect one or both of the following:

Comparison 1: A 50% increase in SSE-FS in subjects receiving a regimen 6 doses of 
80 kBq/kg (88 kBq/kg after implementation of NIST update) radium-223 dichloride 
every 28 days (high dose) over subjects receiving a regimen of 6 doses of 50 kBq/kg
(55 kBq/kg after implementation of NIST update) radium-223 dichloride every 28 
days (standard dose) in a population of radium-223 dichloride-naïve subjects, and / or

Comparison 2: A 65% increase in SSE-FS following 24 weeks in subjects receiving a 
regimen of up to 6 additional doses of radium-223 dichloride 50 kBq/kg (55 kBq/kg 
after implementation of NIST update) every 28 days (extended dose) over subjects 
receiving no further radium-223 dichloride treatment, in a population of subjects 
surviving SSE-free to 24 weeks who received a standard regimen of up to 6 doses of
radium-223 dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update)
and who either completed standard treatment, or remained eligible to receive further 
radium-223 dichloride (not permanently discontinued from treatment) at 24 weeks.
The sample size calculations assume 30 subjects/month enrollment with 7 months ramp-up 
and a 3% loss to follow-up per month.  The accrual period is anticipated to last approximately 
16 months. Overall, 360 subjects are expected to be randomized. The primary endpoint 
cut-off, as defined in Section 8.4, is estimated to be reached in an average of 39 months. 
Comparison 1 will analyze SSE-FS from randomization date in subjects randomized to 
standard dosing and high dose regimens, and SSE-FS truncated at 24 weeks in subjects 
randomized to the extended dose regimen. Subjects randomized to the standard dosing and 
extended dosing regimens will be pooled. Constant hazards are assumed with a median 
SSE-FS of 9 months throughout the study for the standard dosing regimen, a median SSE-FS 
of 9 months for the first 24 weeks from randomization for the extended dosing regimen, and a 
50% improvement (median 13.5, hazard ratio 0.667) throughout the study for the high dose 
regimen. Simulations indicated an average of 186.6 events would occur for this comparison 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 116 of 291
at primary endpoint cut-off, and a 1-sided log-rank test with 0.10 significance gave 
approximately 90.5% power to test H01 versus HA1. 
Comparison 2 will analyze SSE-FS from the 6th dose, in subjects surviving SSE-free to the 
6th dose. (27,28) A median SSE-FS of 9 months with constant hazards is assumed for 
standard dose. Extended dosing is assumed to have the same SSE-FS efficacy as standard 
dosing for the first 24 weeks, and 65% improvement (hazard ratio 0.606) thereafter.  With 
240 of 360 subjects randomized to Treatment Arm A and Treatment Arm C, simulations 
indicated that 44.65% of randomized subjects (107.2 of 240) would have an SSE-FS event or 
loss to follow-up during the first 24 weeks, leaving an estimated 55.35% (132.8) surviving 
SSE-free and eligible for inclusion at 24 weeks.  An average of 74.9 simulated events 
occurred for this comparison, and a 1-sided log-rank test with 0.10 significance gave 
approximately 80.6% power to test H02 versus HA2. 
Simulations assume continuous event and censoring times. Last treatment is assumed to 
occur 44 weeks (10.12 months) after last subject accrued.
Primary endpoint power calculations were based on simulations programmed using SAS 
version 9.2 and used 10,000 replicates.
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 site.  The site must implement processes to ensure this 
happens.  A source document checklist will be used at the site to identify the source data for 
all data points collected and the monitor will work with the site 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, 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 an 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


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 117 of 291

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 site prior to the start of the study to review with the site 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.
The sponsor/designee will monitor the site 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 data system.  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., IVRS / IWRS, laboratory).
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used.
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 site 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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 118 of 291
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.
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
Section modified by Amendments 2 (Section 13.2), 3 (Section 13.3), and 4 (Section 13.4.1.2).
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,
- Safety findings from this study (e.g., SAEs)
- Results of any interim analysis
- Results of parallel clinical studies
- Results of parallel animal studies 
(on 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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 119 of 291
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported, radium-223 dichloride-related AEs and SAEs, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new 
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death. In addition, during the long-term follow-
up, 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.  During long-term follow-up, subjects, their treating health care professional, or 
caregiver will be contacted every 6 months by telephone.  All subjects who transition into this 
separate long-term follow-up study will require a separate signed informed consent.  Subject 
data collected at other standard-of-care visits and / or contacts may be used to satisfy study-
required data.
Transition of all subjects into the separate long-term follow-up study will begin following the 
later of primary endpoint completion or 2 years after the last radium-223 dichloride treatment 
is administered to the last treated subject.  
Until the transition to the long term follow-up study begins, some subjects may begin 
long-term follow-up in this study.  This study will end when all subjects have transitioned 
into the long-term follow-up study or discontinued from this study for another reason (e.g., 
Consent Withdrawn, Lost to Follow-up).
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 site) must be 
returned to the sponsor.  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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 120 of 291
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 IECs / 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 / 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 IEC / IRB has been obtained.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 121 of 291
Each subject / 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.
Only if the subject / 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 / legal representative or 
proxy consenter will receive a copy of the signed and dated form.
The signed ICF 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.
The ICF and any other written information provided to subjects / 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 / 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’s / IRB’s 
approval / favorable opinion in advance of use.
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.
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.
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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 122 of 291
Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the CRF, 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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 123 of 291
12.Reference list
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
1. 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(7):1148-59.
2. Cancer Facts & Figures 2013. American Cancer Society. Available from: 
http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/doc
ument/acspc-036845.pdf. Published 2013. Accessed 07 Mar 2013.
3. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, 
et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 
2012. Eur J Cancer. 2013;49(6):1374-1403.
4. Ye L, Kynaston HG, Jiang WG. Bone metastasis in prostate cancer: molecular and 
cellular mechanisms (Review). Int J Mol Med. 2007;20(1):103-11.
5. Lange PH, Vessella RL. Mechanisms, hypotheses and questions regarding prostate 
cancer micrometastases to bone. Cancer Metastasis Rev. 1998;17(4):331-6.
6. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus 
prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J 
Med. 2004;351(15):1502-12.
7. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacobe L, et al. A 
randomized, placebo-controlled trial of zoledronic acid in patients with 
hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst.
2002;94:1458-68.
8. Smith MR, Egerdie B, Hernández Toriz N, Feldman R, Tammela TL, Saad F, et al.; 
Denosumab HALT Prostate Cancer Study Group. Denosumab in men receiving 
androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009 361(8):745-55.
9. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone 
and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-
2005.
10. Scher HI, Fizazi K, Saad F, Taplin, M-E, Cora N. Sternberg CN, et al. Increased 
survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 
2012;367:1187-97.
11. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. 
Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 124 of 291
prostate cancer progressing after docetaxel treatment: a randomised open-label trial. 
Lancet. 2010;376:1147-54.
12. 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 randomised, 
multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8(7):587-94.
13. Henriksen G, Fisher DR, Roeske JC, Bruland OS, Larsen RH. Targeting of osseous 
sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. 
J Nucl Med. 2003;44(2):252-9.
14. Bayer. Cellular effects of alpha particle radiation from radium-223, Alpharadin III.
DNA damages, double strand breaks observed by γH2A.X flow cytometry.
15. 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(11):3120-5.
16. Bayer HealthCare AG. BAY 88-8223 Investigator’s Brochure, 2012.
17. Bayer HealthCare, internal communication. Nov 2012.
18. Nilsson S, Larsen RH, Fossa SD, Balteskard L, Borch KW, Westlin JE, et al. First 
clinical experience with alpha-emitting radium-223 in the treatment of skeletal 
metastases. Clin Cancer Res. 2005;11(12):4451-9.
19. Nilsson S, Franzén L, Parker C, Bolstad B, Ramdahl T, Thuresson M, et al. Alpha 
emitting radium-223: two years follow up from a randomized phase II study in 
patients with bone metastases from hormone refractory prostate cancer. EJC 
Supplements. 2009;7(2):412.
20. A phase III study of alpharadin (radium-223) in patients with symptomatic hormone 
refractory prostate cancer with skeletal metastases (ALSYMPCA). [database on the 
Internet]. Available from: 
http://clinicaltrials.gov/ct2/show/NCT00699751?term=ALSYMPCA&rank=1.
21. Parker C, Nilsson S, Heinrich D, O'Sullivan JM, Fossa SD, Chodacki A, 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. 30, 2012 (suppl; abstr LBA4512).
22. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD et al. Alpha 
emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 
2013;369:213-23.
23. Parker CC, Pascoe S, Chodacki A, O'Sullivan JM, Germá JR, O'Bryan-Tear CG, et al. 
A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 125 of 291
chloride (Ra 223) in patients with bone metastases and castration-resistant prostate 
cancer. Eur Urol. 2013;63(2):189-97.
24. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate 
method to estimate glomerular filtration rate from serum creatinine: a new prediction 
equation. Modification of diet in renal disease study group. Ann Intern Med. 
1999;130:461-70.
25. Levey AS, Stevens LA, Schid CH, Zhang YL, Castro AF 3rd, Feldman Hi, Kusek 
JW, Eggers P, Van Lente F, Greene T, Coresh J, CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration). A New Equation to Estimate Glomerular Filtration 
Rate. Ann Intern Med. 2009 May 5, 150(9): 604-12.
26. http://www.facit.org/FACITOrg/Questionnaires.
27. Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, et al. 
Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J 
Med. 2012;366:1759-69.
28. Zinner RG, Saxman SB, Peng G, Monberg MJ, Ortuzar WI. Treatment rationale and 
study design for a randomized trial of pemetrexed/carboplatin followed by 
maintenance pemetrexed versus paclitaxel/carboplatin/bevacizumab followed by 
maintenance bevacizumab in patients with advanced non-small-cell lung cancer of 
nonsquamous histology. Clin Lung Cancer. 2010;11(5):352-7.
29. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann 
Acad Med Singapore. 1994;23:129-38.
30. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer 
without previous chemotherapy. N Engl J Med 2012;368(2):138-48.
31. Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation 
counting. Appl Radiat Isot. 2010;68(7-8):1523-8.
32. Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R, Pibida L. Revision of the 
NIST standard for 223Ra: new measurements and review of 2008 data. J Res Natl Inst
Stand Technol. 2015;120:37-57.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 126 of 291
13.Protocol amendments
13.1
Amendment 1
Description of the amendment
Amendment 1 is an amendment to the original protocol dated 09 AUG 2013.  Changes to the 
protocol include:

Clarification of the comparisons performed and populations of inference for the 
primary objective

Reduction of estimated time until CSR is produced with long-term safety evaluations 
reported separately.

Addition of an exploratory objective to evaluate the quality of life based on the 
NCCN FACT-P Symptom Index-17 (NCCN-FACT FPSI-17) with associated data 
collection.

Addition of a secondary analgesic use objective based on the Analgesic 
Quantification Algorithm (AQA). 

Addition of an exploratory objective to explore the impact of baseline body size 
descriptors on the efficacy and safety of study drug.

Addition of an inclusion criteria to only include subjects who are at least 18 years of 
age.

Addition of an inclusion criteria for sexually active males and/or their partners to use 
effective birth control during the treatment period and for 6 months after last dose of 
radium-223 dichloride.

Revised definition of bone progression based on the adapted PCWG2 criteria for 
consistency across the radium-223 program following comments from the FDA on 
another related radium-223 study.  This change affected the time points of 
radiological assessments.

Provide for consistent collection of pain and analgesic use data in every treatment 
arm, every 28 weeks for the first 48 weeks.

Added a clarification of when the primary analysis will be performed in the event that 
too few SSE events occur to trigger the primary analysis (135 SSE-FS events for 
Comparison 1 and 75 SSE-FS events for Comparison 2).

Clarification of the safety analyses performed.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 127 of 291

Clarification of how and when the IVRS / IRWS will be used in the study so that 
study drug is shipped to the investigator sites on-time for the subject’s next dose.

Clarification of central review of radiological and quantitated bone scan endpoints.

Added a study specific dose modification to mandate discontinuation of treatment 
with radium-223 dichloride in subjects who experience Grade 4 neutropenia lasting 
> 7 days despite adequate treatment.

Changed the safety review during the study from an independent data monitoring 
committee to a joint safety review committee; membership may include investigators, 
sponsor team members, and/or independent members.

Changed laboratory assessments from bilirubin to total bilirubin.
13.1.1 Overview of changes
Change 1:
Revised primary objectives to be co-primary objectives to evaluate efficacy in treating 
metastatic bone cancer in subjects with CRPC.  Also clarified the descriptions of the 
populations in the two overall comparisons; the revised descriptions are as follows:
o
The first co-primary objective compares subjects who receive radium-223 
dichloride 50 kBq/kg every 28 days for up to 6 doses with radium-223 
dichloride 80 kBq/kg every 28 days for up to 6 doses in radium-223 
dichloride-naïve subjects.  
o
The second co-primary objective compares subjects who receive radium-223 
dichloride 50 kBq/kg every 28 days for up to 6 additional doses compared to 
no further radium-223 dichloride treatment in subjects with CRPC metastatic 
to the bone who previously received radium-223 dichloride 50 kBq/kg every 
28 days for up to 6 doses, and survived SSE free and are eligible for further 
radium-223 dichloride treatment.
Sections affected include:

Synopsis - Study objectives

Synopsis - Plan for statistical analysis

2. Study objectives

8.4.1 Primary efficacy analysis

8.6 Determination of sample size


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 128 of 291
Rationale:  These changes were made to provide a clearer description of the comparisons and 
populations for the study co-primary and secondary objectives than the descriptions in the 
original protocol version 1.0 (dated 09 AUG 2013).
Change 2:
Added as an exploratory objective and endpoint to evaluate quality of life based on the 
NCCN-FACT FPSI-17 questionnaire.
Sections affected include:

Synopsis - Study objectives

Synopsis - Methodology

2. Study objectives

4.1 Design overview

7.1.1 Tabular overview, Table 7-1 Schedule of procedures

7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C)

7.1.2.3 Doses 2 to 6 (Treatment Arms A and B)

7.1.2.4 Doses 2 to 12 (Treatment Arm C)

7.1.2.5 End of treatment visit

7.1.2.6.1 Active follow-up with clinic visits 

7.3.1 Efficacy variables

7.3.5.2 Time to increase in physical symptoms of disease based on (FPSI-DRS-P) -
new section

12. References

14.8 NCCN FACT-P Symptom Index-17 (NCCN-FACT FPSI-17) Questionnaire -
new section
Rationale:  The NCCN-FACT FPSI-17 questionnaire was added as per input received from 
Bayer Global Health Economics and Outcome Research and from external Pain Experts of 
the Radium 223 Pain Advisory Board.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 129 of 291
Change 3:
Added a secondary objective that analgesic usage and change in analgesic use will be 
analyzed using the Analgesic Quantification Algorithm (AQA).
Sections affected included:

Synopsis - Study objectives

Synopsis - Methodology

Synopsis - Primary / Secondary variables

1.2 Study rationale

2. Study objectives

4.1 Design overview

4.2 Primary and secondary variables

7.3.1 Efficacy variables

7.3.4.5 Change in analgesic use score - new section

7.3.5.5 Additional pain and health related quality of life endpoints

14.10 Analgesic Quantification Algorithm - new section
Rationale:  A secondary endpoint for change in analgesic use supports its use in secondary 
endpoints for pain improvement/progression, and supports a separate descriptive evaluation 
of changes in analgesic use over time.
Change 4:
Added an exploratory objective and endpoint to explore the impact of baseline body size 
descriptors on efficacy and safety of radium-223 dichloride.
Section affected include:

Synopsis - Study objectives

2. Study objectives

7.2.4 Body size descriptors - new section

8.4.3 Analysis of exploratory endpoints


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 130 of 291
Rationale: Post hoc analyses of the impact of body size on the efficacy and safety of 
radium-223 dichloride have previously been performed on the ALSYMPCA database.  After 
reviewing the original protocol version 1.0 (dated 09 Aug 2013), the FDA requested that this
be evaluated prospectively in this study as an exploratory objective and the Sponsor agrees.  
Due to the dosing regimen based on total body weight, the evaluation of the potential impact 
of other body size descriptors on the efficacy and safety of radium-223 dichloride may 
provide information relevant to the radium-223 treatment optimization program.
Change 5:
Added an inclusion criteria to include subjects who are at least 18 years of age and not 
expose adolescent subjects whose bone development may be adversely affected by radium-
223 dichloride.
Sections affected include:

Synopsis - Diagnosis and main criteria for inclusion

5.1.1 Inclusion criteria
Rationale: This change was made to be consistent with the approved label for Xofigo and to 
eliminate any exposure of potential, though unlikely, adolescent subjects whose bone 
development might be affected.
Change 6: 
Added an inclusion criteria to only include male subjects who agree to use condoms, if 
sexually active, and/or their female partners to use effective methods of birth control to 
prevent pregnancy.  This requirement complies with the US package insert.
Sections affected include:

Synopsis - Diagnosis and main criteria for inclusion

5.1.1 Inclusion criteria
Rationale: This change was made to be consistent with the approved label for Xofigo and to 
prevent pregnancy in women of reproductive potential, female sexual partners of male 
subjects exposed to radium-223 dichloride.
Change 7:
Revised the definition of bone progression based on the PCWG2 criteria to being based on 
the adapted PCWG2 criteria.  The reference to the adapted PCWG2 criteria was added.  The 
time points of assessment of radiological progression were revised according to the new 
definition.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 131 of 291
Sections affected included:

Synopsis - Methodology

4.1 Design overview

7.1.1 Tabulated overview, Table 7-1 Schedule of procedures

7.1.2.3 Doses 2 to 6 (Treatment Arms A and B)

7.1.2.4 Doses 2 to 12 (Treatment Arm C)

7.1.2.5 End of treatment visit

7.1.2.6.1 Active follow-up with clinic visits

7.1.2.7.1 End of active follow-up with clinic visits

7.3.4.3 Radiological progression endpoints

7.3.5.1.3 Bone scan time point response rate

12 Reference list

14.2 Recommendations of the Prostate Cancer Clinical Trials Working Group for 
assessment of radiological progression

14.5 Bone scan assessment tool
Rationale:  The definition of bone progression was revised to the adapted PCWG2 criteria to 
be consistent across the radium-223 dichloride program following recent comments from the 
FDA on another radium-223 dichloride study.  Appropriate changes to the time points of the 
assessment of radiological progression were made and a reference to the new definition was 
also added.
Change 8:
Changed the exclusion criteria concerning treatment with an investigational drug by deleting 
“or planned treatment with an investigational drug during the treatment period or follow-up”.  
Subjects would unlikely plan to be treated with another investigational drug years in advance 
and, if they do receive an investigation study drug during the treatment period or follow-up, 
then they would be excluded from the efficacy analysis because of receiving prohibited 
concomitant drugs.
Sections affected include:

Synopsis - Diagnosis and main criteria for inclusion


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 132 of 291

5.1.2 Exclusion criteria
Rationale:  Clarification.
Change 9:
Revised method and schedule of pain and analgesic use assessments to provide for additional
daily electronic patient-reported outcome (ePRO) pain assessments for 7 days and telephone 
contacts to assess BPI-SF and analgesic use, in Arms A and B at Weeks 28, 32, 40, and 44.  
Consistent collection schedules through Week 48 supports deleting language characterizing 
data collected following Week 24 as exploratory. 
Section affected:

Synopsis - Methodology

4.1 Design overview

7.1.1 Tabulated overview, Table 7-1

7.1.2.5 End of treatment visit

7.1.2.6.1 Active follow-up with clinic visits

14.7 Brief Pain Inventory-Short Form
Rationale: Addresses FDA comment requesting a more consistent schedule of collecting 
pain data among the treatment arms to reduce bias in the results.
Change 10:
Changed the point when the primary endpoint will be performed by reducing minimum 
follow-up after last patient last treatment from 24 months to 1 month, and providing that in 
the event that too few SSE events (135 SSE events for Comparison 1 and 75 SEE events for
Comparison 2) occur to trigger the primary analysis.  This change reduces the estimated 
study duration and slightly reduces the estimated power. 
Sections affected include:

Synopsis - Plan for statistical analysis

4.3 End of study

8.4.1 Primary efficacy analysis

8.6 Determination of Sample Size


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 133 of 291
Rationale:  Dependence of primary endpoint completion on safety follow-up is being relaxed 
to enable primary endpoint completion to mature earlier to support FDA post-marketing 
commitment deadlines. Safety events reported after primary endpoint completion will be 
reported in a separate document.
Change 11:
Revised randomization stratification to include to be stratified by worst pain score (WPS) of 
the BPI-SF (WPS ≤4 versus WPS > 4), and provided for collection of selected BPI-SF pain 
data for 4 days prior to randomization to calculating stratification value.
Sections affected include:

Synopsis - Methodology

4.1 Design overview

6.1 Treatments to be administered

6.3 Treatment assignment

7.1.1 Tabulated overview, Table 7-1

7.1.2.1 Screening period

8.1 General considerations
Rationale:  Pain added as randomization stratification factor to address FDA comment 
requesting a method to better ensure that baseline pain levels are consistent across the 
treatment arms.  Not added to efficacy analysis stratification to avoid added risk of sparse 
cells.
Change 12:
Modified end of active follow-up to continue beyond minimum of 2 years from last treatment 
to earlier of first SSE or primary endpoint maturation in patients receiving clinic visits, while 
ending active follow-up at 2 years in all cases in subjects receiving telephone contact only.
Sections affected included;

Synopsis - Methodology

4.1 Design overview

6.8 Post-study therapy


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 134 of 291

7.1.2.6 Active follow-up

7.1.2.6.1 Active follow-up with clinic visits

7.1.2.6.2 Active follow-up without scheduled clinic visits

7.1.2.7.1 End of active follow-up with clinic visits

7.1.2.7.2 End of active follow-up without scheduled clinic visits
Rationale:  End of follow-up was made different for active follow-up with clinic visits and 
telephone-only active follow-up to reflect their different capacities.  To ensure primary 
endpoint completion and adequate study power, patients in study need to continue follow-up 
for SSEs to first SSE if before primary endpoint completion, if after the two-year period 
selected to evaluate safety. As subjects without clinic visits cannot have primary endpoint 
SSE evaluations, telephone-only follow-up need occur only for 2-year safety period. 
Change 13:
Changed the safety review during the study from an independent data monitoring committee 
to a joint safety review committee; membership may include investigators, sponsor team 
members, and/or independent members.
Sections affected included:

Synopsis - Methodology

3 Investigators and other study personnel

4.3 Interim Analyses and Joint Safety Review Committee - new section

8.4.4 Safety analysis
Rationale:  A Data Monitoring Committee, with a stringent membership requirement of only 
independent members, is not necessary for this open-label study.  Therefore, a Joint Safety 
Review Committee (JSRC), whose membership requirements that are less stringent and can 
include investigators, sponsor members, and/or independent members, is adequate for this 
study.  The JSRC’s mandate will be limited to safety to reduce the possibility of any bias 
arising from study principal participation.
Change 14:
Added that Cardinal Health is the radio pharmacy that will prepare and dispense patient ready 
doses of radium-223 dichloride in the US.
Section affected:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 135 of 291

6.4.4 Dose preparation
Rationale:  Inclusion of important dose preparation information.
Change 15:
Revised text to be clearer on when and how IVRS / IWRS will be used to order study drug to 
be shipped to the investigator site so that the study drug is delivered on-time for the subject’s
next visit requiring study drug administration.
Sections affected included:

7.1.1 Tabular overview, Table 7-1 Schedule of procedures

7.1.2.1 Screening period
Rationale:  Clarification
Change 16:
Added that on Study Day 1 visit, study eligibility must be reconfirmed for hematology tests if 
the results are greater than 72 hours prior to the first dose of study drug.  This is not a new 
requirement.  It was in Section 7.1.2.2, but stated differently.
Section affected include:

7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C)
Rationale:  Moved this text and restated to emphasize that hematology results should be 
reconfirmed to be within the entry criteria prior to the first dose of study medication.
Change 17:
A study specific radium-223 dose modification to mandate discontinuation of treatment in 
patients who experience grade 4 neutropenia lasting more than 7 days.
Section affected:

5.2.1 Withdrawal

6.4.7 Dose delays
Rationale:  The study specific radium-223 dose modification was added as per FDA request. 
The addition of the dose modification was agreed with Bayer Global Pharmacovigilance in 
consideration of the higher doses and extended regimen investigated in this trial.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 136 of 291
Change 18:
Modified definition of pain progression, pain improvement rate, and time to pain progression 
to refer to evaluability for analgesic use increase and decrease respectively.
Sections affected include:

7.3.4.4 Pain endpoints

7.3.4.4.1 Pain improvement rate

7.3.4.4.2 Time to pain progression
Rationale:  Changed to be consistent with the radium-223 dichloride program and with FDA 
comment regarding population evaluable for pain endpoints, further clarifies the portion of 
patient population eligible for evaluation for each pain endpoint.
Change 19:
Modified safety analysis section to define treatment-emergent period, and to provide for an 
analysis of safety events arising after primary endpoint completion in a separate document 
from the CSR
Sections affected include:

8.4.4 Safety analysis
Rationale:  Change clarifies treatment-emergent safety event analysis.  As primary endpoint 
completion following amendment is expected to occur before the end of 2-year active safety 
follow-up, this provides for an analysis of events emerging after primary endpoint 
completion, as well as any long-term follow-up events in a separate document.
Change 20:
Added that IVRS / IWRS procedures can be found in the IVRS / IWRS manual.
Section affected:

7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C)
Rationale:  Clarification
Change 21:
Changed the terminology for “active safety follow-up” period to “active follow-up” period 
since efficacy assessments are also included in these visits.  In addition, the terminology for 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 137 of 291
“extended active follow-up” period was changed to “long-term follow-up” period; this 
change was done to ensure the use of a consistent term across the radium-223 program.  
Another revision included changing “2 years of active follow-up” to “active follow-up”.
Sections affected included:

Synopsis - Methodology

4.1 Design overview

6.8 Post-study therapy

7.1.1 Tabulated overview, Table 7-1 Schedule of procedures

7.1.2.6 Active follow-up

7.1.2.7.2 End of active follow-up without scheduled clinic visits

7.1.2.8 Long-term follow-up to 7 years following last dose

7.1.2.8.1 Long-term follow-up (via telephone follow-up)

7.1.2.8.2 End of long-term follow-up

8.4.4 Safety analysis
Rationale:  Clarification
Change 22:
Clarified handling of radiological progression and quantitated bone scan details. 
Sections affected included:

7.3.2 Definition of efficacy variables

7.3.4.3 Radiological progression endpoints

7.3.5.1 Quantitated bone scan endpoints  
Rationale:  Clarifies central radiological reviewer is responsible for imaging endpoints 
including baselines.  Permits details to be addressed in a separate document from the imaging 
charter.
Change 23:
Changed laboratory assessment from bilirubin to total bilirubin.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 138 of 291
Sections affected:

7.1.1 Tabulated overview, Table 7-1 Schedule of procedures

7.1.2.1 Screening period

7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C)

7.1.2.3 Doses 2 to 6 (Treatment Arms A and B)

7.1.2.4 Doses 2 to 12 (Treatment Arm C)

7.1.2.5 End of treatment visit

7.1.2.6.1 Active follow-up with clinic visits

7.1.2.7.1 End of active follow-up with clinic visits

7.5 Safety

7.5.3.1 Laboratory evaluations
Rationale:  Bilirubin was changed to total bilirubin to clarify that direct and indirect bilirubin 
were not necessary.
Change 24: 
Revised text for clarification purposes:
Section affected:

Synopsis - Diagnosis and main criteria for inclusion

Synopsis - Plan for statistical analysis

5.1.1 inclusion criteria

6.4.7 Dose delays

7.1.1 Tabulated overview, Table 7-1 Schedule of procedures

7.1.2.1 Screening period

7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C)

7.1.2.3 Doses 2 to 6 (Treatment Arms A and B)


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 139 of 291

7.1.2.4 Doses 2 to 12 (Treatment Arm C)

7.1.2.5 End of treatment visit

7.1.2.6.1 Active follow-up with clinic visits

7.3.2 Definition of efficacy variables

7.2.5.5 Additional pain and health-related quality of life

8.4.2.1 Analyses of pooled standard dose and high dose from randomization

8.4.4 Safety analysis
Rationale:  Original text was not clear, revised text is clearer.
Change 25:
The list of abbreviations was updated to reflect the usage of abbreviations in the amended 
protocol:
Section affected:

List of abbreviations
Rationale:  Update abbreviation definitions
Change 26:
Revised Section 7.1.1 Tabular overview, Table 7-1 Schedule of procedures to reflect all the 
changes described above in Changes 1 to 21.
Rationale:  Updated Table 7-1 Schedule of procedures to be consistent with Changes 1 to 21.
Change 27:
Updated Section 12 Reference list to include new reference “22” cited in Section 1.1 
Background.
Rationale:  Updated reference list to include an additional reference cited in the amended 
protocol.
Change 28:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 140 of 291
Editorial revisions were made throughout the amended protocol.
Sections affected:

Synopsis - Diagnosis and main criteria for inclusion

Synopsis - Plan for statistical analysis

2 Study objectives

3 Investigators and other study personnel
13.1.2 Changes to the protocol text
General format conventions:

Deleted text = deleted text

Added text = added text
Change 1:
Synopsis - Study objectives and Section 2 Study objectives:
Paragraph 1:
Old text:  
Each of the following objectives will be used to compare radium-223 dichloride 
50 kBq/kg every 28 days for up to 6 doses to radium-223 dichloride 80 kBq/kg 
every 28 days for up to 6 doses and to radium-223 dichloride 50 kBq/kg every 
28 days for up to 12 doses.
New text:
The following objectives will be used to compare radium-223 dichloride 
50 kBq/kg every 28 days for up to 6 doses with radium-223 dichloride 80 kBq/kg 
every 28 days for up to 6 doses in radium-223 dichloride-naïve subjects; and, in 
subjects receiving radium-223 dichloride 50 kBq/kg every 28 days up to 6 doses, 
to compare a regimen of up to a further 6 doses of radium-223 dichloride 
50 kBq/kg every 28 days with no further radium-223 dichloride treatment.
Paragraph 2:
Old text:
Primary objective:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 141 of 291

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 
50 kBq/kg every 28 days for up to 6 doses compared to radium-223 
dichloride 80 kBq/kg every 28 days for up to 6 doses, and compared to 
radium-223 dichloride 50 kBq/kg every 28 days for up to 12 doses in 
subjects with CRPC metastatic to bone
New text:
Co-primary objectives:

To evaluate efficacy as measured by symptomatic skeletal event-free 
survival (SSE-FS) of radium-223 dichloride 50 kBq/kg every 28 days for 
up to 6 doses compared to radium-223 dichloride 80 kBq/kg every 28 days 
for up to 6 doses in subjects with castration-resistant prostate cancer 
(CRPC) metastatic to the bone not previously receiving radium-223 
dichloride; and

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 
50 kBq/kg every 28 days for up to 6 additional doses compared to no 
further radium-223 dichloride treatment in subjects with CRPC metastatic 
to the bone who previously received radium-223 dichloride 50 kBq/kg 
every 28 days for up to 6 doses, and survived SSE-free and are eligible for 
further radium-223 dichloride treatment
Synopsis - Plan for statistical analysis and Section 8.4.1 Primary efficacy analysis:
Comparison 1 and comparison 2 subheadings and text:
Old text:
Comparison 1: Standard dose versus high dose: SSE-FS from randomization
Comparison 1 will test the following hypotheses:
H01: Population SSE-FS from randomization in subjects treated with high dose 
radium-223 dichloride is equal to population SSE-FS from randomization in 
subjects treated with standard dose radium-223 dichloride, versus
HA1: Population SSE-FS from randomization in subjects treated with high dose 
radium-223 dichloride is greater than population SSE-FS from randomization in 
subjects treated with standard dose radium-223 dichloride
Comparison 2: Standard dose versus extended dose: SSE-FS analysis from 
24 weeks
Comparison 2 will test the following hypotheses:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 142 of 291
H02: Population SSE-FS from 24 weeks in subjects treated with extended dose 
radium-223 dichloride is equal to population SSE-FS from 24 weeks in subjects 
treated with standard dose radium-223 dichloride, versus
HA2: Population SSE-FS from 24 weeks in subjects treated with extended dose 
radium-223 dichloride is greater than population SSE-FS from 24 weeks in 
subjects treated with standard dose radium-223 dichloride
New text:
Comparison 1: Standard dose versus high dose: SSE-FS from randomization 
in radium-223 dichloride-naïve subjects
Comparison 1 will test the following hypotheses:
H01: In a population of radium-223 dichloride-naïve subjects with CRPC
metastatic to the bone, population SSE-FS in subjects treated with a regimen of up 
to 6 doses of 80 kBq/kg (high dose) radium-223 dichloride is equal to population 
SSE-FS in subjects treated with a regimen of up to 6 doses of 50 kBq/kg (standard 
dose) radium-223 dichloride, versus
HA1: In a population of radium-223 dichloride-naïve subjects with CRPC
metastatic to the bone, population SSE-FS in subjects treated with a regimen of up 
to 6 doses of 80 kBq/kg (high dose) radium-223 dichloride is greater than 
population SSE-FS in subjects treated with a regimen of up to 6 doses of 
50 kBq/kg (standard dose) radium-223 dichloride.
Comparison 2: No further radium-223 dichloride treatment versus extended 
dosing: SSE-FS analysis from 24 weeks in subjects receiving standard dose 
regimen
Comparison 2 will test the following hypotheses:
H02: In a population of subjects treated with a regimen of up to 6 doses of 
50 kBq/kg (standard dose) radium-223 dichloride who survived SSE-free and are 
eligible for further radium-223 dichloride treatment at 24 weeks, population 
SSE-FS beyond 24 weeks in subjects treated with a regimen of up to an additional 
6 doses of 50 kBq/kg (extended dose) radium-223 dichloride is equal to 
population SSE-FS beyond 24 weeks in subjects receiving no further radium-223 
dichloride treatment beyond the standard dose regimen, versus
HA2: In a population of subjects treated with a regimen of up to 6 doses of 
50 kBq/kg (standard dose) radium-223 dichloride who survived SSE-free and are 
eligible for further radium-223 dichloride treatment at 24 weeks, population
SSE-FS beyond 24 weeks in subjects treated with a regimen of up to an additional 
6 doses of 50 kBq/kg (extended dose) radium-223 dichloride is greater than 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 143 of 291
population SSE-FS beyond 24 weeks in subjects receiving no further radium-223 
dichloride treatment beyond the standard dose regimen.
Section 8.6 Determination of sample size:
Paragraph 1:
Old text:
The sample size is calculated to have the indicated power, separately and with no 
multiple testing adjustment, to detect one or both of the following:

Comparison 1: A 50% increase in SSE-FS in subjects receiving a regimen 
6 doses of 80 kBq/kg radium-223 dichloride every 28 days (high dose) 
over subjects receiving a regimen of 6 doses of 50 kBq/kg radium-223 
dichloride every 28 days (standard dose), and / or

Comparison 2: A 65% increase in SSE-FS following 24 weeks in subjects 
receiving a regimen of 12 doses of 50 kBq/kg radium 223 dichloride every 
28 days (high dose) over subjects receiving a regimen of 6 doses of 
50 kBq/kg radium 223 dichloride every 28 days (standard dose), in 
subjects surviving SSE-FS to 24 weeks and who either completed 6 doses 
of radium 223 dichloride, or remained eligible to receive further radium 
223 dichloride (not permanently discontinued from treatment) at 24 weeks.
New text:
The sample size is calculated to have the indicated power, separately and with no 
multiple-testing adjustment, to detect one or both of the following:

Comparison 1: A 50% increase in SSE-FS in subjects receiving a regimen 
6 doses of 80 kBq/kg radium-223 dichloride every 28 days (high dose) 
over subjects receiving a regimen of 6 doses of 50 kBq/kg radium-223 
dichloride every 28 days (standard dose) in a population of radium-223 
dichloride-naïve subjects, and / or

Comparison 2: A 65% increase in SSE-FS following 24 weeks in subjects 
receiving a regimen of up to 6 additional doses of 50 kBq/kg radium-223 
dichloride every 28 days (extended dose) over subjects receiving no 
further radium-223 dichloride treatment, in a population of subjects 
surviving SSE-free to 24 weeks who received a standard regimen of up to
6 doses of 50 kBq/kg radium-223 dichloride and who either completed 
standard treatment, or remained eligible to receive further radium-223 
dichloride (not permanently discontinued from treatment) at 24 weeks.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 144 of 291
Change 2:
Synopsis - Study objectives and Section 2 Study objectives:
Exploratory objectives, 3rd bullet:
Added text:

Time to increase in physical symptoms of disease based on the NCCN FACT-
P Symptom Index-17 (NCCN-FACT FPSI-17) physical disease related 
symptoms (FPSI-DRS-P) subscale score measured up to Week 48 after the 
start of treatment
Synopsis - Methodology and Section 4.1 Design overview:  
Paragraphs 8 and 9, new text
The NCCN-FACT FPSI-17 questionnaire will be completed by the patient in all 
treatment arms every clinic visit starting on Dose 1, Day 1 up to Week 48 visit.  In 
treatment Arms A and B only the NCCN-FACT FPSI-17 questionnaire will also be 
completed on the day of each telephone contact at Weeks 28, 32, 40 and 44.
Both the pain assessment using the BPI-SF questionnaire and the NCCN-FACT FPSI-
17 questionnaire will be self-administered by the patient using a handheld device.
Section 2 Study objectives:
Exploratory objectives, 3rd bullet:
Added text:

Time to increase in physical symptoms of disease based on the NCCN FACT-P 
Symptom Index-17 physical disease related symptoms (FPSI-DRS-P) subscale score 
measured up to Week 48 after the start of treatment
Section 7.1.1 Tabular overview, Table 7-1 Schedule of procedures:
See Change 26
Section 7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C), 3rd bullet;
Section 7.1.2.3 Doses 2 to 6 (Treatment Arms A and B), 2nd bullet;
Section 7.1.2.4 Doses 2 to 12 (Treatment Arm C), 2nd bullet;
Section 7.1.2.5 End of treatment visit, 2nd bullet; and 
Section 7.1.2.6.1 Active follow-up with clinic visits, 6th paragraph, last bullet


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 145 of 291
Added text:
NCCN-FACT FPSI-17 questionnaire, using a handheld device, is also self-
administered at the beginning of the visit and should be checked for 
completion 
at 
the 
visit
prior 
to 
treatment 
(see 
Section 
14.8).  
In Section 7.1.2.6.1 only - added text at end of previous sentence:  
(Treatment Arms A and B only)
Section 7.1.2.6.1 Active follow-up with clinic visits:
Paragraph 2, last sentence, new text:
Pain data, ......... and NCCN-FACT FPSI-17 questionnaires will also be collected as 
detailed below.
Paragraph 3, 2nd bullet:
Added text:

NCCN-FACT FPSI-17 questionnaire is also administered at the beginning of 
the visit and should be checked for completion at the visit prior to treatment 
(see Section 14.8).  (Treatment Arms A and B only).
Section 7.3.1 Efficacy variables:
Paragraph 4, 5th bullet:
New text:

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 up to 48 weeks after the start of treatment.
Section 7.3.5.2 Time to increase in physical symptoms of disease based on (FPSI-DRS-P):
New section:
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 up to 
Week 48 after start of treatment will be assessed using the NCCN-FACT FPSI-17 
questionnaire (Section 14.8). 
The NCCN-FACT FPSI-17 is a validated instrument that was developed to assess 
symptoms of prostate cancer, symptoms caused by the treatment of prostate cancer, 
and the health related quality of life of prostate cancer patients.(26)  The instrument 
was developed in accordance with recent FDA guidance for the development of 
instruments for electronic patient-reported outcome (ePRO).  The instrument contains 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 146 of 291
17 items, each of which utilizes 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 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, two items represent 
functional well-being and the responses to those items are summed to calculate a 
functional/well-being subscale score.  
The NCCN-FACT FPSI-17 will be self-administered by the subject via an ePRO 
device. 
For each applicable baseline, time to increase in physical symptoms of disease based 
on (FPSI-DRS-P) will be calculated with respect to that baseline, based only on 
assessments through Week 48. Details, including definition of an increase, will be 
provided in the SAP.
Section 12 Reference list:
New reference:
25.  http://www.facit.org/FACITOrg/Questionaires.
Section 14.8 NCCN FACT-P Symptom Index (NCCN-FACT FPSI-17) Questionnaire:
New section which includes a copy of the NCCN-FACT FPSI-17.
Change 3:
Synopsis - Study objectives and Section 2 Study objectives:  
Secondary objectives, 8th bullet:
New text:

To evaluate change in analgesic use as measured by the Analgesic 
Quantification Algorithm (AQA)
Synopsis - Methodology:
Paragraph 10, new text:
The AQA score will be calculated programmatically from the assessments of 
analgesic use in the last 24 hours.
Synopsis - Primary / Secondary variables and Section 7.3.1 Efficacy variables:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 147 of 291
Paragraph 3, 7th bullet:
New text:

Change in analgesic use
Section 7.3.1 Efficacy variables:
Paragraph 4, 10th bullet:
Deleted text:

Analgesic use
Section 1.2 Study rationale:
Paragraph 4, last sentence:
Added text:
Additional secondary objectives include pain improvement rate and time to 
progression based on subjects’ self-assessment of pain, change in analgesic use 
based on subjects’ analgesic use in the last 24 hours as evaluated by the Analgesic 
Quantification Algorithm (AQA).
Section 4.1 Design overview:  
Paragraph 11:
New text:
The AQA score will be calculated programmatically from the assessments of 
analgesic use in the last 24 hours (See Section 14.9).
Section 4.2 Primary and secondary variables:
Paragraph 3:
Old text:
Secondary efficacy variables will be OS, time to first SSE, rPFS, time to 
radiological progression, pain improvement rate, and time to pain progression. 
New text:
Secondary efficacy variables will be OS, time to first SSE, rPFS, time to 
radiological progression, pain improvement rate, time to pain progression, and 
change in analgesic use.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 148 of 291
Section 7.3.4.5 Change in the last 24-hour analgesic use score - new section:
New text:
Change in the last 24 hour analgesic use score is calculated based on the subject’s 
analgesic use in the last 24 hours CRF data.
For each subject, each analgesic medication from analgesic use in the last 
24 hour’s data taken at applicable clinic visits (and in Arms A and B, at telephone 
contacts) will be coded using the WHO drug dictionary and OMEs will be 
calculated from the coded data.
For each subject and applicable visit or telephone contact, analgesic use in the last 
24 hours will be scored using the AQA (see Section 14.9) based on the coded 
medications and corresponding OME quantities.
Details on coding and scoring will described in the SAP.
For each subject, for each applicable baseline and post-baseline time point, the 
subject’s change in the last 24-hour analgesic use is defined as the difference 
between the subject’s last 24 hour AQA score at the post-baseline time point and 
at the applicable baseline.
Section 7.3.5.5 Additional pain and health related quality of life endpoints:
Deleted text:
Subject-reported outcome data not described above, analgesic use data, palliative 
pain relief procedure data, additional BPI-SF data collected at clinic visits, and 
pain data collected following the Week 24 assessment, will be evaluated as 
described in the SAP.
Section 14.9 Analgesic Quantification Algorithm - new section:
New text:  
Analgesic Quantification Algorithm Score Categories
0
No analgesic
1
Non-opioid analgesics
2
Weak opioids (i.e., meperidine, codeine, tramadol)
3
Strong opioids ≤75 mg OME/d
4
Strong opioids >75-150  mg OME/d 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 149 of 291
5
Strong opioids > 150-300 mg OME/d
6 
Strong opioids > 300 mg-600 mg OME/d
7
Strong opioids > 600 mg OME/d
OME, oral morphine equivalents; d, day.
References for the AQA:
Chung K, Barlev A, Braun A, Qian Y, Zagari M. Development of the Analgesic 
Quantification Algorithm (AQA): a new scale to assess analgesic use. Poster 
presented at: Joint 15th Congress of the European Cancer Organization and 34th 
Congress of the European Society for Medical Oncology; September 20-24, 2009; 
Berlin, Germany.
Charles S. Cleeland PhD1,†,*, Jean-Jacques Body MD, PhD2, Alison Stopeck MD3, 
et al. (2013).   Pain outcomes in patients with advanced breast cancer and bone 
metastases: Results from a randomized, double-blind study of denosumab and 
zoledronic acid.  Cancer, Volume 119, Issue 4, pages 832–838.
Change 4:
Synopsis - Study Objectives and Section 2 Study objectives:
Exploratory objectives, 2nd bullet
New text:

To explore the impact of patient body size on the efficacy and safety of 
radium-223 dichloride
Section 7.2.4 Body size descriptors - new section:
New text:
Body size descriptors will be calculated from patient height and weight at the 
applicable baselines.  Details will be described in the statistical analysis plan (SAP).
Section 8.4.3 Analysis of exploratory variables:
Paragraph 3, new text:
An exploratory analysis of the impact of baseline body size descriptors on the efficacy 
and safety of radium-223 dichloride will also be performed with respect to each 
applicable baseline.  Details regarding the baseline body size descriptor definitions, 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 150 of 291
analysis specifications, and applicable baseline definitions will be provided in the 
SAP.
Change 5:
Synopsis - Diagnosis and main criteria for inclusion and Section 5.1.1 Inclusion criteria:
Main inclusion criteria, 3rd bullet:
New text:

Subjects must be ≥ 18 years of age.
Change 6
Synopsis - Diagnosis and main criteria for inclusion and Section 5.1.1 Inclusion criteria:
Main criteria for inclusion, 9th bullet:
New text:

Sexually active males agree to use condoms and/or their female partners of 
reproductive potential to use a method of effective birth control during 
treatment and for 6 months following the completion of treatment with 
radium-223 dichloride.
Change 7:
Synopsis - Methodology (paragraph 5) and Section 4.1 Design overview (paragraph 6):
Added text:
Radiological assessment, including whole body technetium-99 bone scan, MRI / 
CT scan of the abdomen and pelvis, and chest X-ray (in the presence of suspicious 
lesion[s], a chest CT scan will be performed to confirm and characterize the 
lesion[s]), will be performed at Week 8, Week 16, Week 24, then every 12 weeks 
for 2 years after the subject’s last dose of radium-223 dichloride or until 
radiologic progression.  If progression is detected by bone scan, a confirmatory 
bone scan is required at least 6 weeks later.  Radiological assessments will 
continue .....
Section 7.1.1 Tabulated overview, Table 7-1 Schedule of procedures:
See Change 26


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 151 of 291
Section 7.1.2.3 Doses 2 to 6 (Treatment Arms A and B):
Paragraph 1, 18th bullet:
Old text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), and whole body technetium-99 bone 
scan will be performed 12 weeks after the start of treatment (i.e., within 7 days 
prior to starting Dose 4 and documented at the visit)
New text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), and whole body technetium-99 bone 
scan will be performed at 8 weeks and 16 weeks after the start of treatment
(i.e., on Dose 3 and Dose 5 visits)
o
Bone scans will be assessed by adapted PCWG2 criteria (30).  Per 
adapted PCWG2 criteria, confirmation of bone progression by a 2nd
scan ≥ 6 weeks later is required in all cases.  A SPECT or MRI (with 
and without contrast media) should be obtained to clarify any 
suspicious bone scan findings.  The date of confirmed radiological 
progression will be the date of first observation of radiological 
progression.  The patient should remain on study treatment in the 
interim unless the investigator determines that there is immediate need 
to initiate cytotoxic chemotherapy.
Section 7.1.2.4 Doses 2 to 12 (Treatment Arm C):
Paragraph 1, 18th bullet:
Old text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), and whole body technetium-99 bone 
scan will be performed every 12 weeks during the treatment period (i.e., 
within 7 days prior to starting Dose 4, 7, and 10 and documented at the visit)
New text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), and whole body technetium-99 bone 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 152 of 291
scan will be performed at 8 weeks, 16 weeks, 24 weeks, and 36 weeks after 
the start of treatment (i.e., on Dose 3, 5, 7 and 10 Visits). 
o
Bone scans will be assessed by adapted PCWG2 criteria (30).  Per 
adapted PCWG2 criteria, confirmation of bone progression by a 
2nd scan ≥ 6 weeks later is required in all cases.  A SPECT or MRI 
(with and without contrast media) should be obtained to clarify any 
suspicious bone scan findings.  The date of confirmed radiological 
progression will be the date of first observation of radiological 
progression.  The patient should remain on study treatment in the 
interim unless the investigator determines that there is immediate need 
to initiate cytotoxic chemotherapy. 
Section 7.1.2.5 End of treatment visit:
Paragraph 1, 16th bullet:
Old text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), and whole body technetium-99 bone 
within 7 days prior to the EOT visit and documented at the visit, if the last 
tumor evaluation is older than 4 weeks
New text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), and whole body technetium-99 bone 
scan on the EOT visit, if the last tumor evaluation is older than 4 weeks
o
Per adapted PCWG2 criteria, confirmation of bone progression by a 
2nd scan ≥6 weeks later is required in all cases.  A SPECT or MRI 
(with and without contrast media) should be obtained to clarify any 
suspicious bone scan findings.  The date of confirmed radiological 
progression will be the date of first observation of radiological 
progression.
Section 7.1.2.6.1 Active follow-up with clinic visits (paragraph 3, 15th bullet, 1st sub-bullet) 
and Section 7.1.2.7.1 End of active follow-up with clinic visits (paragraph 1, 11th bullet, 
1st sub-bullet):
Added text:
o
Per adapted PCWG2 criteria (29), confirmation of bone progression by 
a 2nd scan ≥6 weeks later is required in all cases.  A SPECT or MRI 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 153 of 291
(with and without contrast media) should be obtained to clarify any 
suspicious bone scan findings.  The date of confirmed radiological 
progression will be the date of first observation of radiological 
progression.
Section 7.3.4.3 Radiological progression endpoints:
Paragraph 1:
Old text:
Radiological progression is radiological progression of soft-tissue disease or 
radiological progression of bone disease, whichever occurs first.  Assessment of 
radiological progression will be made at the site level.
New text:
Radiological progression is radiological progression of soft-tissue disease or 
radiological progression of bone disease, whichever occurs first.  Assessment of 
radiological progression will be made by independent central review. 
Paragraph 2:
Added text:
Radiological progression of soft tissue disease is determined according to RECIST 
1.1 based on MRI or CT scans (see Section 14.1).  Radiological progression of 
osseous disease is determined according to adapted PCWG2 criteria based on 
whole body technetium-99 bone scans (30) (see Section 14.2).  Radiological bone 
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).
Section 7.3.5.1.3 Bone scan time point response rate:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 154 of 291
Paragraph 1, 2nd sentence:
Old text:
The bone scan time point response with respect to the baseline will be assessed as 
described in Section 14.5.
New text:
The bone scan time point response with respect to the baseline will be assessed as 
described in Section 14.3.
Section 12 Reference list:
Reference “29”, added text:
29.
Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate 
cancer without previous chemotherapy. N Engl J Med 2012;368(2):138-48.
Section 14.2 Recommendations of the Prostate Cancer Clinical Trials Working Group 
for assessment of radiological progression
Table 14-4:
Old table:
Table 14-4 Radiological progression free survival definition per modified Response Evaluation 
Criteria in Solid Tumors, version 1.1, or progression by bone scan as adapted by Prostate 
Cancer Clinical Trials Working Group 2 criteria
Site
Criteria for radiological progression
Soft tissue
Soft tissue progression is determined by modified RECIST, version 1.1:

Only lymph nodes with short axis ≥2 cm can be selected as a target lesion
Bone
Progressive disease by bone scan is defined as follows:

First scheduled assessment 12 weeks after the start of treatment with 
radium-223 dichloride

≥ 2 new bone lesions plus 2 additional at confirmation (“2 + 2”) performed 
6 or more weeks later

The date of progression is the date of the first scan that shows the change

Subsequent assessments > 12 weeks after start of treatment with radium-223 
dichloride

≥ 2 new bone lesions
Abbreviations: RECIST = Response Evaluation Criteria in Solid Tumors
New table:
Table 14-4 Radiological progression free survival definition per modified Response Evaluation 
Criteria in Solid Tumors, version 1.1, or progression by bone scan as adapted by Prostate 
Cancer Clinical Trials Working Group 2 criteria
Site
Criteria for radiological progression
Soft tissue
Soft tissue progression is determined by modified RECIST, version 1.1:

Only lymph nodes with short axis ≥2 cm can be selected as a target lesion
Bone
Progressive disease by bone scan as adapted from PCWG2 Consensus Criteria:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 155 of 291

< 12 weeks after randomization:  ≥2 new bone lesions plus 2 additional at 
confirmation (“2+2”)

≥12 weeks after randomization:  ≥2 new bone lesions with subsequent 
confirmation
If progression is detected by bone scan, a confirmatory bone scan is required at least 6 
weeks later.  A 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.
Abbreviations: RECIST = Response Evaluation Criteria in Solid Tumors
14.5 Bone scan assessment tool
Deleted section.
Change 8:
Synopsis - Diagnosis and main criteria for inclusion and Section 5.1.2 Exclusion criteria:
Main criteria for exclusion, 6th bullet:
Deleted text:

Treatment with an investigational drug within the 4 weeks prior to 
randomization, or planned treatment with an investigational drug during the 
treatment period or follow-up
Change 9:
Synopsis - Methodology:
Paragraph 6:
Old text:
Pain endpoints will be based on subject-reported outcome data.  Pain will be 
assessed by means of selected questions from the Brief Pain Inventory Short Form
(BPI-SF) daily for the 7 days immediately prior to Dose 1, Day 1, and then for 
Treatment Arms A and B, daily for 7 days prior to each scheduled dosing visit 
through Week 24 and for the 7 days prior to Weeks 36 and 48, or for Treatment 
Arm C, daily for 7 days prior to each scheduled dosing visit through Week 48.  
Analgesic use will be collected and it will be assessed by the treating physician at 
each visit for all treatment arms from Dose 1, Day 1 until the Week 48 visit.  Pain 
will also be assessed by means of the BPI SF questionnaire for all treatment arms 
at each clinic visit from Dose 1, Day 1 until the Week 48 visit.
New text: 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 156 of 291
Pain endpoints will be based on subject-reported outcome data.  Pain data will be 
collected every 4 weeks through week 48 in all treatment arms using a handheld 
device.  Pain will be assessed by means of selected questions from the BPI-SF
daily for 4 days immediately prior to randomization, in order to stratify patients by 
worst pain score (WPS) ≤4 or > 4, and then as follows:

for Treatment Arms A and B, daily for 7 days prior to each scheduled 
dosing visit from Dose 1, Day 1 through Week 24.  During the Active 
Follow-up, pain data will be collected for the 7 days prior to Week 36 and 
48 visits, and for 7 days prior to each telephone contact at Weeks 28, 32, 
40 and 44.  

for Treatment Arm C, daily for 7 days prior to each scheduled dosing visit 
from Dose 1, Day 1 through Week 48.  
Pain will also be assessed by means of the BPI-SF questionnaire every clinic visit 
from Dose 1, Day 1 visit until the Week 48 visit.  In treatment Arms A and B 
only, the BPI-SF questionnaire will also be completed on the day of each 
telephone contact at Weeks 28, 32, 40 and 44.  
Section 4.1 Design overview:
Paragraph 7
Old text:
Pain endpoints will be based on subject-reported outcome data.  Pain will be 
assessed by means of selected questions from the BPI-SF daily for the 7 days 
immediately prior to Dose 1, Day 1, and then for Treatment Arms A and B, daily 
for 7 days prior to each scheduled dosing visit through Week 24 and for the 7 days 
prior to Weeks 36 and 48, and for Treatment Arm C, daily for 7 days prior to each 
scheduled dosing visit through Week 48.  Analgesic use will be collected and it 
will be assessed by the treating physician at each visit for all treatment arms from 
Dose 1, Day 1 until the Week 48 visit.  Pain will also be assessed by means of the 
BPI SF questionnaire for all treatment arms at each clinic visit from Dose 1, Day 1 
until the Week 48 visit.
New text:
Pain endpoints will be based on subject-reported outcome data.  Pain will be 
assessed by means of selected questions from the BPI-SF daily for 4 days 
immediately prior to randomization, in order to stratify patients by worst pain 
score (WPS) ≤4 or > 4, for the 7 days immediately prior to Dose 1, Day 1, and 
then for Treatment Arms A and B, daily for 7 days prior to each scheduled dosing 
visit through Week 24, for the 7 days prior to Weeks 36 and 48 visits and for 7 
days prior to each telephone contact at Weeks 28, 32, 40 and 44. For Treatment 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 157 of 291
Arm C, pain data will be collected daily for 7 days prior to each scheduled dosing 
visit through Week 48.  Pain will also be assessed by means of the BPI-SF 
questionnaire for all treatment arms at each clinic visit from Dose 1, Day 1 until 
the Week 48 visit and for treatment Arms A and B on the day of each telephone 
contact at Weeks 28, 32, 40 and 44.
Synopsis - Methodology and Section 4.1 Design overview:
Paragraph 10, new text:
Analgesic use will be collected throughout the study.  In addition analgesic use over 
the 24-hour period prior to the day of the visit will be collected by the study 
investigator at each visit for all treatment arms from Dose 1, Day 1 until the 
Week 48 visit, and analgesic use over the 24-hour period prior to each telephone 
contact (in Arms A or B) will be collected by the study investigator at the telephone 
contact at Weeks 28, 32, 40 and 44.
Section 7.1.1 Tabulated overview, Table 7-1:
See Change 26.
Section 7.1.2.1 Screening period:
Paragraph 2, 19th bullet, new text:

When a subject is determined to be eligible, the subject will be trained on daily 
Patient-reported outcome (PRO) pain data collection using a handheld device.  
Eligible subjects will then complete the pain assessment daily
o
for the 4 days immediately prior to randomization.  The average of the 
daily WPS over the 4-day period will be used for stratification (WPS ≤4 
versus WPS >4). 4 days of daily WPS data must be taken before 
randomization can occur. 
o
for the 7 days prior to Dose 1, Day 1.
Section 7.1.2.5 End of treatment visit:
Paragraph 1, 17th bullet:
Old text:

After the visit, subjects will complete the pain assessment daily for the 7 days 
prior to the Week 36 (Treatment Arm A and B only).
New text:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 158 of 291

After the visit, subjects will complete the pain assessment daily for the 7 days 
prior to the Week 28 telephone contact (Treatment Arms A and B only).
Section 7.1.2.6.1 Active follow-up with clinic visits:
Paragraph 2, new text:
In addition to the visits at Weeks 36 and 48 the subjects in Treatment Arms A and B 
will receive telephone contacts at Weeks 28, 32, 40, and 44 to assess for possible SSE 
risks and will continue PRO data collection.  Pain data, 24-hour analgesic use, BPI 
and NCCN-FACT FPSI-17 questionnaires will also be collected as detailed below.
Paragraph 3, 16th bullet:
Old text:

After the Week 36 visit, subjects will complete the pain assessment using
daily for the 7 days prior to the Week 48 visit.
New text:

After the Week 36 visit, subjects will complete the pain assessment daily for 
the 7 days prior to the Week 40 telephone contact.
Paragraphs 4 to 6:
Added text:
Telephone contact for SSE risks and PRO pain and analgesic use data 
collection at Weeks 28 (±7 days), 32 (±7 days), 40 (±7 days), and 44 (±7 days), 
subjects in Treatment Arms A and B only.
The subjects will receive telephone contacts at Weeks 28, 32, 40, and 44 assessing 
for possible SSE risks.  Subjects exhibiting symptoms indicative of possible SSEs 
will be encouraged to visit the clinic early to assess SSE status.  Symptomatic 
skeletal events will not be determined over the phone. 
In the intervals between the visits, the subjects will continue to be followed for 
PRO pain data collection and analgesic use data collection as follows:

Pain will be assessed daily for 7 days prior to each telephone contact at 
Weeks 28, 32, 40 and 44 and the daily PRO pain input data will be 
reviewed for completeness at the telephone contact. 

24-hour analgesic use will be collected by the study investigator at each 
telephone contact at Weeks 28, 32, 40 and 44.  


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 159 of 291

The BPI-SF questionnaire will be completed on the day of each telephone 
contact (should be completed prior to the contact and should be checked 
for completion at the contact; see Section 14.7

NCCN-FACT FPSI-17 questionnaire will be completed on the day of each 
telephone contact (should be completed prior to the contact and should be 
checked for completion at the telephone contact; (see Section 14.8).
Section 14.7 Brief Pain Inventory-Short Form:
Paragraph 3:
Old text:
Assessment of the worst pain score (WPS) via Question 3, of average pain score 
via Question 5, and pain interference with general activity score via Question 9A
on the BPI-SF will occur daily for 7 days prior to each scheduled visit from the 
Dose 1, Day 1 visit through the Week 48 visit.  The data will be collected and 
checked for completeness at each visit.
New text:
Assessment of the worst pain score (WPS) via Question 3 and average pain score 
via Question 5 on the BPI-SF will occur daily for 4 days immediately prior to 
randomization and for 7 days prior to each scheduled visit from the Dose 1, Day 1 
visit through the Week 48 visit.  The data will be collected and checked for 
completeness at each visit.  In Treatment Arms A and B only, pain will also be 
assessed daily for 7 days prior to each  telephone contact at Weeks 28, 32, 40 and 
44 and the daily PRO pain input data will be reviewed for completeness at the 
telephone contact. 
Paragraph 5
Added text:
The BPI-SF will be self-administered by the subject at Dose 1, Day 1 (before the 
start of study treatment) through the Week 48 visit.  In Treatment Arms A and B 
only the BPI-SF questionnaire will also be completed on the day of each 
telephone contact at Weeks 28, 32, 40 and 44 and checked for completion at the 
telephone contact.
Paragraph 9:
Old text:
“Your doctor would like to better understand how you feel, how well you are able 
to do your usual activities, and how you rate your health.  To help us better 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 160 of 291
understand these things about you, we will ask you to answer 3 questions related 
to the worst pain in the last 24 hours, the average level of pain, and how pain 
interferes with your activities for 7 days prior to each scheduled treatment visit 
and at the end of treatment visit.  We will ask you to complete this questionnaire 
about your health at each of these visits.
New text:
“Your doctor would like to better understand how you feel, how well you are able 
to do your usual activities, and how you rate your health.  To help us better 
understand these things about you, we will ask you to answer 2 questions related 
to the worst pain in the last 24 hours and the average level of pain, for 7 days prior 
to each scheduled treatment visit and at the end of treatment visit. We will ask you 
to complete this questionnaire about your health at each of these visits.  
Depending on which treatment you are assigned, you may also be requested to 
answer these 2 questions during the first 6 months of the follow-up period, for 7 
days prior to the visits or telephone contacts and to complete the BPI-SF 
questionnaire on the day of the visits or on the day of the telephone contacts.  
Paragraph 12:
Old text: 
At the beginning of each visit, please check that the subject has answered the 
questions related to the WPS, the average pain score, and pain interference with 
general activity score in the 7 days prior to the visit.  Thank the subject once you 
have reviewed the responses.
New text:
At the beginning of each visit or at each telephone contact (Treatment Arms A and 
B only), please check that the subject has answered the questions related to the 
WPS and the average pain score, in the 7 days prior to the visit.  Thank the subject 
once you have reviewed the responses.
Change 10:
Synopsis - Plan for statistical analysis (paragraph 3); and
Section 8.4.1 Primary efficacy analysis (paragraph 2):
Old text:
Both comparisons will be performed at the time of final analysis, after the latest of 
(1) approximately 135 SSE-FS events in subjects included in Comparison 1 as 
defined below; (2) approximately 75 SSE-FS events following Week 24 in 
subjects included in Comparison 2 as defined below, and (3) the last subject has 
been followed for 2 years from last treatment.  


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 161 of 291
New text:
Both comparisons will be performed at the time of final analysis, after the latest of 
(1) approximately 135 SSE-FS events in subjects included in Comparison 1 as 
defined below; (2) approximately 75 SSE-FS events following Week 24 in 
subjects included in Comparison 2 as defined below, and (3) the last subject has 
been followed for 30 days from last treatment.  In the event the applicable number 
of events is not reached, the primary endpoint analysis will mature 7 years after 
the last subject has received last treatment.
Section 4.4 End of study:
Paragraph 2:
Old text:
The primary endpoint cut-off will be reached at the later of 1) 135 SSE-FS events 
in subjects included in Comparison 1 as defined in Section 8.4 below, and 2) 
75 SSE-FS events following Week 24 in subjects included in Comparison 2 as 
defined in Section 8.4 below, and 3) the last subject has been followed for 2 years
from last treatment.  
New text:
The primary endpoint cut-off will be reached at the later of 1) 135 SSE-FS events 
in subjects included in Comparison 1 as defined in Section 8.4 below, and 2) 
75 SSE-FS events following Week 24 in subjects included in Comparison 2 as 
defined in Section 8.4 below, and 3) the last subject has been followed for 30 days
from last treatment.  In the event the applicable number of events is not reached, 
the primary endpoint analysis will mature 7 years after the last subject has 
received last treatment.
Section 8.6 Determination of Sample Size:
Paragraphs 2 to 4:
Old text:
The sample ..............randomized.  The primary endpoint cut-off, as defined in 
Section 8.4, is estimated to be reached in an average of 55 months. 
Comparison 1 will analyze SSE-FS........................................................................
regimen.  Simulations indicated an average of 197.9 events would occur for this 
comparison at primary endpoint cut-off, and a 1-sided log-rank test with 0.10 
significance gave approximately 92% power to test H01 versus HA1. 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 162 of 291
Comparison 2 will analyze SSE-FS ...............................................................
.......eligible for inclusion at 24 weeks.  An average of 80.6 simulated events 
occurred for this comparison, and a 1-sided log-rank test with 0.10 significance 
gave approximately 84% power to test H02 versus HA2.
New text:
The sample ..............randomized.  The primary endpoint cut-off, as defined in 
Section 8.4, is estimated to be reached in an average of 39 months. 
Comparison 1 will analyze SSE-FS........................................................................
.regimen.  Simulations indicated an average of 186.6 events would occur for this 
comparison at primary endpoint cut-off, and a 1-sided log-rank test with 
0.10 significance gave approximately 90.5% power to test H01 versus HA1. 
Comparison 2 will analyze SSE-FS ...............................................................
.......eligible for inclusion at 24 weeks.  An average of 74.9 simulated events 
occurred for this comparison, and a 1-sided log-rank test with 0.10 significance 
gave approximately 80.6% power to test H02 versus HA2.
Change 11:
Synopsis - Methodology (paragraph 2);
Section 4.1 Design overview (paragraph 2);
Section 6.1 Treatments to be administered (paragraph 2);
Section 6.3 Treatment assignment (paragraph 3);
Section 7.1.1 Tabulated overview, Table 7-1 (footnote “l”); and
Section 7.1.2.1 Screening period (paragraph 4, 2nd sentence):
Added text:
The randomization will be permuted-block, stratified by use of prior 
chemotherapy (≤ 1 regimen versus > 1 regimen), by total ALP (< 220 U/L versus 
≥220 U/L), and by average worst pain score (WPS) of the Brief Pain Inventory 
Short Form (BPI-SF) (WPS ≤4 versus WPS >4).
Section 7.1.2.1 Screening period
Paragraph 2, 19th bullet:
Added text:

When a subject is determined to be eligible, the subject will be trained on 
daily Patient-reported outcome (PRO) pain data collection using a handheld 
device.  Eligible subjects will then complete the pain assessment daily


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 163 of 291
o
for the 4 days immediately prior to randomization.  The average of the 
daily WPS over the 4-day period will be used for stratification (WPS 
≤4 versus WPS >4); 4 days of daily WPS data must be taken before 
randomization can occur. 
o
for the 7 days prior to Dose 1, Day 1.
Paragraph 4, 2nd sentence:
Old text:
The randomization will be permuted-block, stratified by the use of prior 
chemotherapy (≤ 1 regimen versus > 1 regimen) and by total ALP (< 200 U/L 
versus ≥ 220 U/L).
New text:
The randomization will be permuted-block, stratified by the use of prior 
chemotherapy (≤ 1 regimen versus > 1 regimen), by total ALP (< 220 U/L versus 
≥ 220 U/L), and by the average of the daily WPS of the screening BPI-SF (WPS 
≤4 versus WPS >4).
Section 8.1 General considerations
Paragraph 2, 3rd bullet:
New text:

Average WPS of the BPI-SF (WPS ≤4 versus WPS >4)
Change 12:
Synopsis - Methodology (paragraph 13) and Section 4.1 Design overview (paragraph 11):
Old text:
All safety data will be collected beyond the EOT visit, and subjects will come to 
the clinic for safety and SSE evaluations every 12 weeks for 2 years of active 
follow-up.  Every effort will be made to follow subjects through clinic visits; 
however, phone contact will be undertaken for subjects unable to come to the 
clinic.  The active follow-up period will continue for 2 years after the subject’s 
last dose of radium-223 dichloride or until the primary efficacy analysis matures, 
whichever occurs last.  


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 164 of 291
New text:
Following the EOT visit, subjects will enter the active follow-up period and will 
come to the clinic for selected safety and efficacy evaluations every 12 weeks for 
at least 2 years following last study treatment.  Subjects not experiencing an SSE 
by 2 years following last study treatment will continue active follow-up until the 
subject experiences an SSE or the primary endpoint matures, whichever occurs 
first.  During active follow-up, every effort will be made to follow subjects 
through clinic visits; however, phone contacts will be undertaken for subjects 
unable to come to the clinic.  
Synopsis - Methodology (paragraph 14) and Section 4.1 Design overview (paragraph 13):
Old text:
After the 2 years of active follow-up, subjects will enter the extended follow-up 
period and will be followed via telephone follow-up at 6-month intervals for 
investigator-reported, radium-223 dichloride-related SAEs, hematologic toxicity (e.g., 
myelosuppression / myelofibrosis / bone marrow aplasia), new primary malignancies, 
and survival up to 7 years after the last dose of radium-223 dichloride or until death.  
Once a separate extended safety follow-up protocol, for the inclusion of subjects who 
received radium-223 dichloride in the course of Bayer sponsored clinical trials, has 
been implemented, the study subjects surviving after the end of the 2 years of active 
follow-up will be transitioned to this separate extended safety follow-up protocol and 
the current study will be terminated at the time the last study subject is transitioned.
New text:
After the active follow-up, subjects will enter the long-term follow-up period and will 
be followed via telephone follow-up at 6-month intervals for investigator-reported, 
radium-223 dichloride-related SAEs, hematologic toxicity (e.g., myelosuppression / 
myelofibrosis / bone marrow aplasia), new primary malignancies, and survival up to 7 
years after the last dose of radium-223 dichloride or until death.  Once a separate 
extended safety follow-up protocol, for the inclusion of subjects who received 
radium-223 dichloride in the course of Bayer sponsored clinical trials, has been 
implemented, the study subjects surviving after the end of the active follow-up will be 
transitioned to this separate extended safety follow-up protocol and the current study 
will be terminated at the time the last study subject is transitioned.
Section 6.8 Post-study therapy:
Old text:
Subjects will have an EOT visit 30 (± 7) days following the last dose of study drug, 
including early discontinuation of study drug, and will be followed every 12 weeks 
for safety and SSE evaluations.  Every effort will be made to follow subjects through 
clinic visits; however, phone contact will be undertaken for subjects unable to come to 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 165 of 291
the clinic.  The active safety follow-up period will continue for 2 years after the 
subject’s last dose of radium-223 dichloride or until the primary efficacy analysis 
matures, whichever occurs last.  After the 2 years of active follow-up, subjects will 
enter the extended active follow-up period and will be followed via telephone follow-
up at 6-month intervals for investigator-reported, radium-223 dichloride-related 
SAEs, hematologic toxicity (e.g., myelosuppression / myelofibrosis / bone marrow 
aplasia), new primary malignancies, and survival up to 7 years after the last dose of 
radium-223 dichloride or until death.  Once a separate extended safety follow-up 
protocol, for the inclusion of subjects who received radium-223 dichloride in the 
course of Bayer sponsored clinical trials, has been implemented, the study subjects 
surviving after the end of the 2 years of active follow-up will be transitioned to this 
separate extended safety follow-up protocol and the current study will be terminated 
at the time the last study subject is transitioned.
New text:
Subjects will have an EOT visit 30 (± 7) days following the last dose of study drug, 
including early discontinuation of study drug, and will be followed every 12 weeks 
for safety and SSE evaluations.  Every effort will be made to follow subjects through 
clinic visits; however, phone contact will be undertaken for subjects unable to come to 
the clinic.  The active follow-up period will continue for 2 years after the subject’s 
last dose of radium-223 dichloride or until the primary efficacy analysis matures, 
whichever occurs last.  After the active follow-up, subjects will enter the long term 
follow-up period and will be followed via telephone follow-up at 6-month intervals 
for investigator-reported, radium-223 dichloride-related SAEs, hematologic toxicity 
(e.g., myelosuppression / myelofibrosis / bone marrow aplasia), new primary 
malignancies, and survival up to 7 years after the last dose of radium-223 dichloride 
or until death.  Once a separate extended safety follow-up protocol, for the inclusion 
of subjects who received radium-223 dichloride in the course of Bayer sponsored 
clinical trials, has been implemented, the study subjects surviving after the end of the 
active follow-up will be transitioned to this separate extended safety follow-up 
protocol and the current study will be terminated at the time the last study subject is 
transitioned.
Section 7.1.2.6 Active follow-up:
Paragraph 1, last sentence:
Added text:
However, in the event an SSE is identified at an unscheduled clinic visit in an 
active follow-up subject, an unscheduled-visit SSE should be recorded regardless 
of whether the subject is receiving clinic visits or telephone-only follow-up.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 166 of 291
Section 7.1.2.6.1 Active follow-up with clinic visits:
Paragraph 1:
Old text:
The subject should return to the clinic every 12 weeks (± 14 days) following the 
EOT visit for 2 years following the last study treatment or until the primary 
efficacy analysis matures, whichever comes last, preferably in the morning.  
Active follow-up may continue past 2 years if the subject has not had a SSE and 
the required number of events has not taken place.
New text:
The subject should return to the clinic every 12 weeks (± 14 days) following the 
EOT visit until the subject experiences a symptomatic skeletal event or until the 
primary efficacy analysis matures, whichever occurs first; provided that active 
follow-up will not last less than 2 years or more than 7 years following the 
subject's last study treatment.
Section 7.1.2.6.2 Active follow-up without scheduled clinic visits:
Paragraph 1, 2nd sentence:
Old text:
Subjects will be contacted by telephone every 12 weeks (± 14 days) for 2 years 
following the last study treatment or until death, whichever comes last, to 
determine the following:
New text:
Subjects who cannot travel to the clinic will be contacted by telephone every 
12 weeks (± 14 days) for 2 years following the last study treatment to determine 
the following:
Section 7.1.2.7.1 End of active follow-up with clinic visits:
Paragraph 1:
Deleted text:
The active follow-up period will continue for 2 years after the subject’s last dose 
of radium 223 dichloride or until the primary efficacy analysis matures, whichever 
occurs last.  The subject should return to the clinic for the end of follow-up with 
clinic visits, preferably in the morning, and the following assessments will be 
performed:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 167 of 291
Section 7.1.2.7.2 End of active follow-up without scheduled clinic visits:
Paragraph 1:
Old text:
The active follow-up period will continue for 2 years after the subject’s last dose 
of radium-223 dichloride or until death, whichever occurs last.  The end of active 
follow-up procedures for subjects who are in the active follow-up period without 
clinic visits will include the following:
New text:
The active follow-up period without clinic visits will continue for 2 years after the 
subject’s last dose of radium-223 dichloride.  The end of active follow-up 
procedures for subjects who are in the active follow-up period without clinic visits 
will include the following:
Change 13:
Synopsis - Methodology:
Paragraph 12, 1st sentence:
Old text:
An independent Data Monitoring Committee will conduct safety reviews at 
regular intervals.
New text:
A Joint Safety Review Committee will conduct safety reviews at regular intervals.
Section 3 Investigators and other study personnel:
Last paragraph:
Old text:
Independent Data Monitoring Committee
An independent DMC will conduct safety reviews at regular intervals.  There is no 
formal interim analysis planned.  The main objective of these safety reviews is to 
ensure subject safety and to identify whether any protocol modifications are 
needed.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 168 of 291
New text:
Joint Safety Review Committee
A Joint Safety Review Committee (JSRC), which may contain sponsor, 
investigator, and/or independent members, will conduct safety reviews at regular 
intervals.  There is no formal interim analysis planned.  The objective of these 
safety reviews is to ensure subject safety and to identify whether any protocol 
modifications are needed.  The JSRC will not evaluate efficacy.  Details on the 
JSRC and its safety review monitoring will be described in a separate JSRC 
charter.
Section 4.3 Interim Analyses and Joint Safety Review Committee (new section):
New text:
4.3
Interim Analyses and Joint Safety Review Committee
No formal interim analysis is planned.  A JSRC, which may contain sponsor, 
investigator, and/or independent members, will conduct safety reviews at regular 
intervals.  The objective of these safety reviews is to ensure subject safety and to 
identify whether any protocol modifications are needed.  The JSRC will not evaluate 
efficacy.  Details on the JSRC and its safety review monitoring will be described in a 
separate JSRC charter.
Section 8.4.4 Safety Analysis:
Paragraph 1:
Old text:
No formal interim analysis for safety is planned.  An independent DMC will 
review the safety data periodically.  Details on the DMC are described in 
Section 3.
New text:
No formal interim analysis for safety is planned.  A JSRC will review the safety 
data periodically.  Details on the JSRC are described in Section 3.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 169 of 291
Change 14:
Section 6.4.4 Dose preparation:
Paragraph 2, new text:
A radio pharmacy will prepare a patient ready dose for dispensing to the patient.  In 
the US, Cardinal Health is the radio pharmacy that will dispense the patient ready 
dose.
Change 15:
Section 7.1.1 Tabular overview, Table 7-1 Schedule of procedures:
See Change 26.
Section 7.1.2.1 Screening period:
Paragraph 3:
Old text:
The IVRS / IWRS will be used to register subject eligibility and request / confirm
study drug doses.  Once the subject eligibility is approved and registered in the 
IVRS / IWRS, the initial shipment will be triggered.  The order date for the next 
dose cannot be earlier than the pre-defined country lead time.
New text:
The IVRS / IWRS will be used to register requests for eligibility / study drug 
doses.  Once the subject eligibility is approved and registered in the IVRS / IWRS, 
including entry of required demographic and stratification information, the initial 
drug shipment may be prepared.  Additional IxRS transactions for dose orders 
may be required; follow the country-specific guidance in the manual.  The latest
order date for the next dose is no later than the pre-defined lead time (number of 
days from order received to delivery to site in the country) prior to the planned 
dosing date.  The planned date for the next dose must be specified, when the dose 
is requested in the IVRS / IWRS.  At Doses 1 through 5, the site should order the 
next dose in the IVRS / IWRS, as soon as the current visit’s dose is registered in 
the IVRS / IWRS.  The latest order date for the next dose is no later than the pre-
defined lead time (number of days from order received to delivery to site in the 
country) prior to the planned dosing date.  The planned date for the next dose must 
be specified, when the dose is requested in the IVRS / IWRS.  For subject visit 
registrations in the IVRS / IWRS, see the IVRS / IWRS manual.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 170 of 291
Change 16:
Section 7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C):
Moved text and revised:
Old text (paragraph 1, 4th bullet, sub-bullet):

Hematology results should be reviewed and it should be confirmed that the 
values are still within the treatment ranges (ANC ≥ 1.5 x 109/L, platelet count 
≥ 100 x 109/L, and hemoglobin ≥ 9.0 g/dL).
New text (paragraph 1, 1st bullet):
Reconfirmation of eligibility: hematology results obtained within 72 hours of 
Dose 1, Day 1 should be reviewed and it should be confirmed that the values 
are still within the treatment ranges (absolute neutrophil count ≥ 1.5 x 109/L, 
platelet count ≥100 x 109/L, and hemoglobin ≥ 9.0 g/dL). 
Change 17:
Section 5.2.1 Withdrawal:
Paragraph 1, 6th bullet:
Old text:

If the subject experiences Grade 3 or 4 neutropenia or thrombocytopenia 
lasting > 2 weeks despite adequate treatment.  Blood transfusions and biologic 
response modifiers, such as GM-CSF or G-CSF can be used for the treatment 
of hematological abnormalities during the treatment period
New text:

If the subject experiences Grade 3 neutropenia or Grades 3 or 4
thrombocytopenia lasting > 2 weeks or Grade 4 neutropenia lasting >7 days
despite adequate treatment.  Blood transfusions and biologic response 
modifiers, such as GM-CSF or G-CSF can be used for the treatment of 
hematological abnormalities during the treatment period


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 171 of 291
Section 6.4.7 Dose delays:
Myelosuppression, 2nd bullet (new 3rd bullet):
Old text:

If a subject experiences sustained CTCAE Grade 3 or 4 neutropenia or 
thrombocytopenia (see Table 6-1) lasting > 2 weeks despite adequate 
treatment, the subject must be discontinued from treatment with radium-223 
dichloride.
New text:

If a subject experiences sustained CTCAE Grade 3 neutropenia or sustained 
CTCAE Grades 3 or 4 thrombocytopenia (see Table 6-1) lasting > 2 weeks 
despite adequate treatment, the subject must be discontinued from treatment 
with radium-223 dichloride.

If a subject experiences sustained CTCAE Grade 4 neutropenia (see 
Table 6-1) lasting > 1 week despite adequate treatment, the subject must be 
discontinued from treatment with radium-223 dichloride.
Change 18:
Section 7.3.4.4 Pain endpoints:
Old text:
The worst pain score (WPS) is defined for each subject at baseline and at each 
applicable 4-week assessment date, as the mean of the “worst pain score” values in 
the last 24 hours from the preceding 7 days before each scheduled visit per the 
BPI-SF recorded in the subject’s reported outcome pain data.
Secondary pain endpoints are defined with respect to the screening-period baseline 
with randomization date as start date, and are based on data collected as of the Week 
24 assessment.
Additional details on pain endpoints, including analgesic use details, will be provided 
in the SAP.
New text:
The WPS is defined for each subject at baseline and at each applicable 4-week 
assessment date, as the mean of the “worst pain score” values in the last 24 hours 
from the preceding 7 days before each applicable visit or telephone contact per the 
BPI-SF recorded in the subject’s reported outcome pain data.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 172 of 291
Pain endpoints are defined with respect to each applicable baseline and start date.
The screening baseline for pain endpoints will be based on the pre-Dose 1, 7-day pain
assessment.
For purposes of determining pain improvement and pain progression, a daily 
analgesic use score will be calculated programmatically for each subject for each day, 
based on the subject’s complete CRF data on analgesic use.  Analgesic use data will 
be coded using the WHO drug dictionary.  Oral morphine equivalents will be 
calculated.  Each day’s analgesic use in OME units will be calculated using the 
applicable CRF-reported dates and date ranges.  The AQA will be applied to obtain a 
daily analgesic use score.  Details will be described in the SAP.
Additional details on pain endpoints, including details on the applicable baselines, 
evaluability for daily analgesic use increase, calculation of daily analgesic use 
score(s) applicable to each baseline and post-baseline time point, and definition of 
baseline values and “increase” in daily analgesic use for purposes of these endpoints, 
will be provided in the SAP.
Section 7.3.4.4.1 Pain improvement rate:
Added text:
Pain improvement is defined for each baseline in subjects evaluable for pain 
improvement at that baseline, i.e., subjects entering the study with a WPS of at least 4 
and evaluable for analgesic use increase at the respective baseline assessment.  Pain 
improvement with respect to each baseline is defined in each applicable evaluable 
subject at each applicable post-baseline assessment time point as a 30% and 2-point 
decrease in WPS over 2 consecutive measurements conducted at least 4 weeks apart, 
without an increase in analgesic use.
Pain improvement rate is defined for each baseline and applicable post-baseline 
assessment time point as the number of subjects with pain improvement at the time 
point, divided by the total number of subjects evaluable for pain improvement with 
respect to the applicable baseline.
Section 7.3.4.4.2 Time to pain progression:
Old text:
Pain progression is defined in subjects evaluable for pain progression, i.e., subjects 
entering the study with a WPS of at most 7.  A pain progression event consists of an 
increase of ≥ 30% and 2 points in WPS over 2 consecutive measurements conducted 
at least 4 weeks apart, without a decrease in analgesic use, based on the included 
assessments. 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 173 of 291
The time to pain progression is defined as the time (in days) from randomization date
until occurrence of the first pain progression event.  Subjects without pain progression 
as of the last included pain assessment, whether or not surviving, will be censored at 
the last included pain assessment.
New text:
Pain progression is defined for each baseline in subjects evaluable for pain 
progression at the applicable baseline, i.e., subjects with a WPS of ≤ 7 at the 
respective baseline assessment.  Pain assessments will occur daily for one week, 
beginning a week prior to each visit and including the day of the visit.  An evaluable 
pain assessment interval requires completion of a minimum of 4 out of 7 daily 
questions.  Pain progression is defined as the occurrence of either a pain increase or 
an increase in pain management with respect to the applicable baseline, whichever 
occurs first.
A pain increase is defined as follows:

For asymptomatic patients (WPS 0 to < 1 at baseline), pain increase 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 

For mildly symptomatic patients (WPS 1-3 at baseline), pain increase 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 worst pain score of ≥ 
4”

For symptomatic patients with WPS > 3 and ≤ 7 at baseline), pain increase 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.
An increase in pain management is defined as follows:
For patients not on opioids at the applicable baseline, initiation of short or long-acting 
opioid use for pain will constitute an increase in pain management.  For patients being 
treated with ≤600 OME (oral morphine equivalents) of opioids at the applicable 
baseline, an increase by 1 point in the daily AQA score and increase ≥50% in daily 
OMEs will constitute an increase in pain management.  For patients being treated at 
the highest AQA level (> 600 OME/day) at the applicable baseline, an increase ≥50% 
in daily OMEs from that baseline will constitute an increase in pain management.
The time to pain progression is defined for each applicable baseline for applicable 
subjects as the time (in days) from the respective baseline until occurrence of the first 
post-baseline pain progression event.  Subjects without pain progression as of the last 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 174 of 291
applicable post-baseline assessment, whether or not surviving, will be censored at the 
last applicable post-baseline assessment.  Subjects with insufficient applicable 
baseline assessment(s) or without adequate post-baseline assessment(s) will be 
censored at the applicable baseline date. Additional censoring and other details will 
be described in the SAP.
Change 19:
Section 8.4.4 Safety analysis:
Paragraph 5
Old text:
1. Treatment-emergent safety events
This analysis will be performed for safety events observed through the end of 
treatment visit.  For this analysis, subjects will be grouped by treatment arm as 
treated.
3. Safety events emerging following the standard-regimen treatment period
This analysis will be performed in each treatment arm for events following the 
later of 24 weeks from treatment start or 30 days following completion of 
6 doses of radium-223 dichloride treatment.  It will be performed for selected 
safety endpoints collected during active safety follow-up after end of 
treatment.  This analysis will be performed by treatment group as treated.  
New text:
1. Treatment-emergent safety events 
The treatment period for this study extends from the initiation of treatment 
until 30 days after the last administration of radium-223 dichloride.  Events 
starting or worsening within the treatment period will be considered treatment-
emergent.
For the analysis of treatment-emergent safety events, subjects will be grouped 
by treatment arm as treated.
3. Safety events emerging following the standard-regimen treatment period
This analysis will be performed in each treatment arm for events following the 
later of 24 weeks from treatment start or 30 days following completion of 
6 doses of radium-223 dichloride treatment.  It will be performed for selected 
safety endpoints collected during active follow-up after end of treatment 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 175 of 291
through primary endpoint completion.  This analysis will be performed by 
treatment group as treated.
4. Safety events emerging during long-term follow-up following primary 
endpoint completion
Safety events emerging following primary endpoint completion and any 
events emerging during long-term follow-up, will be reported in a separate 
document(s) from the study Clinical Study Report.
Change 20:
Added that IVRS / IWRS procedures can be found in the IVRS / IWRS manual.
Section 7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C):
Last paragraph, 2nd sentence:
Added text:
The order date for the next dose cannot be earlier than the pre-defined country 
lead time, see IVRS / IWRS manual.
Change 21:
Changed the terminology for “active safety follow-up” period to “active follow-up” period 
since efficacy assessments are also included in these visits.  In addition, the terminology for 
“extended active follow-up” period was changed to “long-term follow-up” period; this 
change was done to ensure the use of a consistent term across the radium-223 program.

Synopsis - Methodology

Section 4.1 Design overview

Section 6.8 Post-study therapy

Section 7.1.1 Tabulated overview, Table 7-1 Schedule of procedures

Section 7.1.2.6 Active follow-up

Section 7.1.2.7.1 End of active follow-up with clinic visits

Section 7.1.2.7.2 End of active follow-up without scheduled clinic visits

Section 7.1.2.8 Long-term follow-up to 7 years following last dose

Section 7.1.2.8.1 Long-term follow-up (via telephone follow-up)


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 176 of 291

Section 7.1.2.8.2 End of long-term follow-up

Section 8.4.4 Safety analysis
Change 22:
Section 7.3.2 Definition of efficacy variables:
3rd sentence:
New text:
Details on definitions of starting points and baselines will be provided in the SAP 
or in the imaging charter or other central reviewer documentation.
Section 7.3.4.3 Radiological progression endpoints:
1st paragraph, 2nd sentence:
Old text:
Assessment of radiological progression will be made at the site level.
New text:
Assessment of radiological progression will be made by independent central 
review.
3rd paragraph:
New text:
The central reviewer will determine the applicable baseline values for and assess 
radiological progression  with respect to each applicable baseline. 
4th paragraph:
Added text:
Further details will be defined in the imaging charter and / or related central 
review documentation, and / or the SAP.
Section 7.3.5.1 Quantitated bone scan endpoints:
Added text:
Further details will be defined in the imaging charter and / or related central 
review documentation, and / or the SAP.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 177 of 291
Change 23:
Section 7.1.1 Tabulated overview, Table 7-1 Schedule of procedures:
See Change 26.
Section 7.1.2.1 Screening period (paragraph 2, 8th bullet, 2nd sub-bullet);
Section 7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C) (paragraph 1, 
                         6th bullet, 2nd sub-bullet):
Section 7.1.2.3 Doses 2 to 6 (Treatment Arms A and B) (paragraph 1, 4th bullet, 
                         2nd sub-bullet);
Section 7.1.2.4 Doses 2 to 12 (Treatment Arm C (paragraph 1, 4th bullet, 2nd sub-bullet); 
Section 7.1.2.5 End of treatment visit (paragraph 1, 4th bullet, 2nd sub-bullet);
Section 7.1.2.6.1 Active follow-up with clinic visits (paragraph 3, 4th bullet, 2nd sub-bullet);
Section 7.1.2.7.1 End of active follow-up with clinic visits (paragraph 1, 2nd bullet, 
                           2nd sub-bullet)
Section 7.5 Safety (paragraph 1, 2nd bullet, 2nd sub-bullet); and 
Section 7.5.3.1 Laboratory evaluations (paragraph 1, 2nd bullet): 
Added text: 
o
Chemistry panel, including serum creatinine, sodium, potassium, chloride, 
calcium, phosphorous, magnesium, total bilirubin………..
Change 24:
Synopsis - Diagnosis and main criteria for inclusion (paragraph 2) and 
Section 5.1.1 inclusion criteria (paragraph 1):
4th bullet:
Old text:

Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2.  
In case of ECOG PS 2, the PS has to be due to metastatic prostate cancer to 
the bone.
New text:

Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 2.  
In case of ECOG PS 2, the PS must be due to metastatic prostate cancer to the 
bone.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 178 of 291
7th bullet, “d”:
Added text:
d. Total bilirubin level ≤ 1.5 x institutional upper limit of normal (ULN) (< 3 x 
ULN for subjects with documented Gilbert’s syndrome)
Synopsis - Plan for statistical analysis:
Last paragraph:
Old text:
The following secondary efficacy time-to-event endpoints will have hypothesis 
testing performed to compare the treatment groups: OS, time to first SSE, time to 
radiological progression, and rPFS.  Other endpoints, including safety and 
tolerability variables, will be analyzed descriptively for each treatment group.
New text:
Comparison 2 will be performed using a log-rank test with a 1-sided alpha of 0.1 
stratified by the randomization factors (previous chemotherapy [≤1 regimen 
versus > 1 regimen] and total ALP [< 220 U/L versus ≥220 U/L]).  The extended 
dosing regimen will be declared superior to the standard dosing regimen if the 
1-sided p-value from the stratified log rank test is less than 0.1.
The following secondary efficacy time-to-event endpoints will have hypothesis 
testing performed with comparisons analogous to those for the primary endpoint: 
OS, time to first SSE, time to radiological progression, and rPFS.  Other 
endpoints, including safety and tolerability variables, will be analyzed 
descriptively for each treatment group.
Section 6.4.7 Dose delays:
Under Myelosuppression, paragraph 1, 4th bullet:
Added text:

Blood transfusions are acceptable during the treatment period, but 
erythropoietin is not allowed.  Use of biologic response modifiers, such as 
GM-CSF or G-CSF, is allowed in the management of acute toxicity during the 
treatment period.  Such drugs (and transfusions) cannot be used for 4 weeks 
prior to screening and during the screening period, or prior to the start of 
treatment.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 179 of 291
Section 7.1.1 Tabulated overview, Table 7-1 Schedule of procedures (footnote “o”);
Section 7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C) (paragraph 1, 
                         13th bullet);
Section 7.1.2.3 Doses 2 to 6 (Treatment Arms A and B) (paragraph 1, 10th bullet);
Section 7.1.2.4 Doses 2 to 12 (Treatment Arm C) (paragraph 1, 10th bullet);
Section 7.1.2.5 End of treatment visit (paragraph 1, 10th bullet); and
Section 7.1.2.6.1 Active follow-up with clinic visits (paragraph 3, 9th bullet);
Revised text from “treating physician” to “study investigator”.
Section 7.1.1 Tabulated overview, Table 7-1 Schedule of procedures:
Footnotes “i”, “j”, and “k”: added text:
“using a handheld device”, see Change 26.
Section 7.1.2.2 Initial visit-Dose 1, Day 1 (Treatment Arms A, B, and C) (paragraph 1, 
                         2nd bullet);
Section 7.1.2.3 Doses 2 to 6 (Treatment Arms A and B) (paragraph 1, 1st bullet);
Section 7.1.2.4 Doses 2 to 12 (Treatment Arm C) (paragraph 1, 1st  bullet); and 
Section 7.1.2.5 End of treatment visit (paragraph 1, 1st bullet):
Added text:

BPI-SF questionnaire using a handheld device (should be self-administered at the 
beginning of each visit through Week 48 and should be checked for completion at 
the visit; see Section 14.7).
Section 7.1.2.6.1 Active follow-up with clinic visits:
Paragraph 3, 1st sentence:
Added text:
The following assessments will be performed during the clinic visits:
Paragraph 9:
Added text:
If a subject is no longer able to travel to the clinic due to deteriorating status, the 
subject will enter the active follow-up without visits and will be followed by 
telephone.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 180 of 291
Paragraph 10:
Old text:
If a subject has a SSE in the active safety follow-up period, he will continue the 2-
year active safety follow-up period.
New text:
If a subject has an SSE in the active follow-up period, he will continue the active 
follow-up period for 2 years from last study treatment.  If a subject becomes 
unable to travel to the clinic after 2 years after his last treatment, he will enter 
long-term follow-up. 
Section 7.3.2 Definition of efficacy variables
Paragraph 1, 2nd sentence:
Added text:
Response and progression endpoints are defined with respect to 2 corresponding 
baselines, the screening (or pre-treatment) baseline and 24 weeks.  
Section 7.2.5.5 Additional pain and health-related quality of life endpoints:
Revised title of section:
Added text:
7.3.5.5
Additional pain and health related quality of life endpoints
Section 8.4.2.1 Analyses of pooled standard dose and high dose from randomization
Paragraph 1, 2nd sentence: 
Added text:
For these analyses, the start date will be randomization, and the screening (or 
pre-treatment) baseline will be used.
Section 8.4.4 Safety analysis:
Paragraph 5, 3rd subsection:
Added text:
3. Safety events emerging following the standard-regimen treatment period


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 181 of 291
This analysis will be performed in each treatment arm for events following the 
later of 24 weeks from treatment start or 30 days following completion of 6 doses 
of radium 223 dichloride treatment.  It will be performed for selected safety 
endpoints collected during active follow-up after end of treatment through primary 
endpoint completion.  This analysis will be performed by treatment group as 
treated.
Change 25:
List of abbreviations:
New text:
AQA
Analgesic Quantification Algorithm
CR
Complete response
ePRO
Electronic patient-reported outcome
FPSI-DRS-P
FACT-P Symptom Index-17 physical disease related
                                         symptoms
HA
The Alternative Hypothesis
H0
The Null Hypothesis
JSRC
Joint Safety Review Committee
MBq
Megabecquerel, SI unit of radioactivity
mCi
milli-curie
NCCN
National Comprehensive Cancer Network
NCCN-FACT FPSI-17
NCCN-FACT-P Symptom Index-17
OMEs
Oral morphine equivalents
PRO
Patient-reported outcome
U/L
Units/liter
Change 26:
Section 7.1.1 Tabular overview, Table 7-1 Schedule of procedures:


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 182 of 291
Old table/text:
Table 7.1.1-1 Schedule of procedures
Study Period
Screen
Treatment Arms
A and B
Treatment Arm C
EOT 
Visit
Active Safety
Follow-up
Extended active
follow-up
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone follow-
upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months
End of 
extended 
active
follow-up
Window (days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Informed 
consent
X
Inclusion / 
exclusion 
criteriaf
X
Xg
Xg
Demographic 
data
X
Medical and 
disease history
X
Height
X
Weighth
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomizationi
X
Pain assessmentj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Training on 
daily PRO pain 
collectionll
X
Review daily 
PRO pain input
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
BPI-SFm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Analgesic use 
evaluationn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Vital signso
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 183 of 291
Table 7.1.1-1 Schedule of procedures
Study Period
Screen
Treatment Arms
A and B
Treatment Arm C
EOT 
Visit
Active Safety
Follow-up
Extended active
follow-up
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone follow-
upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months
End of 
extended 
active
follow-up
Window (days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Physical 
examinationp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry panel 
and CBCq
X
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
PSA
X
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
X
X
X
Testosterone
X
Whole body 
technetium-99 
bone scanst
X
X
X
X
X
Xu
X
X
Documentation 
of bone 
metastasesv
X
MRI / CT scan 
abdomen and 
pelvis, chest 
X-rayt
X
X
X
X
X
Xu
X
X
IVRS / IWRSw
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Radium-223 
dichloride 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oral hydrationx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject contact 
cardy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject and 
family 
instructionsz
X
X
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 184 of 291
Table 7.1.1-1 Schedule of procedures
Study Period
Screen
Treatment Arms
A and B
Treatment Arm C
EOT 
Visit
Active Safety
Follow-up
Extended active
follow-up
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone follow-
upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months
End of 
extended 
active
follow-up
Window (days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Record SSEs
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xbb
Xbb
Record 
concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record limited 
concomitant 
medicationcc
X
X
Record therapy 
for prostate 
cancer other 
than radium-223 
dichloride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xdd
X
X
X
Record new 
primary 
malignancies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record AEs and 
SAEsee
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record 
radium-223 
dichloride 
related AEs and 
SAEsff
X
X
X
X
Record 
radium-223 
dichloride 
related SAEsgg
X
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 185 of 291
Table 7.1.1-1 Schedule of procedures
Study Period
Screen
Treatment Arms
A and B
Treatment Arm C
EOT 
Visit
Active Safety
Follow-up
Extended active
follow-up
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone follow-
upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months
End of 
extended 
active
follow-up
Window (days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Record 
SSE-related AEs 
and SAEsff
X
X
Survival status
X
X
X
X
Abbreviations: AE = adverse event; BPI-SF = Brief Pain Inventory Short Form; CBC = complete blood count; CT = computed tomography; 
ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; ICF = informed consent form; IVRS / IWRS = interactive 
voice / web response system; MRI = magnetic resonance imaging; PCWG2 = Prostate Cancer Clinical Trials Working Group 2; 
PS = performance status; PSA = prostate specific antigen; q6 = every 6; q12 = every 12; RECIST = Response Evaluation Criteria in Solid 
Tumors; SAE = serious adverse event; SSE = symptomatic skeletal event; wk = week
a.Once a subject switches from active safety follow-up with clinical visits to active safety follow-up without clinical visits, the subject will not be 
allowed to switch back.  A subject with a possible SSE may, and is encouraged to, return to the clinic at any time to assess for the 
presence of an SSE.
b. Once a separate, extended safety follow-up protocol, for the inclusion of subjects who received radium-223 dichloride in the course of Bayer 
sponsored clinical studies, has been implemented, the study subjects surviving after the end of the 2 years of active follow-up will be 
transitioned to this separate, extended safety follow-up protocol and the current study will be terminated at the time the last study subject 
is transitioned.
c. The maximum period for rescreening screen failed subjects is 35 days (14 days screening + 7-day window + 14 days for rescreening) from 
signing the ICF to randomization.  Rescreening of a subject requires prior approval of the Bayer-designated medical representative (see 
Section 5.1).  Eligibility should be confirmed within 14 ± 7 days of randomization.
d. The subject should return to the clinic in advance of the scheduled dose visit such that results of the laboratory assessment are available 
within 72 hours prior to dosing (each dose period is 28 ± 7 days after the prior dose of radium-223 dichloride).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 186 of 291
e. Subjects who can no longer travel to the clinical site or who receive further anticancer therapy will only be followed up by telephone (active 
follow-up without clinic visits).  Symptomatic skeletal events will not be collected over the phone.
f. The study record or subject’s clinical record must clearly show that informed consent was obtained prior to any other study procedures being 
performed.  Eligibility should be confirmed during the screening period and reconfirmed prior to dosing at Dose 1, Day 1.
g. Reconfirmation of eligibility and registration in the IVRS / IWRS: hematology results obtained within 72 hours of Dose 1, Day 1 should be 
reviewed and it should be confirmed that the values are still within the treatment ranges (absolute neutrophil count ≥ 1.5 x 109/L, platelet 
count ≥100 x 109/L, and hemoglobin ≥ 9.0 g/dL).  
h. Body weight should be obtained without shoes, using a calibrated electronic physician (column) scale with digital display, measurement 
units 0.1 kg.  The same scale should be used for a given subject throughout the study.  At all sites (in US and outside US), weight is to be 
taken only once for each dose.  For non-US sites and US sites not using the central PRD depot, the weight should be performed within 72 
hours prior to dosing.  For US sites using the central PRD depot ONLY, subject weight for the dose day should be obtained at the site 
within 3 to 5 days prior to the dose visit.  This weight must be reported to the country PRD depot to allow adequate time for PRD 
preparation and delivery (approximately 2 days).  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.  Please note this is applicable to all dosing visits.
i. Randomization will be permuted-block, stratified by the use of prior chemotherapy (≤ 1 regimen versus > 1 regimen) and by total alkaline 
phosphatase (< 220 U/L versus ≥220 U/L).  This assessment will occur when the second call is made to the IVRS / IWRS to order drug: ≥
10 to 14 days prior to study treatment administration.
j. Pain will be assessed daily during the screening period for the 7 days prior to Dose 1, Day 1 and then daily for 7 days prior to each 
scheduled treatment visit through the end of Week 48.  Subjects will complete the daily pain assessment.  The daily PRO pain input 
results should be reviewed at the visit to check for completeness.
k. For Treatment Arms A and B only at Weeks 36 and 48 only.
l. When a subject is determined to be eligible, the subject will be trained on daily PRO pain data collection.  The subject will then complete the 
pain assessment daily for the 7 days prior to Dose 1, Day 1.
m. The BPI-SF questionnaire will be completed at each clinic visit from Dose 1, Day 1 until the Week 48 visit.  For further details, see
Section 14.7.
n. Analgesic use will be collected and it will be assessed by the treating physician.
o. Systolic / diastolic blood pressure, respiratory rate, body temperature, and heart rate will be measured after the subject has rested for at 
least 5 minutes.
p. After a complete physical examination at screening, subsequent physical examinations may be 'brief,' but should include any systems with 
symptoms.  All physical examinations will be performed by a physician according to the standard of care.
q. Complete blood count, including hematocrit, hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, 
mean corpuscular hemoglobin concentration, white blood cell count, platelet count, and differential blood count reported as absolute count 
or percentage for neutrophils, lymphocytes, monocytes, eosinophils, and basophils will be collected.  Chemistry panel including serum 
creatinine, sodium, potassium, chloride, calcium, phosphorous, magnesium, bilirubin, total alkaline phosphatase, aspartate transaminase, 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 187 of 291
alanine transaminase, lactate dehydrogenase (screening only), and albumin (screening only).
r. Laboratory assessments should be performed within 72 hours of the visit and the results assessed and documented prior to dosing.
s. The PSA result for each dosing visit may be assessed post-dose.
t. Radiological / progression (according to PCWG2 criteria) will be assessed by means of whole body technetium-99 bone scan, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to confirm and characterize the lesion[s]), and MRI / CT scan 
of the abdomen and pelvis.  Baseline tumor assessment should be performed within 14 (± 7) days of randomization.  If standard of care 
bone scan and / or MRI / CT scan of the abdomen and pelvis and chest X-ray within 8 weeks of randomization are available, they do not 
need to be repeated at baseline.  If they are not available, they should be performed within 14 days ± 7 days of randomization (i.e., during 
the screening period).  Subsequent tumor assessment should be performed every 12 weeks during treatment, within 7 days prior to the 
EOT visit, and every 12 weeks during the active follow-up period with clinic visits for 2 years after the subject’s last dose of radium-223 
dichloride or until radiological progression (according to PCWG2 criteria or RECIST guidelines), or death, whichever comes first.  All 
images should be obtained with the same technique (e.g., CT or MRI) as those obtained at screening.  Schedule deviations of ± 2 weeks 
for imaging / tumor evaluations are allowed.
u. Imaging is not required at the EOT visit if the subject discontinued due to radiological progression or the last tumor evaluation is not older 
than 4 weeks.
v. Bone imaging should be within 8 weeks of randomization.  If no prior documentation is available, a whole body technetium-99 bone scan will 
be obtained at screening (within 14 ± 7 days of randomization).
w. The IVRS / IWRS will be used to register subject eligibility and request / confirm study drug doses.  Once the subject eligibility is approved 
and registered in the IVRS / IWRS, the initial shipment will be triggered.  Subsequent doses should be ordered as soon as the current 
visit's dose is registered in the IVRS / IWRS.  The planned date for the next dose must be specified, when the dose is requested in the 
IVRS / IWRS.  The order date for the next dose cannot be earlier than the pre-defined country lead time.
x. The subject should be encouraged to arrive at the clinic well-hydrated on each dosing day and to drink ad libitum after each dose of 
radium-223 dichloride.  The subject should avoid drinking or eating within 1 hour before and after administration of the study drug.
y. The subject contact card is to be provided at each dosing visit for the subject to carry with him until the next visit.
z. Subject and family instructions should be reviewed with the subject during screening through Dose 1, Day 1.
aa. Subjects identified with possible SSEs will be asked to come to the clinic for an SSE evaluation.  An SSE risk questionnaire will be 
developed.  Symptomatic skeletal events will not be identified over the telephone.
bb. If a subject has an SSE in the active safety follow-up period, he will continue the 2-year active safety follow-up period.  At Weeks 28, 32, 
40, and 44, subjects in Treatment Arms A and B will receive telephone contacts assessing for possible SSE risks.  Subjects exhibiting 
symptoms indicative of possible SSEs will be encouraged to visit the clinic early to assess SSE status.  Symptomatic skeletal events will 
not be determined over the phone.
cc. Limited concomitant medication, including narcotic pain medication, will be recorded during the active follow-up with clinic visits period.  
Contrast agents will only be captured as concomitant medication if there is an AE or SAE related to administration of contrast media.
dd. Subjects who receive further anticancer therapy during the active follow-up period will have an end of active follow-up with clinic visits and 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 188 of 291
will enter the active follow-up without clinic visits (telephone follow-up).
ee. All AEs and SAEs will be assessed and recorded from the time the ICF is signed until 30 days after the last dose of study medication.  All 
AEs should be assessed and documented prior to each dose of radium-223 dichloride.
ff. Any AEs and SAEs occurring beyond 30 days after the last treatment must be documented and reported if considered to be related to study 
medication or if related to an SSE.  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.
gg. Any SAEs 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.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 189 of 291
New table/text:
Table 7-1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term
follow-up (up 
to 7 years 
after last 
dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up 
to 7 years 
post-last dose
End of
Long-term
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Informed 
consent
X
Inclusion / 
exclusion 
criteriaf
X
Xg
Xg
Demographic 
data
X
Medical and 
disease history
X
Height
X
Weighth
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Training on 
daily PRO pain 
collectioni
X
Pain 
assessmentj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Xk
Randomizationl
X
Review daily 
PRO pain input
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Xk
BPI-SFm
Xn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Xk


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 190 of 291
Table 7-1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term
follow-up (up 
to 7 years 
after last 
dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up 
to 7 years 
post-last dose
End of
Long-term
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
NCCN FACT-
P Symptom 
Index-17 
Questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
24-hour
Analgesic use 
collectiono
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xk
Vital signsp
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examinationq
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry 
panel and 
CBCr
X
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
Xs
PSA
X
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
X
X
X
Testosterone
X
Whole body 
technetium-99 
bone scansu
X
X
X
X
X
X
X
Xu
X
X
Documentation 
of bone 
metastasesw
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 191 of 291
Table 7-1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term
follow-up (up 
to 7 years 
after last 
dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up 
to 7 years 
post-last dose
End of
Long-term
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
MRI / CT scan 
abdomen and 
pelvis, chest 
X-rayu
X
X
X
X
X
X
X
Xv
X
X
IVRS / IWRSx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Radium-223 
dichloride 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Oral hydrationy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject contact 
cardz
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject and 
family 
instructionsaa
X
X
X
Record SSEs
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xbb
Xcc
Xcc
Record 
concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record limited 
concomitant 
medicationdd
X
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 192 of 291
Table 7-1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term
follow-up (up 
to 7 years 
after last 
dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up 
to 7 years 
post-last dose
End of
Long-term
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Record therapy 
for prostate 
cancer other 
than 
radium-223 
dichloride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xee
X
X
X
Record new 
primary 
malignancies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record AEs 
and SAEsff
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record 
radium-223 
dichloride 
related AEs 
and SAEsgg
X
X
X
X
Record 
radium-223 
dichloride 
related SAEshh
X
X
Record 
SSE-related 
AEs and 
SAEsgg
X
X


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 193 of 291
Table 7-1  Schedule of procedures
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term
follow-up (up 
to 7 years 
after last 
dose)
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up 
to 7 years 
post-last dose
End of
Long-term
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Survival status
X
X
X
X
Abbreviations: AE = adverse event; BPI-SF = Brief Pain Inventory Short Form; CBC = complete blood count; CT = computed tomography; ECOG = Eastern 
Cooperative Oncology Group; EOT = end of treatment; ICF = informed consent form; IVRS / IWRS = interactive voice / web response system; 
MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network; PCWG2 = Prostate Cancer Clinical Trials Working Group 2; PRO = 
Patient-reported outcome; PS = performance status; PSA = prostate specific antigen; q6 = every 6; q12 = every 12; RECIST = Response Evaluation Criteria 
in Solid Tumors; SAE = serious adverse event; SSE = symptomatic skeletal event; US = United States; wk = week; WPS = worst pain score.
a.Once a subject switches from active follow-up with clinical visits to active follow-up without clinical visits, the subject will not be allowed to switch back.  A subject 
with a possible SSE may, and is encouraged to, return to the clinic at any time to assess for the presence of an SSE.
b. Once a separate, extended safety follow-up protocol, for the inclusion of subjects who received radium-223 dichloride in the course of Bayer sponsored clinical 
studies, has been implemented, the study subjects surviving after the end of the 2 years of active follow-up will be transitioned to this separate, extended 
safety follow-up protocol and the current study will be terminated at the time the last study subject is transitioned.
c. The maximum period for rescreening screen failed subjects is 35 days (14 days screening + 7-day window + 14 days for rescreening) from signing the ICF to 
randomization.  Rescreening of a subject requires prior approval of the Bayer-designated medical representative (see Section 5.1).  Eligibility should be 
confirmed within 14 ± 7 days of randomization.
d. The subject should return to the clinic in advance of the scheduled dose visit such that results of the laboratory assessment are available within 72 hours prior 
to dosing (each dose period is 28 ± 7 days after the prior dose of radium-223 dichloride).
e. Subjects who can no longer travel to the clinical site or who receive further anticancer therapy will only be followed up by telephone (active follow-up without 
clinic visits).  Symptomatic skeletal events will not be collected over the phone.
f. The study record or subject’s clinical record must clearly show that informed consent was obtained prior to any other study procedures being performed.  
Eligibility should be confirmed during the screening period and reconfirmed prior to dosing at Dose 1, Day 1.
g. Reconfirmation of eligibility and registration in the IVRS / IWRS: hematology results obtained within 72 hours of Dose 1, Day 1 should be reviewed and it should 
be confirmed that the values are still within the treatment ranges (absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥100 x 109/L, and hemoglobin
≥9.0 g/dL).


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 194 of 291
h. Body weight should be obtained without shoes, using a calibrated electronic physician (column) scale with digital display, measurement units 0.1 kg.  The same 
scale should be used for a given subject throughout the study.  At all sites (in US and outside US), weight is to be taken only once for each dose.  For non-
US sites and US sites not using the central PRD depot, the weight should be performed within 72 hours prior to dosing.  For US sites using the central PRD 
depot ONLY, subject weight for the dose day should be obtained at the site within 3 to 5 days prior to the dose visit.  This weight must be reported to the 
country PRD depot to allow adequate time for PRD preparation and delivery (approximately 2 days).  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.  Please note this is applicable to all dosing visits.
i. When a subject is determined to be eligible, the subject will be trained on daily PRO pain data collection using a handheld device.  The subject will then 
complete the pain assessment daily for 4 days prior to randomization and then for the 7 days prior to Dose 1, Day 1. 
j. Pain will be assessed during the screening period daily for 4 days prior to randomization and for the 7 days prior to Dose 1, Day 1, then daily for 7 days prior to 
each scheduled treatment visit through the end of Week 48.  Subjects will complete the daily pain assessment using a handheld device.  The daily PRO pain 
input results should be reviewed at the visit to check for completeness.
k. For Treatment Arms A and B only, pain data will be collected daily using the handheld device for 7 days prior to Weeks 36 and 48 visits, and daily for 7 days 
prior to each telephone contact at Weeks 28, 32, 40 and 44.  For Treatment Arms A and B only the BPI-SF and the NCCN FACT-P Symptom Index-17 
(NCCN-FACT FPSI-17) questionnaires will be completed on the day of the Week 36 and 48 visits and on the day of each telephone contact at Weeks 28, 32, 
40 and 44.  Twenty-four (24) hour analgesic use will be collected by the study investigator at Week 36 and 48 Visits and at each telephone contact (in Arms 
A and B) at Weeks 28 (±7 days), 32 (±7 days), 40 (±7 days), and 44 (±7 days). 
l. The randomization will be permuted-block, stratified by the use of prior chemotherapy (≤ 1 regimen versus > 1 regimen), by total alkaline phosphatase 
(< 220 U/L versus ≥220 U/L), and by average WPS of the BPI-SF (WPS ≤4 versus WPS >4).  This assessment will occur when the second call is made to 
the IVRS / IWRS to order drug: ≥ 10 to 14 days prior to study treatment administration. 
m. The BPI-SF questionnaire will be completed at each clinic visit from Dose 1, Day 1 until the Week 48 visit and for Treatment Arms A and B only, on the day of 
each telephone contact at Weeks 28, 32, 40 and 44.  For further details, see Section 14.7. 
n. Prior to randomization, the subject will use the hand-held device to complete selected questions from the BPI-SF questionnaire, Question 3, worst pain in the 
last 24 hours will be completed for at least 4 days during a period of no more than 1 week prior to randomization.  The average of the 4 days will be used as 
the randomization stratification value. 
o. Twenty-four (24)-hour analgesic use will be collected and it will be assessed by the study investigator until the Week 48 visit.  Twenty-four (24)-hour analgesic 
use will also be collected by the study investigator at each telephone contact (in Arms A and B) or visit at Weeks 28, 32, 40, and 44.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 195 of 291
p. Systolic / diastolic blood pressure, respiratory rate, body temperature, and heart rate will be measured after the subject has rested for at least 5 minutes.
q. After a complete physical examination at screening, subsequent physical examinations may be 'brief,' but should include any systems with symptoms.  All 
physical examinations will be performed by a physician according to the standard of care.
r. Complete blood count, including hematocrit, hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, white blood cell count, platelet count, and differential blood count reported as absolute count or percentage for neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils will be collected.  Chemistry panel including serum creatinine, sodium, potassium, chloride, calcium,
phosphorous, magnesium, total bilirubin, total alkaline phosphatase, aspartate transaminase, alanine transaminase, lactate dehydrogenase (screening only), 
and albumin (screening only).
s. Laboratory assessments should be performed within 72 hours of the visit and the results assessed and documented prior to dosing.
t. The PSA result for each dosing visit may be assessed post-dose.
u. Radiological / progression (according to PCWG2 criteria) will be assessed by means of whole body technetium-99 bone scan, chest X-ray (in the presence of 
suspicious lesion[s], a chest CT scan will be performed to confirm and characterize the lesion[s]), and MRI / CT scan of the abdomen and pelvis.  Baseline 
tumor assessment should be performed within 14 (± 7) days of randomization.  If standard of care bone scan and / or MRI / CT scan of the abdomen and 
pelvis and chest X-ray within 8 weeks of randomization are available, they do not need to be repeated at baseline.  If they are not available, they should be 
performed within 14 days ± 7 days of randomization (i.e., during the screening period).  Subsequent tumor assessment should be performed at Week 8, 
Week 16, Week 24 and every 12 weeks thereafter for up to 2 years after the subject’s last dose of radium-223 dichloride or until radiological progression 
(according to PCWG2 criteria or RECIST guidelines), or death, whichever comes first.  If progression is detected by bone scan, a confirmatory bone scan is 
required at least 6 weeks later.  All images should be obtained with the same technique (e.g., CT or MRI) as those obtained at screening.  Schedule 
deviations of ± 2 weeks for imaging / tumor evaluations are allowed.
v. Imaging is not required at the EOT visit if the subject discontinued due to radiological progression or the last tumor evaluation is not older than 4 weeks.
w. Bone imaging should be within 8 weeks of randomization.  If no prior documentation is available, a whole body technetium-99 bone scan will be obtained at 
screening (within 14 ± 7 days of randomization).
x. The IVRS / IWRS will be used to register requests for eligibility / study drug doses.  Once the subject eligibility is approved and registered in the IVRS / IWRS, 
including entry of required demographic and stratification information, the initial drug shipment may be prepared.  Additional IVRS / IWRS transactions for 
dose orders may be required; follow the country-specific guidance in the IVRS / IWRS manual.  The latest order date for the next dose is no later than the 
pre-defined lead time (number of days from order received to delivery to site in the country) prior to the planned dosing date.  The planned date for the next 
dose must be specified, when the dose is requested in the IVRS / IWRS.  At Doses 1 through 5, the site should order the next dose in the IVRS / IWRS, as 
soon as the current visit’s dose is registered in the IVRS / IWRS.  The latest order date for the next dose is no later than the pre-defined lead time (number of 
days from order received to delivery to site in the country) prior to the planned dosing date.  For subject visit registrations in the IVRS / IWRS, see the IVRS / 
IWRS manual.
y. The subject should be encouraged to arrive at the clinic well-hydrated on each dosing day and to drink ad libitum after each dose of radium-223 dichloride.  The 
subject should avoid drinking or eating within 1 hour before and after administration of the study drug.
z. The subject contact card is to be provided at each dosing visit for the subject to carry with him until the next visit.
aa. Subject and family instructions should be reviewed with the subject during screening through Dose 1, Day 1.
bb. Subjects identified with possible SSEs will be asked to come to the clinic for an SSE evaluation.  An SSE risk questionnaire will be developed.  Symptomatic 
skeletal events will not be identified over the telephone.
cc. If a subject has an SSE in the active follow-up period, he will continue active follow-up for 2 years following last study treatment.  At Weeks 28, 32, 40, and 44, 
subjects in Treatment Arms A and B will receive telephone contacts assessing for possible SSE risks.  Subjects exhibiting symptoms indicative of possible 
SSEs will be encouraged to visit the clinic early to assess SSE
status.  Symptomatic skeletal events will not be determined over the phone. 
dd. Except for complete analgesic use information recorded through Week 48, limited concomitant medication, including narcotic pain medication, will be recorded 


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 196 of 291
during the active follow-up with clinic visits period.  Contrast agents will only be captured as concomitant medication if there is an AE or SAE related to 
administration of contrast media. 
ee. Subjects who receive further anticancer therapy during the active follow-up period will have an end of active follow-up with clinic visits and will enter the active 
follow-up without clinic visits (telephone follow-up).  Subjects who receive further anticancer therapy after 2 years from last study treatment will enter long-
term follow-up. 
ff. All AEs and SAEs will be assessed and recorded from the time the ICF is signed until 30 days after the last dose of study medication.  All AEs should be 
assessed and documented prior to each dose of radium-223 dichloride.
gg. Any AEs and SAEs occurring beyond 30 days after the last treatment must be documented and reported if considered to be related to study medication or if 
related to an SSE.  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.
hh. Any SAEs 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.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 197 of 291
Change 27:
Section 12 Reference List:
Reference 22, new text (cited in Section 1.1 Background):
22.
Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD et al. 
Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J 
Med. 2013;369:213-23.
25.
http://www.facit.org/FACITOrg/Questionnaires.
29.
Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate 
cancer without previous chemotherapy. N Engl J Med 2012;368(2):138-48.
Change 28:
Synopsis - Diagnosis and main criteria for inclusion:
Paragraph 1, 7th bullet, item “g”:
Old text:
g. Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease abbreviated formula (Levey AS, et al. 
Ann Intern Med. 1999;130:461-70) (see Section 14.7)
Next text:
g. Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease abbreviated formula (24) (see 
Section 14.6)
Synopsis - Plan for statistical analysis:
Next to last paragraph:
Deleted text (correction of 1-sided alpha value):
Comparison 2 will be performed using a log-rank test with a 1-sided alpha of 
0.1% stratified by the randomization factors (previous chemotherapy [≤1 regimen 
versus > 1 regimen] and total ALP [< 220 U/L versus ≥220 U/L]).  The extended 
dosing regimen will be declared superior to the standard dosing regimen if the 
1-sided p-value from the stratified log rank test is less than 0.1%.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 198 of 291
Section 2 Study objectives:
Paragraph 3, 1st bullet (defined abbreviation):
Added text:
o
The use of external beam radiotherapy (EBRT) to relieve skeletal symptoms
Paragraph 4, 2nd bullet (defined abbreviation):
Added text:

To evaluate overall survival (OS)
Section 3 Investigators and other study personnel:
Paragraph 1:
Deleted text (duplication):
Global Clinical Leader for the study:
Global Clinical Leader for the study:
Paragraph 3 (correction of title and address):
Added text:
European Principal Investigator for the study:
 Italy
Tel: 
13.2
Amendment 2
Description of the amendment
Amendment 2 is an amendment to the integrated protocol version 2.0 dated 19 NOV 2013.  
Changes to the protocol include:

Added CKD-EPI equation as an alternative method for calculation of estimated 
glomerular filtration rate (eGFR).

Updated calculations for GFR.
PPD
PPD
PPD


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 199 of 291

Updated the definition of measureable lymph nodes from a 2-cm cutoff to a 1.5-cm 
cutoff.

Clarified when pain assessments will be collected throughout study.

Removed ± 7 day window for dose delays.

Reorganized the inclusion criterion to specify serum PSA ≥2 ng/mL as an inclusion 
criterion for castration-resistant disease.

Added additional prior therapies and medical history that should be recorded on the 
eCRF. 

Updated sponsor’s medical expert.

Updated sponsor’s medically responsible person.

Updated text for long-term study follow-up period.

Clarified duration between doses.

Updated global clinical leader contact information.

Clarified text regarding reporting of adverse events of neutropenia and hemorrhage.

Clarified continued treatment for subjects with disease progression.

Clarified withdrawal and dose delay for non-hematological thrombocytopenia and 
neutropenia.

Clarified maximum period allowed for screening.

Clarified tumor assessment scan timeline.

Updated US site information on weight measurement.

Added when treatment period is considered to begin for efficacy purposes.

Tumor assessment timing was updated to be consistent throughout protocol.

Clarified laboratory abnormalities related to assessments and documentation of 
adverse events.

Updated current drug manufacturer. 

Revised efficacy variables related to analgesic use and pain management and changed 
the term “pain management” to “analgesic use.”

Updated the radium-223 dichloride dosing and dose calibration to reflect the revised 
NIST standard.

Updated the list of abbreviations to reflect the usage of abbreviations in the amended 
protocol.

Changed “patient” to “subject”.

Updated information on obtaining body weight.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 200 of 291

Removed dosing restriction with bisphosphonates

Removed bone scan lesion index.

Moved change in analgesic use from secondary objective and secondary variable to 
exploratory objective and exploratory endpoints.

Clarified terminology by replacing toxicity with adverse event in dose delays.

Clarified terminology for concomitant cytotoxic chemotherapy.

Added sponsor’s study medical expert to the list of investigator(s) and other study 
personnel.

Revised text for consistency.

Added an additional efficacy analysis set (W24).

Changed terminology from “population” to “analysis set”.
13.2.1 Overview of changes
Change 1:
Added CKD-EPI equation as an alternative method for calculation of eGFR.
Sections affected:

Synopsis - Diagnosis and main criteria for inclusion

5.1.1 Inclusion Criteria

12. Reference List
Rationale:  This change allows sites to use either the standard MDRD equation or the recent 
and more accurate CKD-EPI equation.
Change 2:
Updated calculations for GFR.
Sections affected:

14.6 Calculation for glomerular filtration rate
Rationale:  This updated section provides background information and guidance regarding 
GFR assessment using current methods.
Change 3:
Updated the definition of measureable lymph nodes from a 2-cm cutoff to a 1.5-cm cutoff.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 201 of 291
Sections affected:

14.1 Response evaluation criteria in solid tumors, version 1.1

14.2 Recommendations of the prostate cancer clinical trials working group for 
assessment of radiological progression
Rationale:  This change is consistent with the RECIST 1.1 definition of measurable 
malignant lymph nodes.
Change 4:
Clarified when pain assessments will be collected throughout study.
Sections affected:

4.1 Study design

7.1.1 Tabulated overview

7.1.2.1 Screening period

7.1.2.3 Initial visit - Dose 1, Day 1 (Treatment arms A, B, C)

7.1.2.4 Doses 2 to 6 (Treatment arms A and B)

7.1.2.5 Doses 2 to 12 (Treatment arm C)

7.1.2.6 End of Treatment

7.1.2.7.1 Active follow-up with clinic visits

7.3.4.4 Pain Endpoints
Rationale:  This change was made to eliminate ambiguity in the protocol wording.
Change 5:
Removed ± 7 day window for dose delays.
Sections affected:

5.2.1 Withdrawal

6.4.7 Dose delays
Rationale:  This change was made to correct an error.
Change 6:
Reorganized the inclusion criterion to specify serum PSA ≥2 ng/mL as an inclusion criterion 
for castration-resistant disease.
Sections affected:


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 202 of 291

Synopsis - Diagnosis and main criteria for inclusion

5.1.1 Inclusion criteria
Rationale:  As a separate inclusion criterion, the serum PSA limit implies that all subjects
have to meet the criterion, but it is possible for a subject to have CRPC without a high PSA.  
This reorganization was instituted to clarify that PSA ≥2 ng/mL is a possible symptom of 
CRPC rather than its own qualification criterion.
Change 7:
Added additional prior therapies and medical history that should be recorded on eCRF.
Sections affected:

6.9.1 Prior therapy

7.2.2 Medical history
Rationale:  To collect clinical information for the purpose of identifying and accounting for 
factors that may influence the interpretation of radiographic images by central review.
Change 8:
Updated sponsor’s medical expert.
Sections affected:

Title page
Rationale:  Provide most up to date contact information.
Change 9:
Updated sponsor’s medically responsible person.
Sections affected:

Signature page
Rationale:  Provide most up to date signatory.
Change 10:
Updated text for long-term study follow-up period.
Sections affected:

Synopsis - Methodology

4.1 Design overview


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 203 of 291

6.8 Post-study therapy

7.1.2.7.1 Active follow-up with clinic visits

7.1.2.8.1 End of active follow-up with clinic visits

7.1.2.8.2 End of active follow-up without scheduled clinic visits

Section 7.1.2.9 Long-term follow-up to 7 years following last dose

10. Premature termination of the study
Rationale:  Provide updated information regarding long-term follow-up study that has now 
started.
Change 11:
Clarified duration between doses.
Sections affected:

Synopsis - Methodology

4.1 Design overview
Rationale:  Clarify the text.
Change 12:
Updated global clinical leader contact information.
Sections affected:

3. Investigators and other study personnel
Rationale:  Provide most up to date contact information.
Change 13:
Clarified text regarding reporting of adverse events of neutropenia and hemorrhage.
Sections affected:

7.5.1.3 Assessments and documentation of adverse events
Rationale:  Wording should be consistent with the long-term follow-up study.
Change 14:
Clarified continued treatment for subjects with disease progression.
Sections affected:


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 204 of 291

6.4.7 Dose Delays
Rationale:  For clarity.
Change 15:
Clarified withdrawal and dose delay for non-hematological thrombocytopenia and 
neutropenia.
Sections affected:

5.2.1 Withdrawal

6.4.7 Dose delays
Rationale:  For clarity.
Change 16:
Clarified maximum period allowed for screening.
Sections affected:

5.1 Eligibility

6.4.7 Dose delays
Rationale:  For clarity.
Change 17:
Clarified tumor assessment scan timeline.
Sections affected:

7.1.2.1 Screening period
Rationale:  For clarity.
Change 18:
Updated US site information on weight measurement.
Sections affected:

7.1.1 Tabulated overview

7.1.2.1 Screening period

7.1.2.3 Initial visit - Dose 1, Day 1 (Treatment arms A, B, C)

7.1.2.4 Doses 2 to 6 (Treatment arms A and B)


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 205 of 291

7.1.2.5 Doses 2 to 12 (Treatment arm C)

7.5.3.5 Body weight
Rationale:  All US sites using central PRD depot.
Change 19:
Added when treatment period is considered to begin for efficacy purposes.
Sections affected:

Synopsis: Methodology

4.1 Design Overview

7.1.1 Tabulated Overview

7.1.2.2 Randomization

8.4.4 Safety analysis
Rationale:  For clarity.
Change 20:
Updated tumor assessment timing to be consistent throughout protocol.
Sections affected:

7.1.2.4 Doses 2 to 6 (Treatment arms A and B)

7.1.2.5 Doses 2 to 12 (Treatment Arm C)
Rationale:  For consistency.
Change 21:
Clarified laboratory abnormalities related to assessments and documentation of adverse 
events.
Sections affected:

7.5.1.3 Assessments and documentation of adverse events
Rationale:  For clarity.
Change 22:
Updated current drug manufacturer.
Sections affected:


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 206 of 291

6.2 Identity of study treatment
Rationale:  Bayer acquired Algeta.
Change 23
Revised efficacy variables related to analgesic use and pain management and changed the 
term “pain management” to “analgesic use.”
Sections affected:

7.3.1 Efficacy variables

7.3.4.4 Pain endpoints

7.3.4.4.1 Pain improvement rate

7.3.4.4.2 Time to pain progression

7.3.4.5 Change in the last 24 hour analgesic use score (section relocated to 7.3.5.5.5)

7.3.5.5 Exploratory pain and analgesic use endpoints (section added)
Rationale: For consistency with updated objectives.
Change 24:
Updated the radium-223 dichloride dosing and dose calibration to reflect the revised NIST 
standard.
Sections affected:

Title Page

Synopsis: Title 

Synopsis: Study objectives

Synopsis: Doses

Synopsis: Methodology

Synopsis plan for statistical analysis

1.2 Study rationale

2. Study objectives

4.1 Design overview

6.1 Treatments to be administered

6.2 Identity of study treatments

6.3 Treatment assignment


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 207 of 291

6.4.1 Dose calibration

6.4.3 Dose calculation

7.1.2.2 Randomization

8.1 General considerations

8.4.1 Primary efficacy analysis 

8.4.4 Safety Analyses

8.6 Determination of sample size

12. Reference list
Rationale:  The quantification of radium-223 radioactivity in Xofigo® is based on the primary 
standardization performed by the US 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 IFE, 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 patient dose.  A reassessment of the primary 
standardization was initiated by the NIST.  A discrepancy of approximately 10% between the 
published NIST primary standardization (NIST 2010 [31]) and current measurements was 
confirmed and a revised NIST primary reference standard has been issued (NIST update
[32]).  As a result of the revised NIST primary standardization, an adaption of the numerical 
description of patient dose and the description of radioactive concentration of the drug 
product solution becomes necessary.  This concerns Xofigo® for commercial use and product 
used in clinical trials.  
After the implementation of the new standard (NIST update [32]) the numerical description 
of the patient 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 
agreements have been initiated.   The current standard (NIST 2010 [31]), dial setting and 
dose will remain in effect until a unique implementation date in Q2 2016 as agreed with FDA 
and 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 (NIST 2010
[31]) means that the current patient 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 patients identical to what has been documented and 
administered so far, also when implementing the new official standard, the nominal value of 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 208 of 291
the patient dose will be changed to 55kBq/kg body weight (NIST update [32]). This change 
keeps the same accuracy in the nominal value of the dose.  Thus, there will be no actual 
change in the patient 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 (NIST 2010 [31]) 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 (NIST 2010 [31]) 
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 (NIST update
[32]), 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 patient dose in treatment 
sites  has to be performed using up-dated dial-settings of dose calibrators.  
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 (NIST 2010 [31]); 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 (NIST update [32]) only), though 
the volume of radium-223 dichloride given to each subject will remain the same.  


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 209 of 291
Change 25
The list of abbreviations was updated to reflect the usage of abbreviations in the amended 
protocol.
Sections affected:

List of abbreviations
Rationale:  For consistency.
Change 26
Changed “patient” to “subject”.
Sections affected:

Synopsis: Study objectives

Synopsis: Methodology

2. Study objectives

4.1 Design overview

6.4.1 Dose calibration 

6.4.4 Dose preparation

7.2.4 Body-size descriptors

7.3.4.4.2 Time to pain progression

7.3.5.5 Exploratory pain and analgesic use endpoints
Rationale: For consistency.
Change 27
Updated information on obtaining body weight.
Sections affected:

7.5.3.5 Body weight
Rationale: For clarification.
Change 28
Removed dosing restriction with bisphosphonates.
Sections affected:


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 210 of 291

6.9.2    Concomitant medication
Rationale: For Ra-223 dichloride, there is no evidence of a pharmacokinetic or PD 
interaction that would warrant a two-hour interval between injections.
Change 29
Removed bone scan lesion index.
Sections affected:

7.3.1 Efficacy variables

7.3.5.1.2 Bone scan lesion index (removed)
Rationale: It is not performed by central imaging as per charter.
Change 30
Moved change in analgesic use from secondary objective and secondary variable to 
exploratory objective and exploratory endpoints.
Sections affected:

Synopsis: Study objectives

Synopsis: Primary/secondary variables

2. Study objectives
Rationale: Objectives updated.
Change 31
Clarified terminology by replacing “toxicity” with “adverse event” in dose delays.
Sections affected:

6.4.7 Dose delays
Rationale: For clarification.
Change 32
Clarified terminology for concomitant cytotoxic chemotherapy.
Sections affected:

Synopsis: Background treatment / concomitant medications / prohibited therapies

Synopsis: Diagnosis and main criteria for exclusion


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 211 of 291

5.1.2 Exclusion criteria

5.2.1 Withdrawal

6.4.7 Dose Delays

6.9.1 Prior therapy

6.9.2 Concomitant medication

7.1.2.4 Doses 2 to 6 (Treatment Arms A and B)

7.1.2.5 Doses 2 to 12 (Treatment Arm C)

7.1.2.7.2 Active follow-up without scheduled clinic visits
Rationale: For clarification.
Change 33
Added sponsor’s study medical expert to the list of investigator(s) and other study personnel.
Sections affected:

3. Investigator(s) and other study personnel
Rationale: For clarification.
Change 34
Revised text for consistency.
Sections affected:

5.1 Eligibility

7.1.2.1 Screening Period
Rationale: For consistency.
Change 35
Added analysis set (W24).
Section affected:

8.2 Analysis sets
Rationale:  Two efficacy analysis sets are needed because of study design performing 
2 separate comparisons, but only one set was defined in the original protocol.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 212 of 291
Change 36
Changed terminology from “population” to “analysis set”.
Sections affected:

Synopsis: Plan for statistical analysis

8.2 Analysis sets
Rationale:  To make terminology within the statistical analyses sections consistent.
13.2.2 Changes to the protocol text
Change 1:
Synopsis - Diagnosis and main criteria for inclusion and Section 5.1 Inclusion criteria: 
Old text:
g.
Estimated glomerular filtration rate ≥30 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease abbreviated formula (see Section 14.6) 
(24)
New text:
g.
Estimated glomerular filtration rate ≥30 mL/min/1.73 m2 according to either 
the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
creatinine equation or the Modification of Diet in Renal Disease abbreviated 
formula (see Section 14.6) (24, 25).
Added text:
25. Levey AS, Stevens LA, Schid CH, Zhang YL, Castro AF 3rd, Feldman Hi, Kusek 
JW, Eggers P, Van Lente F, Greene T, Coresh J, CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration). A New Equation to Estimate Glomerular Filtration 
Rate. Ann Intern Med. 2009 May 5, 150(9): 604-12
Change 2:
Section 14.6 Calculation for glomerular filtration rate
Entire section:
Old text:
In accordance with established nephrology practice and guidelines, renal function 
at screening and throughout the study will be assessed by means of the estimated 
GFR, calculated using the abbreviated MDRD study formula.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 213 of 291
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 / 1.73 m2) = k x 186 x [serum creatinine]-1.154 x [age]-0.203
Where k = 1 (men) or 0.742 (women), GFR indicates glomerular filtration rate, 
and serum creatinine is measured in mg/dL.
Subjects with a screening GFR < 30 mL/min/1.73 m2 calculated by this method 
will not be allowed to participate in the study.
New text:
Baseline kidney function will be assessed using the glomerular filtration rate as 
calculated using either the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) creatinine equation, or, when this method is not available, the 
Modification of Diet in Renal Disease (MDRD) equation. 
The MDRD calculation is an established method of estimating GFR based on 4 
variables: serum creatinine level, age, sex, and ethnicity.  This method has 
historically been the National Kidney Foundation’s recommended method of 
estimating the GFR in individuals 18 years or older.  
The MDRD Study Equation:
GFR (mL/min/1.73m2) = k x 186 x [serum creatinine]-1.154 x [age]-0.203
Where k = 1 (men) or 0.742 (women), serum creatinine is measured in mg/dL. 
In an effort to improve upon the MDRD equation, the Chronic Kidney Disease 
Epidemiology Collaboration developed an updated calculation, the CKD-EPI 
creatinine equation, using the same variables as the MDRD equation. This new 
calculation has been validated and is considered to be more accurate than the 
MDRD equation.  The National Kidney Foundation now recommends using the 
CKD-EPI Creatinine Equation for estimating GFR.
The CKD-EPI calculation is based on a serum creatinine value that was obtained 
through use of isotope dilution mass spectrometry (IDMS), a standardized serum 
creatinine assay. Therefore, the CKD-EPI equation is only valid if the laboratory 
used a calibration method for serum creatinine that is traceable to IDMS.  The 
IDMS has been adopted by laboratories globally and is widely available.  If it is 
not clear whether your laboratory uses this serum creatinine reference method, 
please contact the laboratory for confirmation.  


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 214 of 291
CKD-EPI Equation
• Conventional Units (creatinine as mg/dL; age in years):
GFR (mL/min/1.73m2) = 175 x (serum creatinine)-1.154 x (Age)-0.203 x (0.742 
if female) x (1.212 if African American)
• International System of Units (SI) Units (creatinine as µmol/L; age in years):
GFR (mL/min/1.73m2) = 175 x (serum creatinine/88.4)-1.154 x (Age)-0.203 x 
(0.742 if female) x (1.212 if African American)
The standard MDRD calculation should be used for any serum creatinine values 
that are not based on the IDMS assay.  
For convenience and accuracy, a GFR calculator may be used for this study at the 
following URL at the National Kidney Foundation’s web site:  
http://www.kidney.org/professionals/KDOQI/gfr_calculator
Change 3:
Section 14.1 Response evaluation criteria in solid tumors, version 1.1: 
Paragraph 2, 1st bullet:
Old text:

Only lymph nodes with short axis ≥2 cm can be selected as target lesions.
New text:

Only lymph nodes with short axis ≥1.5 cm can be selected as target lesions.
Paragraph 4:
Old text:
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥2 cm in short axis when assessed by CT 
scan.  At baseline and in follow-up, only the short axis will be measured and 
followed.
New text:
Malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥1.5 cm in short axis when assessed by CT 
scan.  At baseline and in follow-up, only the short axis will be measured and 
followed.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 215 of 291
Paragraph 6:
Old text:
Non-Measurable Disease: All other lesions (or sites of disease), including small 
lesions (pathological lymph nodes with short axis ≥1 cm to < 2 cm) are 
considered non-measurable disease.  Leptomeningeal disease, ascites, 
pleural/pericardial effusions, and lymphangitic involvement of skin or lung are all 
non-measurable.
New text:
Non-Measurable Disease: All other lesions (or sites of disease), including small 
lesions (pathological lymph nodes with short axis ≥1 cm to < 1.5 cm) are 
considered non-measurable disease.  Leptomeningeal disease, ascites, 
pleural/pericardial effusions, and lymphangitic involvement of skin or lung are all 
non-measurable.
Section 14.2 Recommendations of the Prostate Cancer Clinical Trials Working Group for 
assessment of radiological progression: 
Criteria for radiological progression:
Old text:

Only lymph nodes with short axis ≥2 cm can be selected as a target lesion
New text:

Only lymph nodes with short axis ≥1.5 cm can be selected as a target lesion
Change 4:
Section 4.1 Study design 
7th paragraph:
Old text:
Pain endpoints will be based on subject-reported outcome data.  Pain will be 
assessed by means of selected questions from the BPI-SF daily for 4 days 
immediately prior to randomization, in order to stratify subjects by worst pain 
score (WPS) ≤4 or > 4, for the 7 days immediately prior to Dose 1, Day 1, and 
then for Treatment Arms A and B, daily for 7 days prior to each scheduled dosing 
visit through Week 24, for the 7 days prior to Weeks 36 and 48 visits and for 7 
days prior to each telephone contact at Weeks 28, 32, 40 and 44. For Treatment 
Arm C, pain data will be collected daily for 7 days prior to each scheduled dosing 
visit through Week 48.  Pain will also be assessed by means of the BPI SF 
questionnaire for all treatment arms at each clinic visit from Dose 1, Day 1 until 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 216 of 291
the Week 48 visit and for treatment Arms A and B on the day of each telephone 
contact at Weeks 28, 32, 40 and 44.  
New text:
Pain endpoints will be based on subject-reported outcome data.  Pain will be 
assessed by means of selected questions from the BPI-SF daily for 4 days 
immediately prior to randomization, in order to stratify subjects by WPS ≤4 or 
> 4, and then daily for 6 days prior to Cycle 1, Day 1 or subsequent visits
including telephone contacts, as applicable, plus the day of the visit or telephone 
contact until Week 48.  Pain will also be assessed by means of the BPI-SF 
questionnaire for all treatment arms at each clinic visit or telephone contact from 
Dose 1, Day 1 until the Week 48 visit and for treatment Arms A and B on the day 
of each telephone contact at Weeks 28, 32, 40, and 44.
Section 7.1.1 Tabulated overview: 
Footnote i, footnote j, and footnote k:
Old text:
i.
When a subject is determined to be eligible, the subject will be trained on 
daily PRO pain data collection using a handheld device.  The subject will then 
complete the pain assessment daily for 4 days prior to randomization and then 
for the 7 days prior to Dose 1, Day 1.
j.
Pain will be assessed during the screening period daily for 4 days prior to 
randomization and for the 7 days prior to Dose 1, Day 1, then daily for 7 days 
prior to each scheduled treatment visit through the end of Week 48.  Subjects 
will complete the daily pain assessment using a handheld device.  The daily 
PRO pain input results should be reviewed at the visit to check for 
completeness.
k.
For Treatment Arms A and B only, pain data will be collected daily using the 
handheld device for 7 days prior to Week 36 and 48 visits, and daily for 7 days
prior to each telephone contact at Weeks 28, 32, 40, and 44.  For Treatment 
Arms A and B only the BPI SF and the NCCN FACT-P Symptom Index-17 
(NCCN-FACT FPSI-17) questionnaires will be completed on the day of the 
Week 36 and 48 visits and on the day of each telephone contact at Weeks 28, 
32, 40, and 44.  Twenty-four (24) hour analgesic use will be collected by the 
study investigator at Week 36 and 48 Visits and at each telephone contact (in 
Arms A and B) at Weeks 28 (±7 days), 32 (±7 days), 40 (±7 days), and 44 (±7 
days).
New text:
i.
When a subject is determined to be eligible, the subject will be trained on 
daily PRO pain data collection using a handheld device.  The subject will then 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 217 of 291
complete the pain assessment daily for 4 days prior to randomization and then 
daily for one week (6 days prior to Cycle 1, Day 1 or subsequent visits, as 
applicable, plus the morning of the visit).  
j.
Pain will be assessed during the screening period daily for 4 days prior to 
randomization and daily for one week (6 days prior to Cycle 1, Day 1 or 
subsequent visits, as applicable, plus the day of the visit).  Subjects will 
complete the daily pain assessment using a handheld device.  The daily PRO 
pain input results should be reviewed at the visit to check for completeness.
k. For Treatment Arms A and B only, pain data will be collected daily using the 
handheld device for one week (6 days prior to the applicable visit, plus the day 
of the visit) prior to Week 36 and 48 visits, and daily for one week (6 days 
prior to the applicable phone call, plus the day of the phone call) prior to each 
telephone contact at Weeks 28, 32, 40, and 44.  For Treatment Arms A and B 
only the BPI SF and the NCCN FACT-P Symptom Index-17 (NCCN-FACT 
FPSI-17) questionnaires will be completed on the day of the Week 36 and 48 
visits and on the day of each telephone contact at Weeks 28, 32, 40, and 44.  
Twenty-four (24) hour analgesic use will be collected by the study investigator 
at Week 36 and 48 Visits and at each telephone contact (in Arms A and B) at 
Weeks 28 (±7 days), 32 (±7 days), 40 (±7 days), and 44 (±7 days).
Section 7.1.2.1 Screening Period: 
19th Bullet :
Old text:
o
for the 7 days prior to Dose 1, Day 1 (Day 7 will be done on the day of Dose 
1, Day 1 of the protocol).
New text:
o
for 6 full days prior to the dosing visit plus the morning of the day of the 
dosing visit prior to Dose 1, Day 1.
Section 7.1.2.3 Initial visit - Dose 1, Day 1 (Treatment arms A, B, C) 
Last bullet:
Old text:

Subjects will complete the pain assessment daily for the 7 days prior to Dose
2, Day 1.
New text

Subjects will complete the pain assessment daily for 6 days prior to the dosing 
visit plus the morning of the dosing visit prior to Dose 1, Day 1


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 218 of 291
Section 7.1.2.4 Doses 2 to 6 (Treatment arms A and B) and Section 7.1.2.5 Doses 2 to 12 
(Treatment arm C)
19th bullet:
Old text:

After each visit, subjects will complete the pain assessment daily for the 7 
days prior to next dose, Day 1 or for the 7 days prior to the EOT visit. 
New text:

Subjects will complete the pain assessment daily for 6 days prior to the dosing 
visit plus the morning of the dosing visit 
Section 7.1.2.6 End of treatment visit
17th bullet:
Old text:

After the visit, subjects will complete the pain assessment daily for the 7 days
prior to the Week 28 telephone contact (Treatment Arms A and B only).
New text:

Subjects will complete the pain assessment daily for 6 days prior to plus the 
morning of the Week 28 telephone contact (Treatment Arms A and B only).  
Section 7.1.2.7.1 Active follow-up with clinic visits
6th paragraph, 1st bullet:
Old text:

Pain will be assessed daily for 7 days prior to each telephone contact at Weeks 
28, 32, 40, and 44 and the daily PRO pain input data will be reviewed for 
completeness at the telephone contact. 
New text:

Pain will be assessed daily for 6 days prior to the visit plus the morning of 
each telephone contact at Weeks 28, 32, 40, and 44 and the daily PRO pain 
input data will be reviewed for completeness at the telephone contact. 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 219 of 291
Section 7.3.4.4 Pain Endpoints: 
Paragraph 3:
Old text:
The screening baseline for pain endpoints will be based on the pre-Dose 1, 7-day 
pain assessment.
New text:
The screening baseline for pain endpoints will be based on the pre-Dose 1, 7-day 
pain assessment. (Day 7 will be done on the day of Dose 1, Day 1 of the 
protocol.)
Change 5:
Section 5.2.1 Withdrawal: 
3rd bullet:
Old text:

A dose delay of more than 4 weeks (maximum of 8 weeks [± 7 days] between 
2 injections)
New text:

A dose delay of more than 4 weeks (maximum of 8 weeks between 2 
injections)
Section 6.4.7 Dose Delays:
Logistical difficulties, Paragraph 3:
Old text:
A dose delay of more than 4 weeks (maximum of 8 weeks [± 7 days] between 2 
injections) will lead to study drug discontinuation.
New text:
A dose delay of more than 4 weeks (maximum of 8 weeks between 2 injections) 
will lead to study drug discontinuation.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 220 of 291
Change 6:
Synopsis - Diagnosis and main criteria for inclusion and 5.1.1 Inclusion Criteria: 
2nd bullet:
Old text:
C. Serum PSA progression defined as 2 subsequent increases in PSA over a 
previous reference value (a minimum of 2 ng/mL [µg/L]) OR
New text:
c.
Serum PSA progression defined as 2 subsequent increases in PSA over a 
previous reference value, with a PSA value of ≥2 ng/mL at the time of the 
second increase, OR
Change 7:
Section 6.9.1 Prior therapy: 
3rd bullet:
Old text:

All other prior medications, including pain medications and taken in the 30 
days prior to start of study treatment (Dose 1) will be recorded in the subject’s 
medical record and in the appropriate eCRF.  The generic or trade name, 
indication, dosage, and start and stop dates must be recorded.
New text:

All other prior medications, including but not limited to pain medications, 
antibiotics, steroids, bisphosphonates, iron therapy, or radiation therapy taken 
in the 30 days prior to start of study treatment (Dose 1) will be recorded in the 
subject’s medical record and in the appropriate eCRF.  The generic or trade 
name, indication, dosage, and start and stop dates must be recorded.
Section 7.2.2 Medical history: 
3rd bullet:
Old text:
Considered relevant to the study up to
New text:
Considered relevant to the study up to 6 months prior to screening: History of 
fractures, trauma, osteomyelitis, joint and dental infections, cellulitis, edema, 
arthritis, metabolic bone disease, or limitation of function; history of orthopedic 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 221 of 291
(e.g., presence and location of prosthetic implants) and non-orthopedic (e.g., ileal 
conduit) surgery that might affect the results of bone scintigraphy; history of 
recent scintigraphy, especially with 131I, 67Ga, or 111In.
Change 8:
Title page 
Old text:
Sponsor’s 
medical expert:
Bayer S.p.A. V.le Certosa 210 
20156 Milan, Italy
New text:
Sponsor’s 
medical expert:
Milano V.le Certosa 210
20156 Milano - Italia
Phone: 
Change 9:
Signature page 
Old text:
Name:
Role: 
Global Clinical Leader, 
New text:
Name:
Role: 
Global Clinical Leader, 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 222 of 291
Change 10:
Synopsis – Methodology (14th paragraph), Section 4.1 Design overview (14th paragraph), 
Section 6.8 Post-study therapy (1st paragraph), Section 7.1.2.8.1 End of active follow-up 
with clinic visits (3rd paragraph), Section 7.1.2.8.2 End of active follow-up without 
scheduled clinic visits (3rd paragraph):
Old text:
After the active follow-up, subjects will enter the long term  follow-up period and 
will be followed via telephone follow-up at 6-month intervals for investigator-
reported, radium 223 dichloride related SAEs, hematologic toxicity (e.g., 
myelosuppression / myelofibrosis / bone marrow aplasia), new primary 
malignancies, and survival up to 7 years after the last dose of radium-223 
dichloride or until death.  Once a separate extended safety follow-up protocol, for 
the inclusion of subjects who received radium-223 dichloride in the course of 
Bayer sponsored clinical trials, has been implemented, the study subjects 
surviving after the end of the active follow-up will be transitioned to this separate 
extended safety follow-up protocol and the current study will be terminated at the 
time the last study subject is transitioned.
New text:
All study subjects will be eligible for further follow-up either in this study or in a 
separate long-term follow-up study for up to 7 years.  The separate long-term 
follow-up study has been set up to follow subjects who received radium-223 
dichloride or placebo in the course of Bayer-sponsored clinical trials.  The long-
term follow-up study has a specific focus on investigator reported, radium-223 
dichloride-related AEs and SAEs, hematologic toxicity (e.g., myelosuppression / 
myelofibrosis / bone marrow aplasia), new primary malignancies including 
leukemias and solid tumors, and survival for up to 7 years after last dose of 
radium-223 dichloride or until death.  During long-term follow-up, subjects will 
be contacted every 6 months by telephone.  All subjects who transition into this 
separate long-term follow-up study will require a separate signed informed 
consent.
Transition of all subjects into the separate long-term follow-up study will begin 
following the later of primary endpoint completion or 2 years after the last 
radium-223 dichloride treatment is administered to the last treated subject.  
Until the transition to the long term follow-up study begins, some subjects may 
begin long-term follow-up in this study.  This study will end when all subjects 
have transitioned into the long-term follow-up study or discontinued from this 
study for another reason (e.g., Consent Withdrawn, Lost to Follow-up).
Section 4.1 Design Overview
Added Text:
Active follow-up period with clinic visits:


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 223 of 291
Subjects who discontinue study treatment and who did not have an SSE will enter 
an active follow-up period with clinic visits. These subjects will be evaluated
every 12 weeks (± 7 days) for pain endpoints, radiological progression, SSEs, 
survival, treatment-related AEs and serious adverse events (SAEs), and the 
initiation of other anti-cancer therapies. 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. During this period, 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 active follow-up period with clinic visits extends from the discontinuation of 
the treatment period until the subject experiences an SSE, can no longer travel to 
the clinic, receives further treatment with cytotoxic chemotherapy for prostate 
cancer, other systemic radioisotopes, hemibody EBRT, or other investigational 
drugs, dies, is lost to follow-up, or withdraws informed consent and actively 
objects to collection of further data. 
Active follow-up period without clinic visits:
Subjects from the treatment period or the active follow-up period with clinic visits 
who can no longer travel to the clinical site will be followed for survival, 
treatment-related AEs and SAEs, SSEs, pain endpoints, and the initiation of other 
anti-cancer therapies with a phone call every 12 weeks (± 7 days). 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. 
During this period, 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 active follow-up period without clinic visits extends from the EOT period or 
the end of active follow-up with clinic visits until the subject experiences an SSE, 
dies, is lost to follow-up, or withdraws informed consent and actively objects to 
collection of further data.
The maximum duration of the active follow-up is 7 years from the last dose of 
radium-223 dichloride received by the subject.
All study subjects will be eligible for further follow-up either in this study or in a 
separate long-term follow-up study for up to 7 years.  The separate long-term 
follow-up study has been set up to follow subjects who received radium-223 
dichloride or placebo in the course of Bayer-sponsored clinical trials.  The 
long-term follow-up study has a specific focus on investigator reported 
radium-223 dichloride-related AEs and SAEs, hematologic toxicity (e.g., 
myelosuppression / myelofibrosis / bone marrow aplasia), new primary 
malignancies, including leukemias and solid tumors, and survival for up to 7 years 
after last dose of radium-223 dichloride or until death.  During long-term follow-


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 224 of 291
up, subjects will be contacted every 6 months by telephone.  All subjects who 
transition into this separate long-term follow-up study will require a separate 
signed informed consent.
Transition of all subjects into the separate long-term follow-up study will begin 
following the later of primary endpoint completion or 2 years after the last 
radium-223 dichloride treatment is administered to the last treated subject.  
Until the transition to the long term follow-up study begins, some subjects may 
begin long-term follow-up in this study.  This study will end when all subjects 
have transitioned into the long-term follow-up study or discontinued from this 
study for another reason (e.g., Consent Withdrawn, Lost to Follow-up).
Section 7.1.2.7.1. Active Follow-up with clinic visits:
Old text:
The subject should return to the clinic every 12 weeks (± 14 days) following the 
EOT visit until the subject experiences a symptomatic skeletal event or until the 
primary efficacy analysis matures, whichever occurs first; provided that active 
follow-up will not last less than 2 years or more than 7 years following the 
subject’s last study treatment.  
In addition to the visits at Weeks 36 and 48, the subjects in Treatment Arms A and 
B will receive telephone contacts at Weeks 28, 32, 40, and 44 to assess for 
possible SSE risks and will continue PRO data collection.  Pain data, 24-hour 
analgesic use, BPI and NCCN-FACT FPSI-17 questionnaires will also be 
collected as detailed below. 
New text:
The subject should return to the clinic every 12 weeks (± 14 days) following the 
EOT visit until the subject experiences a symptomatic skeletal event or until the 
primary efficacy analysis matures, whichever occurs first. Active follow-up will 
continue for 2 years in this study and not more than 7 years total including the 
long term follow-up study (if the subject has signed the ICF).
To the extent possible, subjects discontinuing treatment prematurely should 
nonetheless complete the Week 8, 16, 24, 36, and 48 clinic visits and any 
applicable tumor assessments scheduled with respect to treatment start. Similarly, 
subjects in Treatment Arms A and B should receive Week 28, 32, 40, and 44 
telephone contacts at the regularly scheduled time with respect to treatment start.
In addition to the visits at Weeks 36 and 48 (from the start of treatment) the 
subjects in Treatment Arms A and B will receive telephone contacts at Weeks 28, 
32, 40, and 44 (from the start of treatment) to assess for possible SSE risks and 
will continue PRO data collection.  Pain data, 24-hour analgesic use, BPI and 
NCCN-FACT FPSI-17 questionnaires will also be collected as detailed below.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 225 of 291
Section 7.1.2.9 Long-term follow-up to 7 years following last dose
Old text:
This period starts when subjects have completed the active follow-up period and 
ends 7 years after the last dose of radium-223 dichloride or when the subject dies.  
Once a separate extended safety follow-up protocol, for the inclusion of subjects 
who received radium-223 dichloride in the course of Bayer sponsored clinical 
trials, has been implemented, the study subjects surviving after the end of the 
active follow-up will be transitioned to this separate extended safety follow-up 
protocol and the current study will be terminated at the time the last study subject 
is transitioned.
New text:
This period starts when subjects have completed the active follow-up period and 
ends 7 years after the last dose of radium-223 dichloride or when the subject dies. 
All study subjects will be eligible for further follow-up either in this study or in a 
separate long-term follow-up study for up to 7 years.  The separate long-term 
follow-up study has been set up to follow subjects who received radium-223 
dichloride or placebo in the course of Bayer-sponsored clinical trials.  The 
long-term follow-up study has a specific focus on investigator reported, 
radium-223 dichloride-related AEs and SAEs, hematologic toxicity (e.g., 
myelosuppression / myelofibrosis / bone marrow aplasia), new primary 
malignancies including leukemias and solid tumors, and survival for up to 7 years 
after last dose of radium-223 dichloride or until death.  During long-term follow-
up, subjects will be contacted every 6 months by telephone.  All subjects who 
transition into this separate long-term follow-up study will require a separate 
signed informed consent.
Transition of all subjects into the separate long-term follow-up study will begin 
following the later of primary endpoint completion or 2 years after the last 
radium-223 dichloride treatment is administered to the last treated subject.  
Until the transition to the long term follow-up study begins, some subjects may 
begin long-term follow-up in this study.  This study will end when all subjects 
have transitioned into the long-term follow-up study or discontinued from this 
study for another reason (e.g., Consent Withdrawn, Lost to Follow-up).
Section 10. Premature termination of the study:
Old text:
•
If a separate extended safety follow-up protocol is implemented, the study 
subjects surviving after the end of the active follow-up will be transitioned to this 
separate extended safety follow-up protocol and the current study will be 
terminated at the time the last study subject is transitioned.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 226 of 291
New text:
All study subjects will be eligible for further follow-up either in this study or in a 
separate long-term follow-up study for up to 7 years.  The separate long-term 
follow-up study has been set up to follow subjects who received radium-223 
dichloride or placebo in the course of Bayer-sponsored clinical trials.  The 
long-term follow-up study has a specific focus on investigator reported, 
radium-223 dichloride-related AEs and SAEs, hematologic toxicity (e.g., 
myelosuppression / myelofibrosis / bone marrow aplasia), new primary 
malignancies including leukemias and solid tumors, and survival for up to 7 years 
after last dose of radium-223 dichloride or until death.  During long-term follow-
up, subjects will be contacted every 6 months by telephone.  All subjects who 
transition into this separate long-term follow-up study will require a separate 
signed informed consent.
Transition of all subjects into the separate long-term follow-up study will begin 
following the later of primary endpoint completion or 2 years after the last 
radium-223 dichloride treatment is administered to the last treated subject.  
Until the transition to the long term follow-up study begins, some subjects may 
begin long-term follow-up in this study.  This study will end when all subjects 
have transitioned into the long-term follow-up study or discontinued from this 
study for another reason (e.g., Consent Withdrawn, Lost to Follow-up).
Change 11:
Synopsis - Methodology and Section 4.1 Design overview
3rd paragraph:
Old text:
The treatment period begins at the time of randomization.  During the treatment 
period, study medication is administered every 28 days and may be delivered in an 
outpatient setting. 
New text:
The treatment period begins at the time of randomization.  During the treatment 
period, study medication is administered every 28 days (±7 days) from Dose 1 and 
may be delivered in an outpatient setting. 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 227 of 291
Change 12:
Section 3 Investigators and other study personnel 
1st paragraph:
Old text:
Global Clinical Leader for the study:
Bayer HealthCare Pharmaceuticals, Inc.
100 Bayer Blvd.
PO Box 915
Whippany, New Jersey 07981
Tel: 
New text:
Global Clinical Leader for the study:
Bayer HealthCare Pharmaceuticals, Inc.
100 Bayer Blvd.
PO Box 915
Whippany, New Jersey 07981
Tel: 
Change 13:
Section 7.5.1.3 Assessments and documentation of adverse events
4th paragraph:
Old text:
All AEs and SAEs occurring beyond 30 days after the last treatment have to be 
reported if considered to be related to study medication or if related to an SSE 
(during active follow-up with clinic visits only).  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.  If a subject is unable to 
provide required details for events of interest, this information may need to be 
obtained from the primary provider.
PPD
PPD
PPD
PPD


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 228 of 291
New text:
All AEs and SAEs occurring beyond 30 days after the last treatment have to be 
reported if considered to be related to study medication or if related to an SSE 
(during active follow-up with clinic visits only).  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.  In subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage 
during their chemotherapy treatment must be reported as SAEs at any time and for 
up to 6 months thereafter.  If a subject is unable to provide required details for 
events of interest, this information may need to be obtained from the primary 
provider.
Change 14:
Section 6.4.7 Dose Delays, Disease Progression
2nd paragraph, 4th and 5th sentence:
Added text:
If the subject is not treated with any of the prohibited anti-cancer therapies, the 
administration of study drug may be continued until completion of 6/12 cycles. If, 
in the investigator’s opinion, the subject will continue to receive clinical benefit 
from remaining on study treatment. 
Change 15:
Section 5.2.1 Withdrawal Section 
5th and 6th bullets:
Old text:

If the subject experiences any non-hematological CTCAE Grade 4 toxicity
lasting > 7 days despite adequate treatment

If the subject experiences Grade 3 neutropenia or Grades 3 or 4 
thrombocytopenia lasting > 2 weeks or Grade 4 neutropenia lasting > 7 days
despite adequate treatment.  Blood transfusions and biologic response 
modifiers, such as GM-CSF or G-CSF can be used for the treatment of 
hematological abnormalities during the treatment period.
New text:

If the subject experiences any non-hematological CTCAE Grade 4 adverse 
event lasting > 1 week despite adequate treatment regardless of causality.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 229 of 291

If the subject experiences Grade 3 neutropenia or Grades 3 or 4 
thrombocytopenia lasting > 2 weeks or Grade 4 neutropenia lasting > 1 week
despite adequate treatment regardless of causality.  Blood transfusions and 
biologic response modifiers, such as GM-CSF or G-CSF can be used for the 
treatment of hematological abnormalities during the treatment period.
Section 6.4.7 Dose Delays, Myelosuppression
2nd and 3rd bullets:
Old text:

If a subject experiences sustained CTCAE Grade 3 neutropenia or sustained 
CTCAE Grades 3 or 4 thrombocytopenia (see Table 6-1) lasting > 2 weeks 
despite adequate treatment, the subject must be discontinued from treatment 
with radium-223 dichloride.

If a subject experiences sustained CTCAE Grade 4 neutropenia (see Table 
6-1) lasting > 1 week despite adequate treatment, the subject must be 
discontinued from treatment with radium-223 dichloride. 
New text:

If a subject experiences sustained CTCAE Grade 3 neutropenia or sustained 
CTCAE Grades 3 or 4 thrombocytopenia (see Table 6-1) lasting > 2 weeks 
despite adequate treatment and regardless of causality, the subject must be 
discontinued from treatment with radium-223 dichloride.

If a subject experiences sustained CTCAE Grade 4 neutropenia (see
Table 6-1) lasting > 1 week despite adequate treatment and regardless of 
causality, the subject must be discontinued from treatment with radium-223 
dichloride. 
Section 6.4.7 Dose delays 
1st paragraph:
Old text:
If a subject experiences any non-hematological CTCAE (version 4.03) Grade 4 
toxicity lasting more than 7 days despite adequate treatment, further study drug 
administration must be discontinued.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 230 of 291
New text:
If a subject experiences any non-hematological CTCAE (version 4.03) Grade 4 
toxicity regardless of causality lasting more than 7 days despite adequate 
treatment, further study drug administration must be discontinued.
Change 16:
Section 5.1 Eligibility
2nd paragraph:
Old text:
Rescreening of screen failed subjects is only allowed once after prior approval 
from the Bayer-designated medical representative.  Sponsor approval of 
rescreening for a screen failed subject will be provided by written confirmation to 
the site.  For these subjects who underwent screening procedures (i.e., scans and 
laboratory work) and cannot meet eligibility within the screening period (14 ± 7 
days) due to logistical circumstances, screening procedures may need to be 
repeated.  At the time of rescreening, all expired procedures must be repeated and 
be within 14 ± 7 days prior to randomization.  A maximum window of 35 days is 
permitted from signing the informed consent form (ICF) to randomization.
New text:
Rescreening of screen failed subjects is only allowed once after prior approval 
from the Bayer-designated medical representative.  Sponsor approval of 
rescreening for a screen failed subject will be provided by written confirmation to 
the site.  For these subjects who underwent screening procedures (i.e., scans and 
laboratory work) and cannot meet eligibility within the screening period (14 ± 7 
days) due to logistical circumstances, screening procedures may need to be 
repeated.  At the time of rescreening, all expired procedures must be repeated and 
be within 14 ± 7 days prior to randomization.  The maximum period allowed for 
screening will be 35 days (14 days screening + 7 day window + 14 days for 
rescreening).
Section 6.4.7 Dose delays, Logistical difficulties
1st and 3rd paragraphs:
Old text:
Screening to Dose 1: An additional 14 days will be permitted for the 14-day 
screening window for ‘failed’ quality of investigational product that requires 
replacement or extraordinary logistical issues.  Prior written approval by the 
sponsor designee is required and screening assessments may need to be repeated 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 231 of 291
to be within the 14 (± 7)-day window prior to randomization.  The maximum 
period allowed for screening will be 35 days. 
Doses 2 to 6 (or Doses 2 to 12 for Treatment Arm C): An additional 28 days will 
be permitted for Doses 2 to 6 (or Doses 2 to 12 for Treatment Arm C) for ‘failed’ 
quality of investigational product that requires replacement or extraordinary 
logistical issues.  Prior written approval by the sponsor designee is required.
A dose delay of more than 4 weeks (maximum of 8 weeks [± 7 days] between 2 
injections) will lead to study drug discontinuation.
New text:
Screening to Dose 1: An additional 14 days will be permitted for the 14-day 
screening window for ‘failed’ quality of investigational product that requires 
replacement or extraordinary logistical issues.  Prior written approval by the 
sponsor designee is required and screening assessments may need to be repeated 
to be within the 14 (± 7)-day window prior to randomization.  The maximum 
period allowed for screening will be 35 days (14 days screening + 7-day window 
+ 14 days for rescreening). 
Doses 2 to 6 (or Doses 2 to 12 for Treatment Arm C): An additional 28 days will 
be permitted for Doses 2 to 6 (or Doses 2 to 12 for Treatment Arm C) for ‘failed’ 
quality of investigational product that requires replacement or extraordinary 
logistical issues.  Prior written approval by the sponsor designee is required.
A dose delay of more than 4 weeks (maximum of 8 weeks between 2 injections) 
will lead to study drug discontinuation.
Change 17:
Section 7.1.2.1 Screening period
15th paragraph:
Old text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), and whole body technetium-99 bone 
scan will be performed within 14 ± 7 days of screening (i.e., during the 
screening period).  If MRI / CT scan of the abdomen and pelvis, and chest 
X-ray performed within 8 weeks of randomization are available, they do not 
need to be repeated at baseline. 
New text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 232 of 291
confirm and characterize the lesion[s]), and whole body technetium-99 bone 
scan will be performed within 14 ± 7 days prior to randomization (i.e., during 
the screening period).  If MRI / CT scan of the abdomen and pelvis, and chest 
X-ray performed within 8 weeks of randomization are available, they do not 
need to be repeated at baseline. 
Change 18:
Section 7.1.1 Tabulated overview
Footnote h:
Old text:
Body weight should be obtained without shoes, using a calibrated electronic 
physician (column) scale with digital display, measurement units 0.1 kg.  The 
same scale should be used for a given subject throughout the study.  At all sites (in 
US and outside US), weight is to be taken only once for each dose.  For non-US 
sites and US sites not using the central PRD depot, the weight should be 
performed within 72 hours prior to dosing.  For US sites using the central PRD 
depot ONLY, subject weight for the dose day should be obtained at the site within 
3 to 5 days prior to the dose visit.  This weight must be reported to the country 
PRD depot to allow adequate time for PRD preparation and delivery 
(approximately 2 days).  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.  Please note this is applicable to all dosing visits.
New text:
Body weight should be obtained without shoes, using a calibrated electronic 
physician (column) scale with digital display, measurement units 0.1 kg.  The 
same scale should be used for a given subject throughout the study.  At all sites (in 
US and outside US), weight is to be taken only once for each dose.  For non-US 
sites, the weight should be performed within 72 hours prior to dosing.  For US 
sites, subject weight for the dose day should be obtained at the site within 3 to 5 
days prior to the dose visit.  This weight must be reported to the country PRD 
depot to allow adequate time for PRD preparation and delivery (approximately 2 
days).  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.  Please 
note this is applicable to all dosing visits.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 233 of 291
Section 7.1.2.1 Screening period, Section 7.1.2.3 Initial visit - Dose 1, Day 1 (Treatment 
arms A, B, C), Section 7.1.2.4 Doses 2 to 6 (Treatment arms A and B), Section 7.1.2.5 
Doses 2 to 12 (Treatment arm C), and Section 7.5.3.5 Body weight
Old text:

For non-US sites and US sites not using the central PRD depot, the weight 
should be performed within 72 hours prior to dosing.
New text:

For non-US sites, the weight should be performed within 72 hours prior to 
dosing.
Change 19:
Synopsis – Methodology and Section 4.1 Design Overview
3rd paragraph:
Old text:
The treatment period begins at the time of randomization.  During the treatment 
period, study medication is administered every 28 days (± 7 days) from Dose 1 
and may be delivered in an outpatient setting.  At each visit, prior to receiving 
radium 223 dichloride, the subject will be evaluated for adverse events (AEs) and 
laboratory abnormalities to determine whether it is safe to continue treatment.
New text:
The treatment period for efficacy purposes begins at the time of randomization.  
During the treatment period, study medication is administered every 28 days (± 
7 days) from Dose 1 and may be delivered in an outpatient setting.  At each visit, 
prior to receiving radium 223 dichloride, the subject will be evaluated for adverse 
events (AEs) and laboratory abnormalities to determine whether it is safe to 
continue treatment.
Section 7.1.1 Tabulated overview
Footnote l:
Old text:
l.
The randomization will be permuted-block, stratified by the use of prior 
chemotherapy (≤1 regimen versus > 1 regimen), by total alkaline phosphatase 
(< 220 U/L versus ≥220 U/L), and by average WPS of the BPI-SF (WPS ≤4 
versus WPS > 4).  This assessment will occur when the second call is made to 
the IVRS / IWRS to order drug: ≥ 10 to 14 days prior to study treatment 
administration.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 234 of 291
New text:
l.
The randomization will be permuted-block, stratified by the use of prior 
chemotherapy (≤1 regimen versus > 1 regimen), by total alkaline phosphatase 
(< 220 U/L versus ≥220 U/L), and by average WPS of the BPI-SF (WPS ≤4 
versus WPS > 4).  Treatment group assignment will occur when the subject is 
randomized via IVRS / IWRS; this randomization step at up to 28 days prior 
to Dose 1.  Randomization steps triggers an order for study drug (durations 
vary based on country specific ordering lead times; US depot requires 
additional step).
Section 7.1.2.2 Randomization
1st paragraph:
Old text:
Subjects will be randomized to either: radium-223 dichloride 50 kBq/kg IV every 
28 days for up to 6 doses or radium-223 dichloride 80 kBq/kg IV every 28 days up 
to 6 doses or radium-223 dichloride 50 kBq/kg IV every 28 days up to 12 doses.  
The randomization will be permuted-block, stratified by the use of prior 
chemotherapy (≤1 regimen versus > 1 regimen), by total ALP (< 220 U/L versus 
≥ 220 U/L), and by the average of the daily WPS of the screening BPI-SF (WPS 
≤4 versus WPS > 4).  This assessment will occur when the second call is made to 
the IVRS / IWRS to order drug ≥10 to 14 days prior to study treatment 
administration.
New text:
The treatment period for efficacy purposes begins at the time of randomization.  
Subjects will be randomized to either: radium-223 dichloride 50 kBq/kg 
(55 kBq/kg after new NIST standard implementation) IV every 28 days for up to 6 
doses or radium-223 dichloride 80 kBq/kg (88 kBq/kg after implementation of 
NIST update) IV every 28 days up to 6 doses or radium-223 dichloride 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) IV every 28 days up to 12 
doses.  The randomization will be permuted-block, stratified by the use of prior 
chemotherapy (≤1 regimen versus > 1 regimen), by total ALP (< 220 U/L versus 
≥220 U/L), and by the average of the daily WPS of the screening BPI-SF (WPS 
≤4 versus WPS > 4).  Treatment group assignment will occur when the subject is 
randomized via IVRS / IWRS; this randomization step at up to 28 days prior to 
Dose 1.  Randomization step triggers an order for study drug (durations vary 
based on country specific ordering lead times; US depot requires additional step).


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 235 of 291
Section 8.4.4 Safety Analysis 
5th paragraph
Added text:
The treatment period for safety purposes for this study extends from the initiation 
of treatment until 30 days after the last administration of radium-223 dichloride.  
Events starting or worsening within the treatment period will be considered 
treatment-emergent.
Change 20:
Section 7.1.2.4 Doses 2 to 6 (Treatment Arms A and B)
Old text:

Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in the 
presence of suspicious lesion[s], a chest CT scan will be performed to confirm and 
characterize the lesion[s]), and whole body technetium-99 bone scan will be 
performed at 8 weeks and 16 weeks after the start of treatment (i.e., on Dose 3 and 
Dose 5 visits)
New text:
Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray 
(in the presence of suspicious lesion[s], a chest CT scan will be performed to 
confirm and characterize the lesion[s]), and whole body technetium-99 bone 
scan will be performed at Week 8, Week 16, Week 24, then every 12 weeks for 
2 years after the subject’s last dose of radium-223 dichloride or until radiologic 
progression.
Section 7.1.2.5 Doses 2 to 12 (Treatment Arm C)
Old text:
Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in 
the presence of suspicious lesion[s], a chest CT scan will be performed to confirm 
and characterize the lesion[s]), and whole body technetium-99 bone scan will be 
performed at 8 weeks, 16 weeks, 24 weeks and 36 weeks after the start of 
treatment (i.e., on Dose 3, 5, 7 and 10 Visits).
New text:
Tumor assessment by MRI / CT scan of the abdomen and pelvis, chest X-ray (in 
the presence of suspicious lesion[s], a chest CT scan will be performed to confirm 
and characterize the lesion[s]), and whole body technetium-99 bone scan will be 
performed at Week 8, Week 16, Week 24, then every 12 weeks for 2 years after 
the subject’s last dose of radium-223 dichloride or until radiologic progression.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 236 of 291
Change 21:
Section 7.5.1.3 Assessments and documentation of adverse events: 
2nd paragraph:
Old text:
A laboratory test abnormality should be reported as an AE if it is considered 
clinically relevant (e.g., causing the subject to withdraw from the study), requires 
treatment, causes apparent clinical manifestations, or is judged as relevant by the 
investigator.  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, possibly alternative 
factors (co-morbidities, co-medications), therapeutic action taken, result of 
therapeutic action, and ultimate outcome of the AE.  The investigator’s 
assessment of AEs and laboratory results with grades and causality assessments 
must be documented and retained in the source documentation.
New text:
A laboratory test abnormality should be reported as an AE if it is considered 
clinically relevant (e.g., causing the subject to withdraw from the study), requires 
treatment, causes apparent clinical manifestations, or is judged as relevant by the 
investigator.  Laboratory abnormalities that are not considered clinically 
significant do not need to be entered as an AE. Laboratory abnormalities related to 
the disease under study (e.g. PSA, testosterone) do not need to be recorded as 
AEs.   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, possibly alternative 
factors (co-morbidities, co-medications), therapeutic action taken, result of
therapeutic action, and ultimate outcome of the AE.  The investigator’s 
assessment of AEs and laboratory results with grades and causality assessments 
must be documented and retained in the source documentation.
Change 22:
Section 6.2 Identity of study treatment: 
2nd paragraph:
Old text:
The product is manufactured for Bayer in cooperation with contract partner Algeta 
ASA, Norway. The product is produced according to Good Manufacturing 
Practice (GMP).  The product will be delivered in a glass vial, ready-to-use with a 
certified activity.  Radium-223 dichloride is shipped in a lead container and Type 
A radioactive package according to international transportation guidelines for 
radioactive materials.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 237 of 291
New text:
The product is manufactured by Institute for Energy Technology (IFE), Isotope 
laboratories Instituttveien 18,NO-2007, Kjeller, Norway on behalf of Bayer AS, 
Kjelsäsveien 172 A, N0-0884 Oslo, Norway. The product is produced according 
to Good Manufacturing Practice (GMP).  The product will be delivered in a glass 
vial, ready-to-use with a certified activity.  Radium-223 dichloride is shipped in a 
lead container and Type A radioactive package according to international 
transportation guidelines for radioactive materials.
Change 23
Section 7.3.1 Efficacy variables
7th bullet:
Deleted text:
Change in analgesic use
Section 7.3.1 Efficacy variables
11th, 12th, 13th, 14th, 15th bullet points
Added text:
Increase in analgesic use rate
Time to increase in pain management
Pain improvement without increase in analgesic use rate
Time to pain progression or increase in analgesic use
Change in last 24-hour analgesic use score
Section 7.3.4.4 Pain endpoints
4th and 5th paragraph
Old text:
For purposes of determining pain improvement and pain progression, a daily 
analgesic use score will be calculated programmatically for each subject for each 
day, based on the subject’s complete CRF data on analgesic use.  Analgesic use 
data will be coded using the WHO drug dictionary.  Oral morphine equivalents 
(OMEs) will be calculated.  Each day’s analgesic use in OME units will be 
calculated using the applicable CRF-reported dates and date ranges.  The AQA 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 238 of 291
will be applied to obtain a daily analgesic use score.  Details will be described in 
the SAP. 
Additional details on pain endpoints, including details on the applicable baselines, 
evaluability for daily analgesic use increase, calculation of daily analgesic use 
score(s) applicable to each baseline and post-baseline time point, and definition of 
baseline values and “increase” in daily analgesic use for purposes of these 
endpoints, will be provided in the SAP.
New text:
Additional details on pain endpoints will be provided in the SAP.
Section 7.3.4.4.1 Pain improvement rate
1st paragraph
Old text:
Pain improvement is defined for each baseline in subjects evaluable for pain 
improvement at that baseline, i.e., subjects entering the study with a WPS of at 
least 4 and evaluable for analgesic use increase at the respective baseline 
assessment.  Pain improvement with respect to each baseline is defined in each 
applicable evaluable subject at each applicable post-baseline assessment time 
point as a 30% and 2-point decrease in WPS over 2 consecutive measurements 
conducted at least 4 weeks apart, without an increase in analgesic use.
New text:
Pain improvement is defined for each baseline in subjects evaluable for pain 
improvement at that baseline, i.e., subjects entering the study with a WPS of at 
least 4 at the respective baseline assessment.  Pain improvement with respect to 
each baseline is defined in each applicable evaluable subject at each applicable 
post-baseline assessment time point as a 30% and 2-point decrease in WPS over 2 
consecutive measurements conducted at least 4 weeks apart.
Section 7.3.4.4.2 Time to pain progression
1st paragraph
Old text:
Pain progression is defined for each baseline in subjects evaluable for pain 
progression at the applicable baseline, i.e., subjects with a WPS of ≤7 at the
respective baseline assessment.  Pain assessments will occur daily for one week, 
beginning a week prior to each visit and including the day of the visit.  An 
evaluable pain assessment interval requires completion of a minimum of 4 out of 
7 daily questions.  Pain progression is defined as the occurrence of either a pain 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 239 of 291
increase or an increase in pain management with respect to the applicable 
baseline, whichever occurs first.
New text:
Pain progression is defined for each baseline in subjects evaluable for pain 
progression at the applicable baseline, i.e., subjects with a WPS of ≤7 at the 
respective baseline assessment.  Pain assessments will occur daily for one week, 
beginning a week prior to each visit and including the day of the visit.  An 
evaluable pain assessment interval requires completion of a minimum of 4 out of 
7 daily questions.  Pain progression is defined as the occurrence of a pain increase 
with respect to the applicable baseline.
Section 7.3.4.4.2 Time to pain progression
3rd paragraph
Deleted text:
An increase in pain management is defined as follows: 
For patients not on opioids at the applicable baseline, initiation of short or long-
acting opioid use for pain will constitute an increase in pain management.  For 
patients being treated with ≤600 OME (oral morphine equivalents) of opioids at 
the applicable baseline, an increase by 1 point in the daily AQA score and 
increase ≥ 50% in daily OMEs will constitute an increase in pain management.  
For patients being treated at the highest AQA level (> 600 OME/day) at the 
applicable baseline, an increase ≥ 50% in daily OMEs from that baseline will 
constitute an increase in pain management. 
Section 7.3.5.5 Exploratory pain and analgesic use endpoints
Added text:
For purposes of determining exploratory increase in analgesic use, pain 
improvement without an increase in analgesic use, and pain progression without 
an increase in analgesic use, a daily analgesic use score will be calculated 
programmatically for each subject for each day, based on the subject’s complete 
CRF data on analgesic use.  Analgesic use data will be coded using the WHO drug 
dictionary.  Oral morphine equivalents (OMEs) will be calculated.  Each day’s 
analgesic use in OME units will be calculated using the applicable CRF-reported
dates and date ranges.  The AQA will be applied to obtain a daily analgesic use 
score.  Details will be described in the SAP.
An increase in analgesic use is defined for each baseline in evaluable subjects, i.e.
subjects with a valid AQA analgesic use score at the applicable baseline, as 
follows:
For subjects not on opioids at the applicable baseline, initiation of short or long-
acting opioid use for pain will constitute an increase in analgesic use.  For subjects


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 240 of 291
being treated with ≤600 OME (oral morphine equivalents) of opioids at the 
applicable baseline, an increase by 1 point in the daily AQA score and increase 
≥50% in daily OMEs will constitute an increase in analgesic use.  For subjects
being treated at the highest AQA level (> 600 OME/day) at the applicable 
baseline, an increase ≥50% in daily OMEs from that baseline will constitute an 
increase in analgesic. 
Additional details on analgesic use endpoints, including details on the applicable 
baselines, evaluability for daily analgesic use increase, calculation of daily 
analgesic use score(s) applicable to each baseline and post-baseline time point, 
and definition of baseline values and “increase” in daily analgesic use for 
purposes of these endpoints, will be provided in the SAP.
7.3.5.5.1 Increase in analgesic use rate
Increase in analgesic use rate is defined for each applicable baseline as the number 
of subjects with an increase in analgesic use from that baseline, divided by the 
number of subjects evaluable for analgesic use at that baseline.
7.3.5.5.2 Time to Increase in analgesic use
Time to increase in analgesic use is defined for each applicable baseline for 
applicable subjects as the time (in days) from the respective baseline until 
occurrence of the first post-baseline increase in analgesic use pain progression 
event.  Subjects without increase in analgesic use as of the last applicable 
post-baseline assessment, whether or not surviving, will be censored at the last 
applicable post-baseline assessment.  Subjects with insufficient applicable 
baseline assessment(s) or without adequate post-baseline assessment(s) will be 
censored at the applicable baseline date.  Additional censoring and other details 
will be described in the SAP.
7.3.5.5.3 Pain improvement rate without increase in analgesic use 
Pain improvement without increase in analgesic use is defined for each baseline in 
subjects evaluable for both pain improvement and increase in analgesic use at that 
baseline, as defined in Section 7.3.4.4.1 and Section 7.3.5.5.1  respectively, at the 
applicable baseline assessment.  Pain improvement without increase in analgesic 
use is defined in each applicable evaluable subject at each applicable post-baseline 
assessment time point with respect to each baseline, as a 30% and 2-point 
decrease in WPS over 2 consecutive measurements conducted at least 4 weeks 
apart, without an increase in analgesic use. 
Pain improvement without increase in analgesic use rate is defined for each 
baseline and applicable post-baseline assessment time point as the number of 
subjects with pain improvement without increase in analgesic use at the time
point, divided by the total number of subjects evaluable for pain improvement 
without increase in analgesic use with respect to the applicable baseline. 
7.3.5.5.4 Time to pain progression or increase in analgesic use


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 241 of 291
Time to pain progression is defined for each baseline in subjects evaluable for 
both pain progression and increase in analgesic use, as defined in Section 7.3.4.4.2 
and 7.3.5.5.1 respectively, at the applicable baseline assessment, 
The time to pain progression or increase in analgesic use is defined for each 
applicable baseline for applicable subjects as the time (in days) from the 
respective baseline until occurrence of the first post-baseline pain progression 
(pain increase) event or increase in analgesic use event, whichever occurs first.  
Subjects with neither pain progression nor an increase in analgesic use as of the 
last applicable post-baseline assessment, whether or not surviving, will be 
censored at the last applicable post-baseline assessment.  Subjects not evaluable 
for both pain progression and increase in analgesic use, and subjects without 
adequate post-baseline assessment(s), will be censored at the applicable baseline 
date.  Additional censoring and other details will be described in the SAP. 
7.3.5.5.5 Change in the last 24-hour analgesic use score
Change in the last 24-hour analgesic use score is calculated based on the subject’s 
analgesic use in the last 24 hours CRF data. 
For each subject, each analgesic medication from analgesic use in the last 24 
hour’s data taken at applicable clinic visits (and in Arms A and B, at telephone 
contacts) will be coded using the WHO drug dictionary and OMEs will be 
calculated from the coded data. 
For each subject and applicable visit or telephone contact, analgesic use in the last 
24 hours will be scored using the AQA (see Section 14.9) based on the coded 
medications and corresponding OME quantities. 
Details on coding and scoring will described in the SAP. 
For each subject, for each applicable baseline and post-baseline time point, the 
subject’s change in the last 24-hour analgesic use is defined as the difference 
between the subject’s last 24 hour AQA score at the post-baseline time point and 
at the applicable baseline. 
Change 24
Title page, Synopsis: Title, Synopsis: Study Objectives, Synopsis: Doses, Synopsis: 
Methodology, Synopsis: Plan for statistical analysis, Section 1.2 Study rationale, Section 
2. Study objectives, Section 4.1 Design overview, Section 6.1 Treatments to be 
administered, Section 6.3 Treatment assignment, Section 6.4.3 Dose calculation, Section 
7.1.2.2 Randomization, Section 8.1 General considerations, Section 8.4.1 Primary efficacy 
analysis, Section 8.4.4 Safety analyses, Section 8.6 Determination of sample size
Global Change
Old text:
50 kBq/kg


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 242 of 291
New text:
50 kBq/kg (55 kBq/kg after implementation of NIST update)
Old text:
80 kBq/kg
New text:
80 kBq/kg (88 kBq/kg after implementation of NIST update)
Section 6.2 Identity of study treatment
1st Paragraph and 3rd paragraph 
Old text:
The alpha particle-emitting radiopharmaceutical, radium-223 dichloride, is a 
ready-to-use, sterile, non-pyrogenic, clear and colorless aqueous solution of 
radium-223 dichloride for IV administration.  Radium-223 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 
1,000 kBq/mL.  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.
The volume per vial is 6 mL, corresponding to 6 MBq at the reference day.  
Radium-223 dichloride has a shelf life of 28 days from production day, when 
stored at ambient temperature.  The shelf life has been demonstrated for 
temperatures from cold storage (2ºC to 8°C) up to 40°C.  In addition, it has been 
shown that the product quality is not jeopardized upon freezing.  For the US, study 
drug may be forwarded to the country depot in vials, where it will be prepared as a 
patient ready dose ([PRD], in a syringe) before being delivered to the site.
New text:
The alpha particle-emitting radiopharmaceutical, radium-223 dichloride, is a 
ready-to-use, sterile, non-pyrogenic, clear and colorless aqueous solution of 
radium-223 dichloride for IV administration.  Radium-223 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 
1,000 kBq/mL (1,100 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.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 243 of 291
The volume per vial is 6 mL, corresponding to 6 MBq (6.6 MBq after 
implementation of NIST update) at the reference day.  Radium-223 dichloride has 
a shelf life of 28 days from production day, when stored at ambient temperature.  
The shelf life has been demonstrated for temperatures from cold storage (2ºC to 
8°C) up to 40°C.  In addition, it has been shown that the product quality is not 
jeopardized upon freezing.  For the US, study drug may be forwarded to the 
country depot in vials, where it will be prepared as a patient ready dose ([PRD], in 
a syringe) before being delivered to the site.
Section 6.4.1 Dose calibration
3rd Paragraph:
Added text:
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 current NIST standard for radium-223 dichloride 
(NIST 2010 [31]) will remain in effect for this protocol until all Health 
Authorities for which Bayer holds a marketing application for radium-223 
dichloride have approved the regulatory variations for Xofigo®, anticipated Q2 
2016. All sites will be notified by Bayer when regulatory approvals are in place 
and the updated NIST standardization is to be implemented.  Upon notification, 
and prior to the implementation, all sites will need to add a new dial-setting to 
their dose calibrators for the new NIST standardization for radium-223 dichloride 
(NIST update [32]), which should be documented on the appropriate study forms.  
This step will be performed so that all sites will have the new dial setting (NIST 
update [32]) in place at the time of implementation.  The current dial setting 
(NIST 2010 [31]) will be used until the worldwide global implementation date 
anticipated for Q2 2016.
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 
patients 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.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 244 of 291
Section 6.4.3 Dose calculation
1st Paragraph
Old text:
Body Weight (kg) x 50 or 80 kBq/kg
= volume to be injected (mL)
DK x 1,000 kBq/mL
New text:
Body Weight (kg) x 50 kBq/kga
= volume to be injected (mL)
DK x 1,000 kBq/mLb
a 55 kBq/kg after implementation of NIST update 
b 1100 kBq/mL after implementation of NIST update 
Added text:
For high dose treatment arm:
Body Weight (kg) x 80 kBq/kgc
= volume to be injected (mL)
DK x 1,000 kBq/mLb
c 88 kBq/kg after implementation of NIST update 
b 1100 kBq/mL after implementation of NIST update 
Section 12. Reference list
Added text:
31. Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid 
scintillation counting. Appl Radiat Isot. 2010;68(7-8):1523-8.
32. 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 per section 12
Change 25
List of abbreviations
Added text:
CKD-EPI
Chronic kidney disease epidemiology
CRF
Complete report form
eGFR
Estimated Glomerular
IDMS
Isotope Dilution Mass Spectrometry


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 245 of 291
NIST
National Institute of Standards and Technology
SI
International System of Units
WHO
World Health Organization
Change 26
Synopsis: Study objectives, Synopsis: Methodology, Section 2. Study objectives, Section 
4.1 Design overview, Section 6.4.1 Dose calibration, Section 6.4.4 Dose preparation, 
Section 7.2.4 Body-size descriptors, Section 7.3.4.4.2 Time to pain progression, Section 
7.3.5.5 Exploratory pain and analgesic use endpoints
Global Change
Old text:
patient
New text:
subject
Change 27
7.1 Schedule of procedures
Old text:
h
Body weight should be obtained without shoes, using a calibrated electronic 
physician (column) scale with digital display, measurement units 0.1 kg.  The 
same scale should be used for a given subject throughout the study.  At all 
sites (in US and outside US), weight is to be taken only once for each dose.  
For non-US sites the weight should be performed within 72 hours prior to 
dosing.  For US sites, subject weight for the dose day should be obtained at the 
site within 3 to 5 days prior to the dose visit.  This weight must be reported to 
the country PRD depot to allow adequate time for PRD preparation and 
delivery (approximately 2 days).  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.  Please note this is applicable to all dosing visits.  
New text:
h
Body weight should be obtained without shoes, using a calibrated electronic 
physician (column) scale with digital display, measurement units 0.1 kg.  The 
same scale should be used for a given subject throughout the study.  At all 
sites (in US and outside US), weight is to be taken only once for each dose.  
For non-US sites the weight should be performed within 72 hours prior to 
dosing.  For US sites, subject weight for the dose day should be obtained at the 
site within 3 to 5 days prior to the dose visit.  This weight must be reported to 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 246 of 291
the country PRD depot to allow adequate time for PRD preparation and 
delivery (approximately 2 days).  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.  Please note this is applicable to all dosing visits.  
Body weight can be obtained at the local healthcare provider on a calibrated 
scale and the results sent by fax to the Principal Investigator with advanced 
notice and agreement from the Covance Medical Monitor for each subject.  No 
other procedures can be done at the local healthcare provider.
Section 7.5.3.5 Body weight
2nd bullet
Old text:
For US sites using the central PRD depot ONLY, subject weight for the dose 
day should be obtained at the site within 3 to 5 days prior to the dose visit.  
This weight must be reported to the country PRD depot to allow adequate time 
for PRD preparation and delivery (approximately 2 days).  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.  
New text:
For US sites using the central PRD depot ONLY, subject weight for the dose 
day should be obtained at the site within 3 to 5 days prior to the dose visit.  
This weight must be reported to the country PRD depot to allow adequate time 
for PRD preparation and delivery (approximately 2 days).  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.  Body weight can be 
obtained at the local healthcare provider on a calibrated scale and the results 
sent by fax to the Principal Investigator with advanced notice and agreement 
from the Covance Medical Monitor for each subject.  No other procedures can 
be done at the local healthcare provider.
Change 28
Section 6.9.2 Concomitant medication
3rd paragraph
Deleted text:
Injection of these therapies should be performed at least 2 hours before or after 
study drug administration.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 247 of 291
Change 29
Section 7.3.1 Efficacy variables
8th bullet 
Deleted text:
Bone scan lesion index
Section 7.3.5.1.2 Bone scan lesion index
Entire section
Deleted text:
7.3.5.1.2
Bone scan lesion index
Bone scan lesion intensity is defined for each subject at the screening baseline and 
each subsequent radiological assessment time point, as the mean normalized 
intensity of the set of technetium-99 pixels identified as bone lesion (sum of the 
pixel intensities divided by the total number of bone lesion pixels) based on 
central review.
Change 30
Synopsis: Secondary objectives, 2. Study objectives
9th bullet
Deleted text:
To evaluate change in analgesic use as measured by the Analgesic Quantification 
Algorithm (AQA)
Synopsis: Exploratory objectives, 2. Study objectives
5th bullet
Added text:
To evaluate change in analgesic use as measured by the Analgesic Quantification 
Algorithm (AQA)
Primary / Secondary variables
10th bullet


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 248 of 291
Deleted text:
Change in analgesic use
Change 31
Section 6.4.7 Dose delays
12th paragraph
Old text:
Any other toxicity:
If a subject experiences any non-hematological CTCAE (version 4.03) Grade 4 
toxicity regardless of causality lasting more than 7 days despite adequate 
treatment, further study drug administration must be discontinued.
New text:
Any other adverse event:
If a subject experiences any non-hematological CTCAE (version 4.03) Grade 4 
adverse event regardless of causality lasting more than 7 days despite adequate 
treatment, further study drug administration must be discontinued.
Change 32
Synopsis: Background treatment / concomitant medications / prohibited therapies,
Synopsis: Diagnosis and main criteria for exclusion, Section 5.1.2 Exclusion criteria, 
Section 5.2.1 Withdrawal, Section 6.4.7 Dose Delays, Section 6.9.1 Prior therapy, Section 
6.9.2 Concomitant medication, Section 7.1.2.4 Doses 2 to 6 (Treatment Arms A and B), 
Section 7.1.2.5 Doses 2 to 12 (Treatment Arm C), Section 7.1.2.7.2 Active follow-up 
without scheduled clinic visits
Global Change
Deleted text:
including standard doses of prohibited
Section 7.1.2.7.2 Active follow-up without scheduled clinic visits
1st paragraph
Old text:
This period starts when subjects can no longer travel to the clinic or if the subject 
receives further treatment with anticancer therapies during the follow-up period, 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 249 of 291
including standard doses of prohibited cytotoxic chemotherapy for prostate 
cancer, including taxanes, estramustine, and mitoxantrone, other systemic 
radioisotopes (samarium-153, strontium-89, rhenium-186, or rhenium-188), 
hemibody EBRT, or other investigational drugs.  Subjects who cannot travel to the 
clinic will be contacted by telephone every 12 weeks (± 14 days) for 2 years 
following the last study treatment to determine the following:
New text:
This period starts when subjects can no longer travel to the clinic or if the subject 
receives further treatment with any of the following anticancer therapies during 
the follow-up period: cytotoxic chemotherapy for prostate cancer, including 
taxanes, estramustine, and mitoxantrone, other systemic radioisotopes (samarium-
153, strontium-89, rhenium-186, or rhenium-188), hemibody EBRT, or other 
investigational drugs.  Subjects who cannot travel to the clinic will be contacted 
by telephone every 12 weeks (± 14 days) for 2 years following the last study 
treatment to determine the following:
Change 33
Section 3. Investigators and other study personnel
2nd paragraph
Added text:
Study Medical Expert for the study:
Milano V.le Certosa 210
20156 Milano – Italia
Phone: 
Change 34
Section 5.1 Eligibility
1st paragraph
Old text:
Eligibility should be confirmed within 14 (± 7) days of randomization.  At Dose 1, 
Day 1, the hematology values need to be confirmed to be within the treatment 
ranges (absolute neutrophil count [ANC] ≥1.5 x 109/L, platelet count ≥100 x 
109/L, and hemoglobin ≥9.0 g/dL) prior to dosing.
PPD
PPD


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 250 of 291
Rescreening is not permitted in cases in which the initial laboratory test results do 
not support eligibility.
New text:
Eligibility should be confirmed within 14 (± 7) days prior to randomization.  At 
Dose 1, Day 1, the hematology values need to be confirmed to be within the 
treatment ranges (absolute neutrophil count [ANC] ≥1.5 x 109/L, platelet count 
≥100 x 109/L, and hemoglobin ≥9.0 g/dL) prior to dosing.
Rescreening is not permitted in cases in which the initial safety laboratory test 
results do not support eligibility.
Section 7.1.2.1 Screening period
16th bullet, 1st subbullet
Old text:
o
If standard of care bone scan within 8 weeks of randomization is available, 
they do not need to be repeated at baseline.  If they are not available, they
should be performed within 14 ± 7 days of randomization (i.e., during the 
screening period).
New text:
o
If standard of care bone scan within 8 weeks of randomization is available, the 
scan does not need to be repeated at baseline.  If this scan is not available, the 
scan should be performed within 14 ± 7 days prior to randomization (i.e., 
during the screening period).
Change 35
Section 8.2 Analysis Sets
2nd paragraph
Added text:
Week 24 (W24): All ITT subjects in Arm A (standard dose) and Arm C (extended 
dosing) treated with radium-223 dichloride, and eligible for further treatment at 
W24. The Week 24 dataset will be used for the analysis of efficacy endpoints 
related to Comparison 2 and associated evaluations.  Subjects will be included in 
W24 analyses according to the treatment to which they were randomized.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 251 of 291
Change 36
Synopsis:  Plan for statistical analysis
8th paragraph
Old text:
The hazard ratio (high dose / standard dose) will be computed together with 
2-sided 80% and 95% confidence intervals using a stratified Cox regression model 
with treatment as a factor and previous chemotherapy [≤1 regimen versus > 1 
regimen] and total ALP [< 220 U/L versus ≥220 U/L] as strata in the model for 
the ITT population.  Kaplan-Meier survival distribution tables and plots will also 
be produced for both Treatment Arms A and B.  Additional details will be 
provided in the statistical analysis plan.
New text:
The hazard ratio (high dose / standard dose) will be computed together with 
2-sided 80% and 95% confidence intervals using a stratified Cox regression model 
with treatment as a factor and previous chemotherapy [≤1 regimen versus > 1 
regimen] and total ALP [< 220 U/L versus ≥220 U/L] as strata in the model for 
the ITT analysis set.  Kaplan-Meier survival distribution tables and plots will also 
be produced for both Treatment Arms A and B.  Additional details will be 
provided in the statistical analysis plan.
8.2 Analysis sets
1st and 3rd paragraph
Old text:
The following 2 populations will be defined:
Intent-to-treat (ITT): 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 were randomized.
Safety: All randomized subjects who have received at least one study drug 
administration.  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.
New text:
The following 3 analysis sets will be defined:


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 252 of 291
Intent-to-treat (ITT): All randomized subjects.  The ITT analysis set 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 were randomized.
Safety: All randomized subjects who have received at least one study drug 
administration.  This safety analysis set will be used in the analyses of all safety 
endpoints.  Subjects will be included in the analyses according to the treatment 
they received.
13.3
Amendment 3 
Description of the amendment
Amendment 3 is an amendment to the integrated protocol version 3.0 dated 13 AUG 2015.  
Changes to the protocol include:

Updated the protocol to reflect the recent Bayer AG legal entity name change.

Updated procedures for long-term follow-up.

Added an option for the study site to obtain information directly from the subject’s 
primary health care professional or caregiver.

Updated the study Global Clinical Leader and study medical expert names.

Updated analysis for Comparison 2 from 24 weeks to the 6th dose.

Revised the definition for consistency across the radium-223 program.

Deleted text for central reviewer as responsible party to determine baseline values and 
assess radiological progression.
13.3.1 Overview of changes
Change 1:
Updated the protocol to reflect the recent Bayer AG legal entity name change
Sections affected:

Headers

Title Page:  Sponsor
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 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 253 of 291
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.
Change 2:
Updated procedures for long-term follow-up
Sections affected:

Synopsis-Methodology

4.1 Design overview

5.1 Withdrawal

6.8 Post-study therapy

7.1.1 Tabulated overview

7.1.2.8.1 End of active follow-up with clinic visits

7.1.2.8.2 End of active follow-up without scheduled clinic visits

7.1.2.9 Long-term follow-up to 7 years following last dose

7.1.2.9.1 Long-term follow-up (via telephone follow-up)

10 Premature termination of the study
Rationale:  Updated long-term assessments specified in this protocol, to be consistent with 
current version of the long-term follow-up Study 16996 protocol.
Change 3: 
Added an option for the study site to obtain information directly from the subject’s primary 
health care professional
Section affected:

Synopsis-Methodology

4.1 Design overview

6.8 Post-study therapy

7.1.1 Tabulated overview

7.1.2.7.1 Active follow-up with clinic visits

7.1.2.7.2 Active follow-up without scheduled clinic visits

7.1.2.8.1 End of active follow-up with clinic visits

7.1.2.8.2 End of active follow-up without scheduled clinic visits

7.1.2.9 Long-term follow-up to 7 years following last dose


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 254 of 291

7.1.2.9.1 Long-term follow-up (via telephone follow-up)

10 Premature termination of the study
Rationale:  Provides the option for sites to collect study data directly from subject’s health 
care professionals or caregiver in case the subject or his/her care provider is unable to provide 
information or to obtain cleaner data.
Change 4:
Updated the study Global Clinical Leader and study medical expert names
Sections affected:

Title page

Signature of the sponsor’s medically responsible person

3. Investigators and other study personnel
Rationale: Change reflects the current medical expert and protocol signatory.
Change 5:
Updated analysis for Comparison 2 from 24 weeks to 6th dose date
Sections affected included:

Synopsis-Study objectives

Synopsis-Plan for statistical analysis

2.0 Study objectives

4.4 End of study

7.3.2 Definition of efficacy variables

7.3.5.6 Additional pain and health related quality of life endpoints

8.2 Analysis sets

8.4.1 Primary efficacy analysis

8.4.2.2 Analyses of standard dosing and extended dosing from the 6th dose date

8.6 Determination of sample size
Rationale: The ‘Week 24 baseline value’ is defined as the last non-missing value on or 
before the date of the 6th injection. Ideally, this visit would be the date of the 7th injection for 
Arm C subjects and expected 7th injection date for Arm A subjects. However, the end of 
treatment visit (30±7 days from last dose) for Arm A subjects could be missing due to 
consent withdrawal or happen out of visit window. Hence, there is no comparable visit for 
Arm A subjects that could be used as the expected 7th injection date. To account for this and 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 255 of 291
achieve comparability between the two arms, the 6th injection date is used as the reference 
date for Comparison 2 subjects.
Change 6:
Updated text for consistency
Sections affected included:

7.3.5.2 Time to increase in physical symptoms of disease based on FPSI-DRS-P

7.3.5.3.1 Total alkaline phosphatase response rate

7.3.5.3.2 Time to total alkaline phosphatase progression

7.3.5.4.1 Prostate specific antigen response rate

7.3.5.4.2 Time to prostate specific antigen progression
Rationale:  Revised the definition for consistency across the radium-223 program.
Change 7:
Deleted text for central reviewer as responsible party to determine baseline values and assess 
radiological progression.
Sections affected included:

7.3.4.3 Radiological progression endpoints
Rationale:  Re-baselining after 6 injections was considered at study start; hence the sentence 
regarding the central reviewer’s responsibility to determine the applicable baseline was 
included in the protocol. As re-baselining was never implemented in the study and was never 
included in the Central Review Charter, the sentence was removed from the protocol.
13.3.2 Changes to the protocol text
Change 1:
Header
Old text: 
Integrated Clinical Study Protocol
No.  16507
03 SEP 2014
Version 3.0
Page:  255 of 291
New text: 
Integrated Clinical Study Protocol
BAY 88-8223 / 16507
Dd Mmm yyyy   
Version 4.0
Page: 255 of 291


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 256 of 291
Title page: Sponsor
This section was changed as a result of Modification 1.
Old text:
Bayer HealthCare AG, D-51368 Leverkusen, Germany
New text:
(Non-US): Bayer AG, D-51368 Leverkusen, Germany
(US territory): Bayer HealthCare Pharmaceuticals Inc., 100 Bayer Boulevard, P.O. Box 915, 
Whippany, NJ 07981-0915, USA
Change 2 and Change 3:
Synopsis – Methodology, 6.8 Post-study therapy, 7.1.2.8.1 End of active follow-up with 
clinic visits, 7.1.2.8.2 End of active follow-up without scheduled clinic visits, 10 Premature 
termination of the study
Old text:
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported, radium-223 dichloride-related AEs and serious AEs, hematologic 
toxicity (e.g., myelosuppression / myelofibrosis / bone marrow aplasia), new primary 
malignancies, including leukemias and solid tumors, and survival for up to 7 years after last 
dose of radium-223 dichloride or until death.  During long-term follow-up, subjects will be 
contacted every 6 months by telephone.  All subjects who transition into this separate long-
term follow-up study will require a separate signed informed consent.
New Text:
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported, radium-223 dichloride-related AEs and serious AEs, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new 
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death.  During long-term follow-up, subjects, their 
treating health care professional, or caregiver will be contacted every 6 months by telephone.  


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 257 of 291
All subjects who transition into this separate long-term follow-up study will require a 
separate signed informed consent.  Subject data collected at other standard-of-care visits and /
or contacts may be used to satisfy study-required data.
4.1 Design Overview
Old text:
Active follow-up period with clinic visits:
Subjects who discontinue study treatment and who did not have an SSE will enter an active 
follow-up period with clinic visits.  These subjects will be evaluated every 12 weeks 
(± 7 days) for pain endpoints, radiological progression, SSEs, survival, treatment-related AEs 
and serious adverse events (SAEs), and the initiation of other anti-cancer therapies.  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.  During this period, 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.
New text:
Active follow-up period with clinic visits:
Subjects who discontinue study treatment and who did not have an SSE will enter an active 
follow-up period with clinic visits.  These subjects will be evaluated every 12 weeks 
(± 7 days) for pain endpoints, radiological progression, SSEs, survival, treatment-related AEs 
and serious adverse events (SAEs), and the initiation of other anti-cancer therapies for 
prostate cancer, and cytotoxic chemotherapy and radiotherapy for any new malignancy.  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.  During this period, 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.
Old text:
Active follow-up period without clinic visits:
Subjects from the treatment period or the active follow-up period with clinic visits who can 
no longer travel to the clinical site will be followed for survival, treatment-related AEs and 
SAEs, SSEs, pain endpoints, and the initiation of other anti-cancer therapies with a phone call 
every 12 weeks (± 7 days).  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.  During this period, 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.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 258 of 291
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported radium-223 dichloride-related AEs and SAEs, hematologic toxicity 
(e.g., myelosuppression / myelofibrosis / bone marrow aplasia), new primary malignancies, 
including leukemias and solid tumors, and survival for up to 7 years after last dose of 
radium-223 dichloride or until death.  During long-term follow-up, subjects will be contacted 
every 6 months by telephone.  All subjects who transition into this separate long-term follow-
up study will require a separate signed informed consent.
New text:
Subjects from the treatment period or the active follow-up period with clinic visits who can 
no longer travel to the clinical site will be followed for survival, treatment-related AEs and 
SAEs, SSEs, pain endpoints, and the initiation of other anti-cancer therapies (for prostate 
cancer, and cytotoxic chemotherapy and radiotherapy for any new malignancy) with a phone 
call every 12 weeks (± 7 days).  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.  During this period, 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.
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported radium-223 dichloride-related AEs and SAEs, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new 
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death.  During long-term follow-up, subjects, their 
treating health care professional, or caregiver will be contacted every 6 months by telephone.  
All subjects who transition into this separate long-term follow-up study will require a 
separate signed informed consent.  Subject data collected at other standard-of-care visits and / 
or contacts may be used to satisfy study-required data.
5.2.1 Withdrawal
Old text:


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 259 of 291
For any subject who prematurely discontinues study treatment, the EOT assessments must be 
completed.  The subject will remain in the study throughout the follow-up period.  In all 
cases, the reason for discontinuation from study treatment must be recorded in the electronic 
case report form (eCRF) and in the source documentation.
New text:
For any subject who prematurely discontinues study treatment, the EOT assessments must be 
completed.  The subject will remain in the study throughout the follow-up period.  Any 
subject who withdraws from the study procedures but does not withdraw consent should enter 
active follow-up without clinic visits for survival assessment (see Section 7.1.2.8.2).  In all 
cases, the reason for discontinuation from study treatment must be recorded in the electronic 
case report form (eCRF) and in the source documentation.
7.1.1 Tabulated overview


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 260 of 291
Old text:
Table 7-1 Schedule of procedures (continued)
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term 
follow-up 
(up to 
7 years after 
last dose) 
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up 
to 7 years 
post-last dose
End of
Long-term 
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Record 
radium-223 
dichloride 
related 
AEs and 
SAEsgg
X
X
X
X
Record 
radium-223 
dichloride 
related 
SAEshh
X
X
b. Once a separate, extended safety follow-up protocol, for the inclusion of subjects who received radium-223 dichloride in the course 
of Bayer sponsored clinical studies, has been implemented, the study subjects surviving after the end of the 2 years of active follow-
up will be transitioned to this separate, extended safety follow-up protocol and the current study will be terminated at the time the last 
study subject is transitioned.


Integrated Clinical Study Protocol
No.  16507
28 MAR 2018
Version 5.0
Page: 261 of 291
New text:
Table 7-1  Schedule of procedures (continued)
Study Period
Screen
Treatment Arms A and B
Treatment Arm C
EOT 
Visit
Active
Follow-up (at least 
2 years after last dose)
Long-term 
follow-up 
(up to 
7 years after 
last dose) 
Visit
1
2
3
4
5
6
7
2
3
4
5
6
7
8
9
10
11
12
13
With 
clinic 
visitsa
Without 
scheduled 
clinic 
visitsa
Phone 
follow-upb
Dose
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
Frequency / 
Timing
Within 14 
days prior to 
randomc
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
0d
Day 1, Week 
4d
Day 1, Week 
8d
Day 1, Week 
12d
Day 1, Week 
16d
Day 1, Week 
20d
Day 1, Week 
24d
Day 1, Week 
28d
Day 1, Week 
32d
Day 1, Week 
36d
Day 1, Week 
40d
Day 1, Week 
44d
30 days 
post-last dose
q12 wkse
End of active 
visits
q12 wks
End of active 
visits
q6 months up 
to 7 years 
post-last dose
End of
Long-term 
follow-up
Window 
(days)
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±14
±14
±14
±14
±14
±14
Record 
chemotherapy 
for other 
malignancies
X
X
X
X
X
X
Record 
radium-223 
dichloride 
related AEs 
and SAEsgg
X
X
X
X
b. Subjects, their treating health care professional, or caregiver will be contacted every 6 months by telephone.  Once a separate, 
extended safety follow-up protocol, for the inclusion of subjects who received radium-223 dichloride in the course of Bayer 
sponsored clinical studies, has been implemented, the study subjects surviving after the end of the 2 years of active follow-up will be 
transitioned to this separate, extended safety follow-up protocol and the current study will be terminated at the time the last study 
subject is transitioned.  Subject data collected at other standard-of-care visits and / or contacts may be used to satisfy study-required 
data.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 262 of 291
7.1.2.7.1 Active follow-up with clinic visits
Added text:

Recording of cytotoxic chemotherapy and radiotherapy for any new primary malignancy
7.1.2.7.2 Active follow-up without scheduled clinic visits
Added text:

Recording of cytotoxic chemotherapy and radiotherapy for any new primary malignancy
7.1.2.8.1 End of active follow-up with clinic visits
Added text:

Recording of cytotoxic chemotherapy and radiotherapy for any new primary malignancy
Old text:
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported, radium-223 dichloride-related AEs and serious AEs, hematologic 
toxicity (e.g., myelosuppression / myelofibrosis / bone marrow aplasia), new primary 
malignancies, including leukemias and solid tumors, and survival for up to 7 years after last 
dose of radium-223 dichloride or until death.  During long-term follow-up, subjects will be 
contacted every 6 months by telephone.  All subjects who transition into this separate long-
term follow-up study will require a separate signed informed consent.
New text:
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported, radium-223 dichloride-related AEs and serious AEs, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new 
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death.  During long-term follow-up, subjects, their 
treating health care professional, or caregiver will be contacted every 6 months by telephone.  
All subjects who transition into this separate long-term follow-up study will require a 
separate signed informed consent.  Subject data collected at other standard-of-care visits and / 
or contacts may be used to satisfy study-required data.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 263 of 291
7.1.2.8.2 End of active follow-up without scheduled clinic visits
Added text:

Recording of cytotoxic chemotherapy and radiotherapy for any new primary malignancy
Old text:
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported, radium-223 dichloride-related AEs and serious AEs, hematologic 
toxicity (e.g., myelosuppression / myelofibrosis / bone marrow aplasia), new primary 
malignancies, including leukemias and solid tumors, and survival for up to 7 years after last 
dose of radium-223 dichloride or until death.  During long-term follow-up, subjects will be 
contacted every 6 months by telephone.  All subjects who transition into this separate long-
term follow-up study will require a separate signed informed consent.
New text:
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  The separate long-term follow-up study has 
been set up to follow subjects who received radium-223 dichloride or placebo in the course of 
Bayer-sponsored clinical trials.  The long-term follow-up study has a specific focus on 
investigator reported, radium-223 dichloride-related AEs and serious AEs, all occurrences of 
leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer or any other new 
primary malignancy, cancer treatment (including any systemic cytotoxic chemotherapy or 
radiotherapy for any malignancy; all systemic anti-cancer therapies for prostate cancer, 
including androgen synthesis inhibitors / androgen-receptor antagonists, systemic 
radioisotopes and radiation treatment; excluding analgesics), in subjects who receive 
cytotoxic chemotherapy: all occurrences of febrile neutropenia or hemorrhage during their 
chemotherapy treatment and for up to 6 months thereafter, and survival for up to 7 years after 
last dose of radium-223 dichloride or until death.  During long-term follow-up, subjects, their 
treating health care professional, or caregiver will be contacted every 6 months by telephone.  
All subjects who transition into this separate long-term follow-up study will require a 
separate signed informed consent.  Subject data collected at other standard-of-care visits and / 
or contacts may be used to satisfy study-required data.
7.1.2.9 Long-term follow-up to 7 years following last dose
Old text:
This period starts when subjects have completed the active follow-up period and ends 7 years 
after the last dose of radium-223 dichloride or when the subject dies.  All study subjects will 
be eligible for further follow-up either in this study or in a separate long-term follow-up study 
for up to 7 years.  The separate long-term follow-up study has been set up to follow subjects 
who received radium-223 dichloride or placebo in the course of Bayer-sponsored clinical 
trials.  The long-term follow-up study has a specific focus on investigator reported radium-
223 dichloride-related AEs and SAEs, hematologic toxicity (e.g., myelosuppression / 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 264 of 291
myelofibrosis / bone marrow aplasia), new primary malignancies, including leukemias and 
solid tumors, and survival for up to 7 years after last dose of radium-223 dichloride or until 
death.  During long-term follow-up, subjects will be contacted every 6 months by telephone.  
All subjects who transition into this separate long-term follow-up study will require a 
separate signed informed consent.
New text:
This period starts when subjects have completed the active follow-up period and ends 7 years 
after the last dose of radium-223 dichloride or when the subject dies.  All study subjects will 
be eligible for further follow-up either in this study or in a separate long-term follow-up study 
for up to 7 years.  The separate long-term follow-up study has been set up to follow subjects 
who received radium-223 dichloride or placebo in the course of Bayer-sponsored clinical 
trials.  The long-term follow-up study has a specific focus on investigator reported radium-
223 dichloride-related AEs and SAEs, all occurrences of leukemia, myelodysplastic 
syndrome, aplastic anemia, primary bone cancer or any other new primary malignancy, 
cancer treatment (including any systemic cytotoxic chemotherapy or radiotherapy for any 
malignancy; all systemic ant-cancer therapies for prostate cancer, including androgen 
synthesis inhibitors / androgen-receptor antagonists, systemic radioisotopes and radiation 
treatment; excluding analgesics), in subjects who receive cytotoxic chemotherapy: all 
occurrences of febrile neutropenia or hemorrhage during their chemotherapy treatment and 
for up to 6 months thereafter, and survival for up to 7 years after last dose of radium-223 
dichloride or until death.  During long-term follow-up, subjects, their treating health care 
professional, or caregiver will be contacted every 6 months by telephone.  All subjects who 
transition into this separate long-term follow-up study will require a separate signed informed 
consent.  Subject data collected at other standard-of-care visits and / or contacts may be used 
to satisfy study-required data.
7.1.2.9.1 Long-term follow-up (via telephone follow-up)
Old text:
Subjects will be contacted by telephone every 6 months (± 14 days) for 7 years following the 
last study treatment or until death to determine the following:

Survival status

All SAEs occurring during this period have to be documented and reported if 
considered to be related to study medication.  Concomitant medication associated 
with these events will not 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.

Recording of new primary malignancies

All occurrences of hematological conditions such as myelodysplastic syndrome, 
aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary 
malignancy, such as acute myeloid leukemia, must be reported as SAEs at any time 
and regardless of the investigator’s causality assessment.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 265 of 291
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.
New text:
Subjects, their treating health care professional, or caregiver will be contacted by telephone 
every 6 months (± 14 days) for 7 years following the last study treatment or until death to 
determine the following:

Survival status

Recording of prostate cancer therapies

All radium-223 dichloride/placebo related adverse events (AEs) 

All SAEs occurring during this period have to be documented and reported if 
considered to be related to study medication.  Concomitant treatment associated with 
these events will not be collected unless it is cancer medication / treatment (including 
any systemic cytotoxic chemotherapy or radiotherapy for any malignancy; all 
systemic ant-cancer therapies for prostate cancer, including androgen synthesis 
inhibitors / androgen-receptor antagonists, systemic radioisotopes and radiation 
treatment; excluding analgesics).  If a subject is unable to provide required details for 
events of interest, this information will need to be obtained from the primary provider.

Recording of new primary malignancies

Recording of cytotoxic chemotherapy and radiotherapy for any new primary 
malignancy

All occurrences of hematological conditions such as myelodysplastic syndrome, 
aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary 
malignancy, such as acute myeloid leukemia, must be reported as SAEs at any time 
and regardless of the investigator’s causality assessment

In subjects who receive cytotoxic chemotherapy: all occurrences of febrile 
neutropenia or hemorrhage during their chemotherapy treatment and for up to 6 
months thereafter.
Subject data collected at other standard-of-care visits and / or contacts may be used to satisfy 
study-required data.
Since this information will be collected over the telephone from the subject, their treating 
health care professional, or caregiver, 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.
Training for conducting the follow-up contacts will be provided to clinical site personnel 
including, but not limited to, use of a telephone script. Subject data collected at other 
standard-of-care visits and / or contacts may be used to satisfy study-required data.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 266 of 291
7.1.2.9.2 End of long-term follow-up
Old text:
The end of study procedures for subjects who are in the long-term follow-up period will 
include the following:

Survival status

All SAEs have to be documented and reported if considered to be related to study 
medication.  Concomitant medication associated with these events will not 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.

Recording of new primary malignancies

All occurrences of hematological conditions such as myelodysplastic syndrome, 
aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary 
malignancy, such as acute myeloid leukemia, must be reported as SAEs at any time 
and regardless of the investigator’s causality assessment.
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.
New text:
The end of study procedures for subjects who are in the long-term follow-up period will 
include the following:

Survival status

Recording of prostate cancer therapies

All SAEs occurring during this period have to be documented and reported if 
considered to be related to study medication.  Concomitant treatment associated with 
these events will not be collected unless it is cancer medication / treatment (including 
any systemic cytotoxic chemotherapy or radiotherapy for any malignancy; all 
systemic ant-cancer therapies for prostate cancer, including androgen synthesis 
inhibitors / androgen-receptor antagonists, systemic radioisotopes and radiation 
treatment; excluding analgesics).  If a subject is unable to provide required details for 
events of interest, this information will need to be obtained from the primary provider.

Recording of new primary malignancies

Recording of cytotoxic chemotherapy and radiotherapy for any new primary 
malignancy

All occurrences of hematological conditions such as myelodysplastic syndrome, 
aplastic anemia, myelofibrosis, and primary bone cancer or any other new primary 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 267 of 291
malignancy, such as acute myeloid leukemia, must be reported as SAEs at any time 
and regardless of the investigator’s causality assessment

In subjects who receive cytotoxic chemotherapy: all occurrences of febrile 
neutropenia or hemorrhage during their chemotherapy treatment and for up to 6 
months thereafter.
Subject data collected at other standard-of-care visits and / or contacts may be used to satisfy 
study-required data.
Since this information will be collected over the telephone from the subject, their treating 
health care professional, or caregiver, 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.
Change 4: 
Title page
Old text:
Sponsor’s medical expert:
Milano V.le Certosa 210
20156 Milano - Italia
Phone: 
New text:
Sponsor’s medical expert:
Rua Domingos Jorge, 1100, 
Predio 9301 2o andar 
04779-900 São Paulo – SP - Brasil
Phone: 
Signature of the sponsor’s medically responsible person
Old text:
Name:
Role: 
Global Clinical Leader, 
New text:
Name:
Role: 
Global Clinical Leader, 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 268 of 291
3. Investigators and other study personnel
Old text:
Bayer HealthCare Pharmaceuticals, Inc.
100 Bayer Blvd.
PO Box 915
Whippany, New Jersey 07981
Tel: 
Milano V.le Certosa 210
20156 Milano – Italia
Phone: 
New text:
Bayer HealthCare Pharmaceuticals, Inc.
100 Bayer Blvd.
PO Box 915
Whippany, New Jersey 07981
Phone: 
Rua Domingos Jorge, 1100, 
Predio 9301 2o andar 
04779-900 São Paulo – SP - Brasil
Phone: 
  
Change 5
Synopsis-Plan for statistical analysis
Old text:
Both comparisons will be performed at the time of final analysis, after the latest of (1) 
approximately 135 SSE-FS events in subjects included in Comparison 1 as defined below; (2) 
approximately 75 SSE-FS events following Week 24 in subjects included in Comparison 2 as 
defined below, and (3) the last subject has been followed for 30 days from last treatment.  In 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 269 of 291
the event the applicable number of events is not reached, the primary endpoint analysis will 
mature 7 years after the last subject has received last treatment.
Comparison 2: No further radium-223 dichloride treatment versus extended dosing: SSE-FS 
analysis from 24 weeks in subjects receiving standard-dose regimen
H02: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) (standard dose) radium-223 dichloride who 
survived SSE-free and are eligible for further radium-223 dichloride treatment at 24 weeks, 
population SSE-FS beyond 24 weeks in subjects treated with a regimen of up to an additional 
6 doses of 50 kBq/kg (55 kBq/kg after implementation of NIST update) (extended dose) 
radium-223 dichloride is equal to population SSE-FS beyond 24 weeks in subjects receiving 
no further radium-223 dichloride treatment beyond the standard dose regimen, versus
HA2: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) (standard dose) radium-223 dichloride who 
survived SSE-free and are eligible for further radium-223 dichloride treatment at 24 weeks, 
population SSE-FS beyond 24 weeks in subjects treated with a regimen of up to an additional 
6 doses of 50 kBq/kg (55 kBq/kg after implementation of NIST update) (extended dose) 
radium-223 dichloride is greater than population SSE-FS beyond 24 weeks in subjects 
receiving no further radium-223 dichloride treatment beyond the standard dose regimen.
Comparison 2 will be an analysis of SSE-FS from 24 weeks from randomization in subjects 
surviving SSE-free to 24 weeks completing and / or not discontinued from treatment.  It will 
compare subjects in Treatment Arm A with subjects in Treatment Arm C.  
New text:
Both comparisons will be performed at the time of final analysis, after the latest of (1) 
approximately 135 SSE-FS events in subjects included in Comparison 1 as defined below; (2) 
approximately 75 SSE-FS events following the 6th dose in subjects included in Comparison 2 
as defined below, and (3) the last subject has been followed for 30 days from last treatment.  
In the event the applicable number of events is not reached, the primary endpoint analysis 
will mature 7 years after the last subject has received last treatment.
Comparison 2: No further radium-223 dichloride treatment versus extended dosing: SSE-FS 
analysis from the date of the 6th dose in subjects receiving standard-dose regimen
H02: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) (standard dose) radium-223 dichloride who 
survived SSE-free and are eligible for further radium-223 dichloride treatment at 24 weeks, 
population SSE-FS beyond the 6th dose in subjects treated with a regimen of up to an 
additional 6 doses of 50 kBq/kg (55 kBq/kg after implementation of NIST update)3 (extended 
dose) radium-223 dichloride is equal to population SSE-FS beyond the 6th dose in subjects 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 270 of 291
receiving no further radium-223 dichloride treatment beyond the standard dose regimen, 
versus
HA2: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) (standard dose) radium-223 dichloride who 
survived SSE-free and are eligible for further radium-223 dichloride treatment at 24 weeks, 
population SSE-FS beyond the 6th dose in subjects treated with a regimen of up to an 
additional 6 doses of 50 kBq/kg (55 kBq/kg after implementation of NIST update)3 (extended 
dose) radium-223 dichloride is greater than population SSE-FS beyond the 6th dose in 
subjects receiving no further radium-223 dichloride treatment beyond the standard dose 
regimen.
Comparison 2 will be an analysis of SSE-FS from the 6th dose in subjects surviving SSE-free 
to the completion of the 6th dose.  It will compare subjects in Treatment Arm A with subjects 
in Treatment Arm C.  
4.4 End of Study
Old text:
The primary endpoint cut-off will be reached at the later of 1) 135 SSE-FS events in subjects 
included in Comparison 1 as defined in Section 8,4 below, and 2) 75 SSE-FS events 
following Week 24 in subjects included in Comparison 2 as defined in Section 8.4 below, and 
3) the last subject has been followed for 30 days from last treatment.  In the event the 
applicable number of events is not reached, the primary endpoint analysis will mature 7 years 
after the last subject has received last treatment.
New text:
The primary endpoint cut-off will be reached at the later of 1) 135 SSE-FS events in subjects 
included in Comparison 1 as defined in Section 8.4 below, and 2) 75 SSE-FS events 
following the 6th dose in subjects included in Comparison 2 as defined in Section 8.4 below, 
and 3) the last subject has been followed for 30 days from last treatment.  In the event the 
applicable number of events is not reached, the primary endpoint analysis will mature 7 years 
after the last subject has received last treatment.
7.3.2 Definition of efficacy variables
Old text:
In this study, time-to-event endpoints are defined with respect to 2 distinct start dates, 
randomization date and 24 weeks.  Response and progression endpoints are defined with 
respect to 2 corresponding baselines, the screening (or pre-treatment) baseline and 24 weeks.  
Details on definitions of starting points and baselines will be provided in the SAP or in the 
imaging charter or other central reviewer documentation.
New text:
In this study, time-to-event endpoints are defined with respect to 2 distinct start dates, 
randomization date and the date of the 6th dose.  Response and progression endpoints are 
defined with respect to 2 corresponding baselines, the screening (or pre-treatment) baseline 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 271 of 291
and the 6th dose date.  Details on definitions of starting points and baselines will be provided 
in the SAP or in the imaging charter or other central reviewer documentation.
7.3.5.6 Additional pain and health related quality of life endpoints
Old text:
Subject-reported outcome data not described above, palliative pain relief procedure data, 
additional BPI-SF data collected at clinic visits, and pain data collected following the Week 
24 assessment, will be evaluated as described in the SAP.
New text:
Subject-reported outcome data not described above, palliative pain relief procedure data, 
additional BPI-SF data collected at clinic visits, and pain data collected will be evaluated as 
described in the SAP.
8.2 Analysis sets
Old text:
Week 24 (W24):  All ITT subjects in Arm A (standard dose) and Arm C (extended dosing) 
treated with radium-223 dichloride and eligible for further treatment at W 24.  The W24
dataset will be used for the analysis of efficacy endpoints related to Comparison 2 and 
associated evaluations.  Subjects will be included in W24 analyses according to the treatment 
to which they were randomized.
New text:
Week 24 (W24):  All ITT subjects in Arm A (standard dose) and Arm C (extended dosing) 
treated with radium-223 dichloride and eligible for further treatment at W 24 (i.e., 7th 
injection).  Week 24 applies to subjects who received the 6th injection without any dose 
delays. As dose delays are allowed per protocol, 6th injection can occur after Week 24 for 
subjects who had dose delays. Hence, this population is defined based on the number of 
injections not based on the timing.  The W24 dataset will be used for the analysis of efficacy 
endpoints related to Comparison 2 and associated evaluations.  Subjects will be included in 
W24 analyses according to the treatment to which they were randomized.
8.4.1 Primary efficacy analysis
Old text:
Both comparisons will be performed at the time of final analysis, after the latest of 
(1) approximately 135 SSE-FS events in subjects included in Comparison 1 as defined below; 
(2) approximately 75 SSE-FS events following Week 24 in subjects included in 
Comparison 2 as defined below; and (3) the last subject has been followed for 30 days from 
last treatment. In the event the applicable number of events is not reached, the primary 
endpoint analysis will mature 7 years after the last subject has received last treatment.
Comparison 2: No further radium-223 dichloride treatment versus extended dosing: SSE-FS 
analysis from 24 weeks in subjects receiving standard-dose regimen


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 272 of 291
H02: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg 
(55 kBq/kg after implementation of NIST standard update) (standard dose) radium-223 
dichloride who survived SSE-free and are eligible for further radium-223 dichloride 
treatment at 24 weeks, population SSE-FS beyond 24 weeks in subjects treated with a 
regimen of up to an additional 6 doses of 50 kBq/kg (55 kBq/kg after implementation of 
NIST update) (extended dose) radium-223 dichloride is equal to population SSE-FS beyond 
24 weeks in subjects receiving no further radium-223 dichloride treatment beyond the 
standard dose regimen, versus
HA2: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) (standard dose) radium-223 dichloride who 
survived SSE-free and are eligible for further radium-223 dichloride treatment at 24 weeks, 
population SSE-FS beyond 24 weeks in subjects treated with a regimen of up to an additional 
6 doses of  50 kBq/kg (55 kBq/kg after implementation of NIST update) (extended dose) 
radium-223 dichloride is greater than population SSE-FS beyond 24 weeks in subjects 
receiving no further radium-223 dichloride treatment beyond the standard dose regimen.
Comparison 2 will be an analysis of SSE-FS from 24 weeks from randomization in subjects 
surviving SSE-free to 24 weeks completing and / or not discontinued from treatment.  It will 
compare subjects in Treatment Arm A with subjects in Treatment Arm C.
New text:
Comparison 2: No further radium-223 dichloride treatment versus extended dosing: SSE-FS 
analysis from the 6th dose in subjects receiving standard-dose regimen
H02: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg 
(55 kBq/kg after implementation of NIST standard update) (standard dose) radium-223 
dichloride who survived SSE-free and are eligible for further radium-223 dichloride 
treatment at 24 weeks, population SSE-FS beyond the 6th dose in subjects treated with a 
regimen of up to an additional 6 doses of 50 kBq/kg (55 kBq/kg after implementation of 
NIST update) (extended dose) radium-223 dichloride is equal to population SSE-FS beyond 
the 6th dose in subjects receiving no further radium-223 dichloride treatment beyond the 
standard dose regimen, versus
HA2: In a population of subjects treated with a regimen of up to 6 doses of 50 kBq/kg
(55 kBq/kg after implementation of NIST update)2 (standard dose) radium-223 dichloride 
who survived SSE-free and are eligible for further radium-223 dichloride treatment at 24 
weeks, population SSE-FS beyond the 6th dose in subjects treated with a regimen of up to an 
additional 6 doses of  50 kBq/kg (55 kBq/kg after implementation of NIST update)2
(extended dose) radium-223 dichloride is greater than population SSE-FS beyond the 6th 
dose in subjects receiving no further radium-223 dichloride treatment beyond the standard 
dose regimen.
Comparison 2 will be an analysis of SSE-FS from the 6th dose, in subjects surviving 
completion of to the 6th dose.  It will compare subjects in Treatment Arm A with subjects in 
Treatment Arm C.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 273 of 291
8.4.2.2 Analyses of standard dosing and extended dosing from the 6th dose date
Old text:
For the following secondary endpoint analyses, subjects will be classified into 2 treatment 
groups: (1) the “standard dose” treatment group, consisting of applicable ITT subjects in 
Treatment Arm A, and (2) the “extended dosing” treatment group, consisting of applicable 
ITT subjects in Treatment Arm C.  For these analyses, the start date will be 24 weeks, and the 
24 week assessment baseline will be used. 
For secondary endpoint time-to-event analyses for these treatment groups, subjects included 
will have survived to the 24 week start date without having experienced the applicable event, 
and will have completed and / or not been discontinued from treatment.  Details defining 
these analyses will be provided in the SAP.
New text:
For the following secondary endpoint analyses, subjects will be classified into 2 treatment 
groups: (1) the “standard dose” treatment group, consisting of applicable ITT subjects in 
Treatment Arm A, and (2) the “extended dosing” treatment group, consisting of applicable 
ITT subjects in Treatment Arm C.  For these analyses except for rPFS, the 6th dose date will 
be used as the reference date.  For rPFS, randomization date will be used as the reference 
date.
For secondary endpoint time-to-event analyses for these treatment groups, subjects included 
will have survived to the 6th dose date without having experienced the applicable event, and 
will have completed and / or not been discontinued from treatment.  Details defining these 
analyses will be provided in the SAP.
8.6 Determination of sample size
Old text:
Comparison 2 will analyze SSE-FS from 24 weeks in subjects surviving SSE-free to 24 
weeks completing and / or without prior permanent discontinuation from treatment.(27,28)  A 
median SSE-FS of 9 months with constant hazards is assumed for standard dose.  Extended 
dosing is assumed to have the same SSE-FS efficacy as standard dosing for the first 24 
weeks, and 65% improvement (hazard ratio 0.606) thereafter.  With 240 of 360 subjects 
randomized to Treatment Arm A and Treatment Arm C, simulations indicated that 44.65% of 
randomized subjects (107.2 of 240) would have an SSE-FS event or loss to follow-up during 
the first 24 weeks, leaving an estimated 55.35% (132.8) surviving SSE-free and eligible for 
inclusion at 24 weeks.  An average of 74.9 simulated events occurred for this comparison, 
and a 1-sided log-rank test with 0.10 significance gave approximately 80.6%2 power to test 
H02 versus HA2.
New text:
Comparison 2 will analyze SSE-FS from the 6th dose, in subjects surviving SSE-free to the 
6th dose.(27,28)  A median SSE-FS of 9 months with constant hazards is assumed for 
standard dose.  Extended dosing is assumed to have the same SSE-FS efficacy as standard 
dosing for the first 24 weeks, and 65% improvement (hazard ratio 0.606) thereafter.  With 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 274 of 291
240 of 360 subjects randomized to Treatment Arm A and Treatment Arm C, simulations 
indicated that 44.65% of randomized subjects (107.2 of 240) would have an SSE-FS event or 
loss to follow-up during the first 24 weeks, leaving an estimated 55.35% (132.8) surviving 
SSE-free and eligible for inclusion at 24 weeks.  An average of 74.9 simulated events 
occurred for this comparison, and a 1-sided log-rank test with 0.10 significance gave 
approximately 80.6% power to test H02 versus HA2.
Change 6
7.3.5.2 Time to increase in physical symptoms of disease based on FPSI-DRS-P
Old text:
For each applicable baseline, time to increase in physical symptoms of disease based on 
(FPSI-DRS-P) will be calculated with respect to that baseline, based only on assessments 
through Week 48. Details, including definition of an increase, will be provided in the SAP.
New text:
Time to increase in physical symptoms of disease based on (FPSI-DRS-P) will be calculated 
with respect to baseline value collected prior to first dosing, based only on assessments 
through Week 48. Details, including definition of an increase, will be provided in the SAP.
7.3.5.3.1 Total alkaline phosphatase response rate
Old text:
Total ALP response is defined with respect to each applicable baseline, as a ≥30% reduction 
of the blood total-ALP level compared to the baseline value.
New text:
Total ALP response is defined with respect to each applicable baseline, as a ≥30% reduction 
of the blood total-ALP level compared to the baseline value, confirmed by a second 
consecutive ALP value 4 or more weeks later but within 9 weeks, among evaluable subjects.
7.3.5.3.2 Time to total alkaline phosphatase progression
Old text:
Total ALP progression is defined with respect to each applicable baseline, as a ≥25% 
increase above the applicable nadir (lowest respective baseline or post-baseline) value.
New text:
25% increase from 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 consecutive value obtained 3 or more weeks later but within 9 weeks in subjects with 
an initial ALP decline from the baseline.
7.3.5.4.1 Prostate specific antigen response rate
Old text:
Prostate specific antigen response is defined in each evaluable subject with respect to each 
applicable baseline as a ≥30% reduction of the blood PSA level, compared to the baseline 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 275 of 291
value, confirmed by a second subsequent PSA value with a ≥30% reduction from the 
applicable baseline approximately 4 or more weeks later. 
New text:
Prostate specific antigen response is defined in each evaluable subject with respect to each 
applicable baseline as a ≥30% reduction of the blood PSA level, compared to the baseline 
value, confirmed by a second subsequent PSA value with a ≥30% reduction from the 
applicable baseline approximately 4 or more weeks later but within 9 weeks.
7.3.5.4.2 Time to prostate specific antigen progression
Old text:
Prostate specific antigen progression is defined with respect to each applicable baseline, as a 
≥25% increase above the applicable nadir (lowest baseline or post-baseline) value, and an 
increase in absolute value of ≥2 ng/mL above the nadir.
New text:
Prostate specific antigen progression is defined with respect to each applicable baseline, as a 
25% increase from baseline value and an increase in absolute value of 2 ng/mL, at least 12 
weeks from the applicable 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 consecutive value obtained 3 or more weeks later but within 9 weeks  in subjects with 
an initial PSA decline from the baseline.
Change 7
7.3.4.3 Radiological progression endpoints
Deleted text:
The central reviewer will determine the applicable baseline values for and assess radiological 
progression with respect to each applicable baseline.
13.4
Amendment 4
Description of the amendment
Amendment 4 is an amendment to the integrated protocol version 4.0 dated 16 MAY 2017.  
Changes to the protocol include:

Addition that radium-223 dichloride should not be given with abiraterone plus 
prednisone/prednisolone.

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 
causality to study treatment.

Based on the available data on radium-223 dichloride, initiation of BHAs during the 
follow-up periods, including bisphosphonates or denosumab, should be considered 
taking into consideration applicable guidelines.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 276 of 291

Updated the study GCL and study medical expert names.

Minor clarifications
13.4.1 Overview of changes
13.4.1.1 Change 1:
Addition that radium-223 dichloride should not be given with abiraterone plus 
prednisone/prednisolone.
Sections affected include:

Synopsis - Background treatment / concomitant medications / prohibited therapies

6.9.2 Concomitant medication

7.1.1 Tabulated overview, Schedule of procedures
Rationale: The ERA 223 study, a phase III randomized trial in prostate cancer patients 
examining radium-223 dichloride versus placebo in combination with abiraterone and 
prednisone (study number 15396, NCT02043678) was unblinded based on the Independent 
Data Monitoring Committee (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 mCRPC is considered unfavorable.
13.4.1.2 Change 2:
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 - Methodology

4.1 Design overview

6.8 Post-study therapy

7.1.1 Tabulated overview

7.1.2.7.1 Active follow-up with clinic visits

7.1.2.7.2 Active follow-up without scheduled clinic visits

7.1.2.8.1 End of active follow-up with clinic visits

7.1.2.8.2 End of active follow-up without scheduled clinic visits


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 277 of 291

7.1.2.9 Long-term follow-up to 7 years following last dose

7.1.2.9.1 Long-term follow-up (via telephone follow-up)

7.1.2.9.2 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

10 Premature termination of the study
Rationale: The ERA 223 study, a phase III randomized trial in prostate cancer patients 
examining radium-223 dichloride versus placebo in combination with abiraterone and 
prednisone (study number 15396, NCT02043678) was unblinded 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 these data European Health Authorities requested 
that all bone fractures and bone associated events (e.g., osteoporosis) occurring during study 
and in the follow-up period should be documented regardless of causality to study treatment.
13.4.1.3 Change 3:
The option of starting a BHA during the follow-up periods, including bisphosphonates or 
denosumab, should be considered taking into consideration applicable guidelines.
Sections affected include:

Synopsis - Methodology

6.9.2 Concomitant medication
Rationale:  The ERA 223 study, a phase III randomized trial in prostate cancer patients 
examining radium-223 dichloride versus placebo in combination with abiraterone and 
prednisone (study number 15396, NCT02043678) was unblinded 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 on radium-223 dichloride, the 
option of starting a BHA including bisphosphonates or denosumab should be considered, 
taking into consideration applicable guidelines.
13.4.1.4 Change 4:
Updated the study GCL and Study Medical Expert names.
Sections affected:

Title page

Signature of the sponsor’s medically responsible person


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 278 of 291

3 Investigators and other study personnel
Rationale: Change reflects the current medical expert and protocol signatory.
13.4.1.5 Minor clarifications: 

Added the definition for Independent Data Monitoring Committee (IDMC) and bone 
health agent (BHA) in the list of abbreviations and in the text where appropriate.

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 are provided in a separate tracked changes document.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 279 of 291
14.Appendices
14.1
Response Evaluation Criteria in Solid Tumors, version 1.1
Section modified by Amendment 2 (Section 13.2).
Soft tissue response and progression will be evaluated in this study using a modified version 
of the modified RECIST guidelines version 1.1.
Modification to RECIST:

Only lymph nodes with short axis ≥1.5 cm can be selected as target lesions.

Disease progression at first assessment needs to be confirmed by a second scan 6 or more 
weeks later as required per the PCWG2 guidance.(1)  In case of unequivocal progression, 
a confirmatory scan is not mandatory and it will be performed at the investigator’s 
discretion.

Bone lesions will not be recorded as non-target lesions or assessed per modified RECIST.  
Radiological progression of bone lesions will be determined according to PCWG2 criteria 
based on whole body technetium-99 bone scans.
Measurable Disease: Note: Subjects are excluded if they have visceral metastases as 
assessed by abdominal and pelvic MRI / CT scan or chest X-ray.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥1.5 cm in short axis when assessed by CT scan.  At baseline and in follow-up, 
only the short axis will be measured and followed.
Malignant lymph nodes situated in a previously irradiated area are not considered measurable 
unless there has been demonstrated progression in the lesion.
Non-Measurable Disease: All other lesions (or sites of disease), including small lesions 
(pathological lymph nodes with short axis ≥1 cm to < 1.5 cm) are considered 
non-measurable disease.  Leptomeningeal disease, ascites, pleural / pericardial effusions, and 
lymphangitic involvement of skin or lung are all non-measurable.
Target Lesions: All measurable lesions up to a maximum of 5 lesions in total, representative 
of all involved regions should be identified as target lesions and be recorded and measured at 
baseline.  These 5 lesions should be selected on the basis of their size (lesions with the 
longest short axis), and should be suitable for reproducible repeated measurements.  A sum of 
nodal short axes of target lesions will be calculated and reported as the baseline sum 
diameters.  The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression of the measurable dimension of the disease.  If there are 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 280 of 291
> 5 measurable lesions, those not selected as target lesions will be considered together with 
non-measurable disease as non-target lesions.
Non-target Lesions: All non-measurable lesions (or sites of disease) plus any measurable 
lesions over and above the 5 listed as target lesions.  Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.”
Best Response
All subjects will have their best response on study classified as outlined below:
Complete Response (CR): 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 (PR): 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.
Stable Disease: Steady state of disease.  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD; 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 PD.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 281 of 291
Table 14–1  Response for subjects with target and non-target lesions
Target lesions
Non-target 
lesions
New lesions
Overall 
response
Best response for this 
category also requires
CR
CR
No
CR
CR
Non-CR / Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Documented at least 6 weeks 
from start of study treatment
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial 
response; SD = stable disease
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the objective progression even after 
discontinuation of treatment.
Table 14–2 Response for subjects with non-target lesions only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR / Non-PD
No
Non-CR / non-PDa
Not evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations: CR = complete response; NE = not evaluable; PD = progressive disease
a Non-CR / non-PD is preferred over “stable disease” for non-target disease.
Note: Radiological progression of bone lesions will be determined according to PCWG2 
criteria based on whole body technetium-99 bone scans.
Methods of Measurement
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.
Chest X-ray - In the presence of suspicious lesion(s), a chest CT scan will be performed to 
confirm and characterize the lesion(s).  However, a chest CT scan is preferable.
CT / MRI - CT scan is the best currently available and reproducible method to measure target 
lesions selected for response assessment.  When CT scans are used, spiral CT scans should be 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 282 of 291
used in this study.  The minimum size for a measurable lesion should be twice the slice 
thickness.  An MRI is also acceptable.  This applies to the chest, abdomen, and pelvis.
Ultrasound - Ultrasound is not useful in assessment of lesion size and should not be used as 
method of measurement.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.
Endoscopy / Laparoscopy - The utilization of these techniques for objective tumor evaluation 
is not advised.
Cytology / Histology - These techniques can be used to differentiate between PR and CR in 
rare cases.
14.2
Recommendations of the Prostate Cancer Clinical Trials Working Group 
for assessment of radiological progression
Section modified by Amendments 1 (Section 13.1) and 2 (Section 13.2).
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(7):1148-59.
Table 14–3  Recommendations of the Prostate Cancer Clinical Trials Working Group 
2 for assessment of radiological progression
Site
PCWG2 criteria for radiological progression
Soft tissue
The modified RECIST criteria for progression should be used, with the additional 
requirement that progression at the first assessment should be confirmed by a second 
scan 6 or more weeks later.
Bone
Defined as the appearance of ≥2 new lesions, and, for the first reassessment only, a 
confirmatory scan performed 6 or more weeks later that shows a minimum of 2 or more 
additional new lesions
The date of progression is the date of the first scan that shows the change.
Abbreviations: PCWG2 = Prostate Cancer Clinical Trials Working Group 2; RECIST = Response 
Evaluation Criteria in Solid Tumors
Table 14–4  Radiological progression free survival definition per modified Response 
Evaluation Criteria in Solid Tumors, version 1.1, or progression by bone scan as 
adapted by Prostate Cancer Clinical Trials Working Group 2 criteria
Site
Criteria for radiological progression
Soft tissue
Soft tissue progression is determined by modified RECIST, version 1.1:

Only lymph nodes with short axis ≥1.5 cm can be selected as a target lesion
Bone
Progressive disease by bone scan as adapted from PCWG2 Consensus Criteria:

< 12 weeks after randomization:  ≥2 new bone lesions plus 2 additional at 
confirmation (“2+2”)

≥12 weeks after randomization:  ≥2 new bone lesions with subsequent 


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 283 of 291
confirmation
If progression is detected by bone scan, a confirmatory bone scan is required at least 
6 weeks later.  A 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.  
Abbreviations: RECIST = Response Evaluation Criteria in Solid Tumors
14.3
Quantitative bone scan response criteria
Table 14–5  Quantitative bone scan response criteria
Time point response
Criteria
Responder
30% or greater resolution of the applicable bone scan lesion 
area compared to the respective baseline
Stable disease
Not meeting the criteria for responder, progressive disease, or 
unable to evaluate
Progressive disease
Two or more new areas of radiotracer uptake attributable to 
metastatic disease in regions of bone that had not previously 
shown radiotracer uptake or greater than 30% increase from 
baseline in bone scan lesion area in areas attributable to 
metastatic disease.
Unable to evaluate
Assigned if bone scan results cannot be interpreted due to 
inconsistent image acquisition parameters compared to the 
reference scan, incomplete imaging, or other similar technical 
deficiencies.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 284 of 291
14.4
National Cancer Institute - Common Terminology Criteria for Adverse 
Events, Version 4.03
US Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
Version 4.03 published 14 June 2010. Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 285 of 291
14.5
Eastern Cooperative Oncology Group performance status
Table 14–6  Eastern Cooperative Oncology Group 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)
14.6
Calculation for glomerular filtration rate
Section modified as of Amendment 2 (Section 13.2).
Baseline kidney function will be assessed using the GFR as calculated using either the 
Chronic Kidney Disease Epidemiology Collaboration creatinine equation, or, when this 
method is not available, the Modification of Diet in Renal Disease (MDRD) equation.
The MDRD calculation is an established method of estimating GFR based on 4 variables: 
serum creatinine level, age, sex, and ethnicity.  This method has historically been the 
National Kidney Foundation’s recommended method of estimating the GFR in individuals 18 
years or older.  
The MDRD Study Equation:
GFR (mL/min/1.73m2) = k x 186 x [serum creatinine]-1.154 x [age]-0.203
Where k = 1 (men) or 0.742 (women), serum creatinine is measured in mg/dL. 
In an effort to improve upon the MDRD equation, the Chronic Kidney Disease Epidemiology 
Collaboration developed an updated calculation, the CKD-EPI creatinine equation, using the 
same variables as the MDRD equation. This new calculation has been validated and is 
considered to be more accurate than the MDRD equation.  The National Kidney Foundation 
now recommends using the CKD-EPI Creatinine Equation for estimating GFR.
The CKD-EPI calculation is based on a serum creatinine value that was obtained through use 
of isotope dilution mass spectrometry (IDMS), a standardized serum creatinine assay. 
Therefore, the CKD-EPI equation is only valid if the laboratory used a calibration method for 
serum creatinine that is traceable to IDMS.  The IDMS has been adopted by laboratories 
globally and is widely available.  If it is not clear whether your laboratory uses this serum 
creatinine reference method, please contact the laboratory for confirmation.  


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 286 of 291
CKD-EPI Equation

Conventional Units (creatinine as mg/dL; age in years):

GFR (mL/min/1.73m2) = 175 x (serum creatinine)-1.154 x (Age)-0.203 x (0.742 if 
female) x (1.212 if African American)

SI Units (creatinine as µmol/L; age in years):

GFR (mL/min/1.73m2) = 175 x (serum creatinine/88.4)-1.154 x (Age)-0.203 x (0.742 
if female) x (1.212 if African American)
The standard MDRD calculation should be used for any serum creatinine values that are not 
based on the IDMS assay.   
For convenience and accuracy, a GFR calculator may be used for this study at the following 
URL at the National Kidney Foundation’s web site:  
http://www.kidney.org/professionals/KDOQI/gfr_calculator
14.7
Brief Pain Inventory-Short Form
Section modified as of Amendment 1 (Section 13.1).
The severity of pain and its impact on daily functions will be self-assessed by the study 
subjects using the BPI-SF (29) measure.
The BPI-SF allows subjects to rate the severity of their pain and the degree to which their 
pain interferes with common dimensions of feeling and function (e.g., general activity, 
walking, work, mood, enjoyment of life, relations with others, and sleep).  The BPI-SF is an 
11-item, self-administered, clinically valid, reliable, and responsive measure developed to 
assess pain related to cancer.  The instrument is available in validated multilingual versions; 
on average, it requires less than 10 minutes to complete the questionnaire.
All BPI 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.  It has a 24-hour recall period.  Assessment of the worst pain score (WPS) via 
Question 3 and average pain score via Question 5 on the BPI-SF will occur daily for 4 days 
immediately prior to randomization and for 7 days prior to each scheduled visit from the 
Dose 1, Day 1 visit through the Week 48 visit.  The data will be collected and checked for 
completeness at each visit.  In Treatment Arms A and B only, pain will also be assessed daily 
for 7 days prior to each  telephone contact at Weeks 28, 32, 40 and 44 and the daily PRO pain 
input data will be reviewed for completeness at the telephone contact.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 287 of 291
The BPI-SF will be self-administered by the subject at Dose 1, Day 1 (before the start of 
study treatment) through the Week 48 visit.  In Treatment Arms A and B only the BPI-SF 
questionnaire will also be completed on the day of each telephone contact at Weeks 28, 32, 
40 and 44 and checked for completion at the telephone contact.
At the beginning of each scheduled visit, before meeting with the investigator, subjects will 
be asked to complete the BPI-SF, with the exception of Question 2 (locating areas of pain on 
a diagram) and Question 7 (regarding use of pain medication).  Subjects will not be asked to 
answer Question 2 because the information will not be used for the score.  Subjects will not 
be asked to answer Question 7 because pain medication used is captured elsewhere in the 
eCRF.  The items are aggregated into 2 dimensions: (1) Pain Severity Index, using the sum of 
the 4 items on pain intensity and (2) Function Interference Index, using the sum of the 7 pain 
interference items.  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.
The BPI-SF should be self-administered by the subject alone during his scheduled visit at the 
site.  The instrument should be administered at the start of the visit, before the subject sees 
the physician so that any interaction between the subject and physician will not influence the 
subject’s responses to the questionnaire.  The questionnaire should also be administered 
before the subject is asked about AEs and concurrent illnesses, again so that any discussions 
of health problems do not influence the subject’s responses.
A quiet place should be provided for the subject to complete the BPI-SF.  It is important that 
the subject completes the BPI-SF alone, without any advice from family members or friends 
who may accompany him.
How should the Questionnaire and daily PRO pain collection be introduced?
A sample script for introducing the questionnaire and daily PRO pain collection is given 
below.
“Your doctor would like to better understand how you feel, how well you are able to do your 
usual activities, and how you rate your health.  To help us better understand these things 
about you, we will ask you to answer 2 questions related to the worst pain in the last 24 hours
and the average level of pain, for 7 days prior to each scheduled treatment visit and at the end 
of treatment visit. We will ask you to complete this questionnaire about your health at each of 
these visits. Depending on which treatment you are assigned, you may also be requested to 
answer these 2 questions during the first 6 months of the follow up period, for 7 days prior to 
the visits or telephone contacts and to complete the BPI-SF questionnaire on the day of the 
visits or on the day of the telephone contacts.
You will be provided with written instructions on how to do this. You should read each 
question and then tick the appropriate number that matches your answer.  Remember that this 
is not a test and there are no right or wrong answers.  Choose the answer that best describes 
the way you feel.  I will quickly review the questionnaire when you are done to make sure 
that all the questions have been answered.  You should answer these questions by yourself.  


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 288 of 291
Your spouse or other family members should not help you when you answer the 
questionnaire.  I will be nearby in case you want to ask me any questions.  Please let me 
know when you have finished the questionnaire.”
What to do if the subject asks for clarification?
Some subjects may ask the meaning of specific questions.  If this happens, the staff member 
can assist the subject by re-reading the question for them verbatim.  If the subject asks what 
something means, do not try to explain what the question means, but tactfully suggest that the 
subject use his own interpretation of the question.  All subjects should answer the questions 
based on what they think the questions mean, or the study results may be biased.
Questionnaire completion and review of worst pain score over the previous 7 days
At the beginning of each visit or at each telephone contact (Treatment Arms A and B only), 
please check that the subject has answered the questions related to the WPS and the average 
pain score, in the 7 days prior to the visit.  Thank the subject once you have reviewed the 
responses.
When the subject has completed the questionnaire, check that all of the questions have been 
answered.  If the questionnaire is not complete, point out to the subject that some of the 
questions were not answered.  If the subject does not quickly volunteer to answer these items, 
ask him whether he had any difficulty completing the questionnaire.  If the subject says that 
he had trouble understanding a question, ask him why he had difficulty with that item.  Re-
read the question for him verbatim, but do not attempt to explain or reword the question, as 
explained before.  If the subject is still unable to answer the question, accept the 
questionnaire as is.
Some subjects may be confused by the response choices.  They may want to respond with “I 
don’t know” or some other response choice that is not available.  If this happens, try to help 
the subject choose one of the response categories by saying something like: “I know that it 
may be difficult for you to choose an answer, but which of these answers do you think comes 
closest to the way that you are thinking or feeling?”  If the subject still cannot select an 
answer, accept the questionnaire as is.
Occasionally, subjects may not report having difficulty with a question or the response 
choices, but still may hesitate or refuse to answer an item or items.  If this happens, accept the 
questionnaire as is.
If a subject asks for interpretation of his responses or asks for his scores on the questionnaire, 
tell him that you are not trained to score or interpret the questionnaire.  Emphasize that their 
answers will be kept confidential.
Thank the subject once he has completed the questionnaires and you have checked them for 
completeness.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 289 of 291
14.8
NCCN FACT-P Symptom Index-17 (NCCN-FACT FPSI-17)
Questionnaire
Section modified as of Amendment 1 (Section 13.1).
The NCCN-FACT FPSI-17 questionnaire will be completed by the subject at the specified 
visits, see Section 7 and Table 7–1.


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 290 of 291
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
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
GE6
I worry that my condition will get worse ......
0
1
2
3
4
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
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)
03 March 2010
Copyright 2001
Page 1 of 1
D
R
S-
P
T
S
E
F
W
B
D
R
S-
E


Integrated Clinical Study Protocol
BAY 88-8223 / 16507
28 MAR 2018
Version 5.0
Page: 291 of 291
14.9
Analgesic Quantification Algorithm
Section modified by Amendment 1 (Section 13.1).
Analgesic Quantification Algorithm Score Categories
0
No analgesic
1
Non-opioid analgesics
2
Weak opioids (i.e., meperidine, codeine, tramadol)
3
Strong opioids ≤75 mg OME/d
4
Strong opioids > 75-150 mg OME/d 
5
Strong opioids > 150-300 mg OME/d
6 
Strong opioids > 300 mg-600 mg OME/d
7
Strong opioids > 600 mg OME/d
Abbreviations: d = day; OME = oral morphine equivalents.
References for the AQA:
Chung K, Barlev A, Braun A, Qian Y, Zagari M. Development of the Analgesic 
Quantification Algorithm (AQA): a new scale to assess analgesic use. Poster presented at: 
Joint 15th Congress of the European Cancer Organization and 34th Congress of the European 
Society for Medical Oncology; September 20-24, 2009; Berlin, Germany.
Charles S. Cleeland PhD, Jean-Jaques Body MD PhD, Alison Stopeck MD, et al. (2013).  
Pain outcomes in patients with advanced breast cancer and bone metastases: Results from a 
randomized, double-blind study of denosumab and zoledronic acid.  Cancer, Volume 119, 
Issue 4, pages 832–838.

SAP_003.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A three arm randomized, open-label Phase II study of radium-223 
dichloride 50 kBq/kg (55 kBq/kg after implementation of National 
Institute of Standards and Technology [NIST] update) versus 80 
kBq/kg (88 kBq/kg after implementation of new NIST update and 
versus 50 kBq/kg (55 kBq/kg after implementation of NIST 
update) in an extended dosing schedule in subjects with castration-
resistant prostate cancer metastatic to the bone 
NCT Number: 
NCT02023697 
Document Date: 
08 OCT 2018 
 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
1 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
A three arm randomized, open-label Phase II study of radium-223 
dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update) 
versus 80 kBq/kg (88 kBq/kg after implementation of NIST update) , and 
versus 50 kBq/kg (55 kBq/kg after implementation of NIST update) in an 
extended dosing schedule in subjects with castration-resistant prostate 
cancer metastatic to the bone
[Standard dose versus high dose and versus extended standard dose radium-223 
dichloride in castration-resistant prostate cancer metastatic to the bone]
BSP study drug
BAY 88-8223 / Radium-223 dichloride / Xofigo
[Study purpose:]
Efficacy, dose-Finding
Clinical study 
phase:
II
Date:
17MAY2017
Study No.:
16507
Version:
Final 2.0
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
PPD
PPD


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
2 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Table of Contents
1.
Introduction......................................................................................................................... 4
2.
Study Objectives................................................................................................................. 5
3.
Study Design....................................................................................................................... 7
3.1
Study periods and duration.......................................................................................... 9
3.2
Schedule of procedures................................................................................................ 9
3.3
Planned Analyses......................................................................................................... 9
3.4
Determination of sample size ...................................................................................... 9
4.
General Statistical Considerations.................................................................................... 11
4.1
General Principles...................................................................................................... 11
4.2
Handling of Dropouts ................................................................................................ 11
4.3
Handling of Missing Data.......................................................................................... 11
4.3.1
Imputation rules.............................................................................................. 11
4.4
Interim Analyses and Data Monitoring ..................................................................... 11
4.5
Data Rules.................................................................................................................. 12
4.5.1
Determining Baseline Values ......................................................................... 12
4.5.2
Pooling cut-off date for Arm C subjects in Comparison 1............................. 12
4.6
Validity Review......................................................................................................... 12
4.6.1
Protocol Deviations ........................................................................................ 13
4.7
Additional Statistical Considerations ........................................................................ 13
4.7.1
Delayed Effect Efficacy Assumptions............................................................ 13
5.
Analysis Sets..................................................................................................................... 13
6.
Statistical Methodology.................................................................................................... 14
6.1
Population characteristics.......................................................................................... 14
6.1.1
Disposition of Subjects................................................................................... 14
6.1.2
Demographic and Baseline Characteristics .................................................... 14
6.1.3
Medical history............................................................................................... 16
6.1.4
Extent of Exposure ......................................................................................... 16
6.1.5
Prior and Concomitant Medications............................................................... 17
6.2
Efficacy...................................................................................................................... 18
6.2.1
Primary Efficacy Analysis.............................................................................. 18
6.2.2
Secondary Efficacy Analysis.......................................................................... 20
6.2.3
Exploratory Analysis ...................................................................................... 22
6.3
Pharmacokinetics / pharmacodynamics..................................................................... 29
6.4
Safety......................................................................................................................... 29
6.4.1
Adverse events................................................................................................ 29
6.4.2
Deaths ............................................................................................................. 31
6.4.3
Clinical Laboratory Data ................................................................................ 31
6.4.4
New Primary Malignancies ............................................................................ 33
6.5
Analysis of Other Endpoints...................................................................................... 33
6.5.1
ECOG Performance Status............................................................................. 33


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
3 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
6.5.2
Quality of Life ................................................................................................ 33
6.5.3
Long Term Safety........................................................................................... 33
6.6
Examination of Subgroups ........................................................................................ 33
7.
Document history and changes in the planned statistical analysis ................................... 34
8.
References......................................................................................................................... 35
9.
Appendices........................................................................................................................ 37
9.1
Censoring Rules......................................................................................................... 37
9.1.1
Censoring rules for Symptomatic Skeletal Event-Free Survival (SSE-FS) ... 37
9.1.2
Censoring rules for Overall Survival  (OS).................................................... 38
9.1.3
Censoring rules for other time-to-event endpoints......................................... 39
9.1.4
Censoring rules for time to radiological progression ..................................... 40
9.1.5
Censoring rules for radiological progression-free survival (rPFS) ................ 42
Abbreviations
AD
Associated Document
AE
Adverse event
ALP
Alkaline phosphatase
APAC
Asia-Pacific
ATC
Anatomical Therapeutic Class
BPI-SF
Brief Pain Inventory – Short Form 
BSP
Bayer Schering Pharma
CBC
Complete blood count
CRPC
Castration-resistant prostate cancer
CI
Confidence interval
CSR
Clinical Study Report
CT
Computer tomography
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee
DRS-E
Disease Related Symptoms – Emotional
DRS-P
Disease Related Symptoms – Physical
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
ePRO
Electronic Patient Reported Outcomes
F/WB
Function/Well Being
FAS
Full Analysis Set
FACT
Functional Assessment of Cancer Therapy
FPSI
Functional assessment of cancer therapy Prostate Symptom Index
FPSI-17
Functional assessment of cancer therapy Prostate Symptom Index – 17 items
FU
Follow-Up
GCP
Good Clinical Practices
GMS
Global Medical Standards
HEOR
Health Economics, Outcomes & Reimbursement
IBW
Ideal Body Weight
ICH
International Committee on Harmonization
ID
Identifier
INN
International Non-proprietary Name
ITT
Intent-to-treat
IV
Intravenous


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
4 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
IVRS/IWRS
Interactive voice/web response system
IXRS
Interactive response system (independent of type)
JSRC
Joint Safety Review Committee
kBq
Kilobecquerel
LCL
Lower Confidence Limit
LTFU
Long-Term Follow-Up
LTFUAE
Long-Term Follow-Up Adverse Event
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network
NIS
Non-interventional Study
NIST
National Institute of Standards and Technology
nMiss
Number of missing values
OS
Overall survival
PC
Prostate cancer
mPCWG2
Modified Prostate Cancer Working Group 2
PRO
Patient Reported Outcomes
PSA
Prostate specific antigen
PT
Preferred Term
QoL
Quality of Life
Ra-223
Radium-223 dichloride
rPFS
Radiological progression free survival
SAE
Serious Adverse Event
SAF
Safety
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
SOP
Standard Operating Procedure
SSE
Symptomatic skeletal event
SSE-FS
Symptomatic skeletal event free survival
Std
Standard Deviation
TAS
(Bayer) Therapeutic Area (Oncology) Standards
TBW
Total Body Weight
TEAE
Treatment-Emergent Adverse Event
TTP
Time to progression
uCi
Microcurie
UCL
Upper Confidence Limit
W12
Week 12
W24
Week 24
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
1. Introduction
Protocol 16507 is a 3-arm, randomized, open-label Phase II study to compare the efficacy and 
safety of a “standard dose” regimen of radium-223 dichloride  with, a “high dose” regimen 
and an “extended dose” regimen, in subjects with castration-resistant prostate cancer 
metastatic to bone .


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
5 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
The study’s 3 arms are:

Arm A: 6 doses of 50 kBq/kg (55 kBq/kg after implementation of NIST update) 
radium-223 dichloride every 4 weeks (“standard” dose regimen)

Arm B: 6 doses of 80 kBq/kg (88 kBq/kg after implementation of NIST update) 
radium-223 dichloride every 4 weeks (“high dose” regimen)

Arm C: 12 doses of 50 kBq/kg (55 kBq/kg after implementation of NIST update) 
radium-223 dichloride every 4 weeks (“extended dose” regimen)
The study’s co-primary endpoints are:

Symptomatic skeletal event free survival from randomization (SSE-FS1) for the 
“standard dose” vs. “high dose” comparison (Comparison 1).

Symptomatic skeletal event free survival from the 6th dose (SSE-FS2) for the 
“standard dose” vs. “extended dose” comparison (Comparison 2)
Two analyses of efficacy and safety are planned in this study:

A final analysis to occur after the latest of the following maturation criteria are met:
o
135 SSE-FS (SSE-FS1) events in subjects included in Comparison 1 
o
75 SSE-FS (SSE-FS2) events following the 6th dose in subjects included in 
Comparison 2
o
The last subject has been followed for 30 days from last treatment.

An updated analysis to occur after the last subject has completed the active follow-up 
period in this study for two years following last dose of Ra-223 dichloride (if after 
primary endpoint cut-off). 
Additional details on the timing of the analyses are described in Section 3.3 below.
This Statistical Analysis Plan (SAP) specifies the analyses and data presentations planned for 
both the final and the updated analysis. 
This SAP was written based on the following documentation:
Document
Date
Version
Protocol
9August 2013
1.0
Protocol Amendment no. 1
20 November 2013
2.0
Protocol Amendment no. 2
16 August 2015
3.0
Protocol Amendment no. 3
16 May 2017
4.0
2. Study Objectives
Co-primary objectives:

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 doses 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
6 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
compared to radium-223 dichloride 80 kBq/kg (88 kBq/kg after implementation of 
NIST update); and

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 additional 
doses compared to no further radium-223 dichloride treatment in subjects with CRPC 
metastatic to the bone who previously received radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 doses, and 
survived SSE free and are eligible for further radium-223 dichloride treatment.
Symptomatic skeletal events (SSEs) are defined as:
o
The use of external beam radiotherapy (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
Secondary objectives:

To evaluate safety and tolerability

To evaluate overall survival (OS)

To evaluate pain improvement rate

To evaluate time to pain progression

To evaluate time to first SSE

To evaluate time to radiological progression

To evaluate radiological progression-free survival (rPFS)
Exploratory objectives:

To evaluate quantitated whole body technetium-99 bone scan tumor burden area and
index, and determine bone tumor response

To explore the impact of patient body size on the efficacy and safety of radium-223
dichloride

Time to increase in physical symptoms of disease based on the NCCN FACT-P
Symptom Index-17 (NCCN-FACT FPSI-17) physical disease related symptoms
(FPSI-DRS-P) subscale score measured up to Week 48 after the start of treatment

To evaluate laboratory indicators of efficacy, including:
o
PSA response
o
Time to PSA progression
o
ALP response
o
Time to ALP progression


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
7 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
o
Percentage change in ALP from baseline

To evaluate change in analgesic use.
3. Study Design
This is a three arm, randomized, open-label Phase II study of radium-223 dichloride 50 
kBq/kg (55 kBq/kg after implementation of NIST update) versus 80 kBq/kg (88 kBq/kg after 
implementation of NIST update) , and versus 50 kBq/kg (55 kBq/kg after implementation of 
NIST update) in an extended dose schedule in subjects with castration-resistant prostate 
cancer metastatic to the bone. Approximately 360 subjects will be randomized in this study. 
The randomization will be stratified by use of prior chemotherapy (≤ 1 regimen versus > 1 
regimen), by total ALP (< 220 U/L versus ≥ 220 U/L), and by average worst pain score 
(WPS) of the Brief Pain Inventory – Short Form (BPI-SF) (WPS ≤4 versus WPS > 4).
A schematic of the study design is presented in Figure 3–1. 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
8 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Figure 3–1: Study Design Schematic
Arm C:  TREATMENT PERIOD
Radium-223 Cl2 IV 55 kBq/kg 
every 4 weeks for 12 cycles
Subjects evaluated for efficacy, 
safety, NCCN-FACT FPSI-17, 
and BPI-SF at each 4 week visit
1:1:1 RANDOMIZATION and STRATIFICATION by:

Use of prior chemotherapy (≤ 1 regimen vs. > 1 regimen)

Average WPS of the BPI-SF (≤ 4 vs. > 4)

Total ALP < 220 U/L versus total ALP ≥ 220 U/L
INFORMED CONSENT
SCREENING 
Subject fulfills eligibility criteria
Subject inclusion
Arm A:  TREATMENT PERIOD
Radium-223 Cl2 IV 55 kBq/kg 
every 4 weeks for 6 cycles
Subjects evaluated for 
efficacy, safety, NCCN-FACT 
FPSI-17, and BPI-SF at each 4 
week visit
ACTIVE FOLLOW-UP PERIOD WITH CLINIC VISITS
Subjects who discontinue treatment and did not have an on-study SSE will 
be followed until the subject experiences an on-study SSE, can no longer 
travel to the clinic, dies, is lost to follow-up, receives further treatment 
with cytotoxic chemotherapy for prostate cancer, other systemic 
radioisotopes, hemibody EBRT or other investigational drugs, or withdraws 
informed consent and actively objects to collection of further data.  
Subjects will be evaluated every 12 weeks (± 7 days) for SSEs, survival,
radiological progression, pain endpoints, and safety.
ACTIVE FOLLOW-UP PERIOD WITHOUT CLINIC VISITS
Subjects without SSE but who can no longer travel to the clinical site will be followed up for SSE, 
survival, pain endpoints, and safety with a phone call every 12 weeks (± 7 days).  The maximum 
duration of the active follow-up is 7 years from the last dose of radium-223 dichloride received by 
the subject.
LONG-TERM FOLLOW-UP
Subjects who have experienced an SSE will be monitored via telephone call every 6 months for 
survival and safety until 7 years after the last dose of radium-223 dichloride or when the subject 
dies.  
Arm B:  TREATMENT PERIOD
Radium-223 Cl2 IV 88 kBq/kg 
every 4 weeks for 6 cycles
Subjects evaluated for 
efficacy, safety, NCCN-FACT 
FPSI-17,and  BPI-SF at each 4 
week visit


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
9 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
3.1
Study periods and duration
The study periods will consist of screening/randomization, treatment, active follow-up with 
clinic visits, active follow-up without clinic visits, and long-term follow-up.  
Long-term follow-up:
All study subjects will be eligible for further follow-up either in this study or in a separate 
long-term follow-up study for up to 7 years.  
Transition of all subjects into the separate long-term follow-up study will begin following the 
later of primary endpoint completion or 2 years after the last radium-223 dichloride treatment 
is administered to the last treated subject.
Until the transition to the long term follow-up study begins, some subjects may begin long-
term follow-up in this study.  This study will end when all subjects have transitioned into the 
long-term follow-up study or discontinued from this study for another reason (e.g., Consent 
Withdrawn, Lost to Follow up).
Data collected in the separate long-term follow-up study is outside the scope of this SAP. 
3.2
Schedule of procedures
See Protocol Table 7-1. 
3.3
Planned Analyses
The final analysis of this study will take place after the primary endpoint cut-off is reached. 
The primary endpoint cut-off will be reached at the later of 

135 SSE-FS events in subjects included in Comparison 1, and 

75 SSE-FS events following the 6th dose in subjects included in Comparison 2, and 

the last subject has been followed for 30 days from last treatment. 
3.4
Determination of sample size
The sample size is based on two separate comparisons with no multiple-testing adjustment: 
Comparison 1:
H01: SSE-FShigh dose = SSE-FSstandard dose, versus
HA1: SSE-FShigh dose > SSE-FSstandard dose.
This comparison will consider SSE-FS following randomization.  Arm C subjects will be
pooled with Arm A for the standard dose group.  Refer to pooling algorithm in Section 4.5.2
and Censoring rules in Table 9–1.
Comparison 2:


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
10 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
H02: SSE-FSextended dose = SSE-FS Standard dose, versus
HA2: SSE-FSextended dose > SSE-FS Standard dose.
This comparison will include Arm A and Arm C subjects who received 6 or more doses. 
The sample size calculations assume 30 subjects/month enrollment with 7 months ramp-up 
and a 3% loss to follow-up per month. The accrual period is anticipated to last approximately 
16 months. Overall, 360 subjects are expected to be randomized at a 1:1:1 ratio. The primary 
endpoint cut-off, as defined in Section 3.3, is estimated to be reached in an average of 39.1 
months.

Comparison 1 assumes:
o
Arm A (standard dose) subjects have constant  median SSE-FS of 9 months 
throughout the study 
o
Arm C (extended dose) subjects have median SSE-FS of 9 months during the 
first 24 weeks of the study
o
Arm B (high dose) subjects have constant 50% improvement in SSE-FS 
(median 13.5, hazard ratio 0.667) . 
Simulations indicated an average of 186.61 events would occur for this comparison at primary 
endpoint cut-off, and a 1-sided log-rank test with 0.10 significance gave approximately 90.5% 
power to test H01 versus HA1.

Comparison 2 assumes: 
o
Arm A (standard dose) subjects have constant median SSE-FS of 9 months 
o
Arm C Extended dose subjects have

Median SSE-FS of 9 months for the first 24 weeks

A 65% improvement (median 14.85, hazard ratio 0.606) thereafter. 
With 240 of 360 subjects randomized to Treatment Arm A and Treatment Arm C, simulations 
indicated that 44.65% of randomized subjects (107.2 of 240) would have a SSE-FS event or 
loss to follow-up during the first 24 weeks, leaving an estimated 55.35% (132.8) surviving 
SSE-free and eligible for inclusion at 24 weeks. An average of 74.91 simulated events 
occurred for this comparison, and a 1-sided log-rank test with 0.10 significance (0.2 for two-
sided test) gave approximately 80.6% power to test H02 versus HA2.
Simulations assume continuous event and censoring times. Last treatment is assumed to occur 
44 weeks (10.12 months) after last subject accrued.
Primary endpoint power calculations were based on simulations programmed using SAS 
version 9.2 and used 10,000 replicates.
The simulations, taking into account the correlated nature of the data supporting the two 
comparisons in this study design, indicated that the proportion of replicates rejecting at least 
one null hypothesis was 16.4%, and the proportion of replicates rejecting both was 2.3%.


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
11 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
4. General Statistical Considerations
4.1
General Principles
The statistical evaluation will be performed by using the software package SAS release 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). Descriptive statistics will summarize the number 
of data available and missing data, mean, standard deviation, minimum, quartiles, median,
and maximum for continuous data, and frequency tables (number of data available and 
missing, and percent of available data) for categorical data.
4.2
Handling of Dropouts
A “dropout” is defined as a randomized subject who discontinues study participation prior to 
start of study treatment for any reason. 
Dropouts and subjects withdrawn from study treatment will not be replaced. Refer to Section 
5.2.1 in the study protocol for withdrawal of subjects from study.
4.3
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.
4.3.1 Imputation rules 
Unless otherwise specified data will not be imputed, and rules for imputation are specified in 
the dataset specification documents.
4.4
Interim Analyses and Data Monitoring
No interim analysis for efficacy is planned.
A Joint Safety Review Committee (JSRC) will perform monitoring for safety and protocol 
compliance. The JSRC will meet at regular intervals as specified by the JSRC charter, 
approximately every 6 months, and may decide to meet more frequently. The JSRC will be 
supported by an independent Statistical Analysis Center (SAC) as specified in the Charter. 
Reports to the JSRC will be specified in a separate document. 
The conduct of the JSRC is generally similar to a Data Monitoring Committee, except that 
membership may include sponsor, investigator, and/or independent members, and interim 
results of this open-label trial may be disclosed to the sponsor.  Further details are described 
in the JSRC charter.


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
12 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
4.5
Data Rules
4.5.1 Determining Baseline Values
This study has two distinct baselines for efficacy analyses, the randomization baseline and the 
Week 24baseline.
Randomization baseline value for efficacy parameters: is defined as the last non-missing
value on or before the date of randomization.  
Week 24 baseline: Unless otherwise specified, the ‘Week 24 baseline’ is defined as the date 
of the 6th injection. This baseline is defined only for those subjects who are eligible for 
Comparison 2 analyses. That is, subjects who had received at least 6 injections.
Week 24 baseline value for efficacy parameters: Unless otherwise specified, the ‘Week 24
baseline value’ is defined as the last non-missing value on or before the date of the 6th
injection.
Ideally, this visit would be the date of the 7th injection for Arm C subjects and expected 7th
injection date for Arm A subjects. However, the end of treatment visit(30±7 days from last 
dose) for Arm A subjects could be missing due to consent withdrawal or happen out of visit 
window. Hence, there is no comparable visit for Arm A subjects that could be used as the 
expected 7th injection date.   
To account for this and achieve comparability between the two arms, the 6th injection date is 
used as the reference date for Comparison 2 subjects. It should be noted that this could lead to 
a somewhat dilution of the treatment effect in Arm C due to an early reference date.  
Baseline value for safety parameters: is defined as the last non-missing value on or before 
the date of first dose.
4.5.2 Pooling cut-off date for Arm C subjects in Comparison 1
For Comparison 1, Arm C subjects are planned to be pooled with Arm A subjects. This 
pooling will be done such a way that only comparable data from Arm C subject pooled. The 
following algorithm will be used to identify the cut-off date for pooling:
Arm C: Pooling cut-off date = 7*28 + randomization date; for subjects that were randomized 
but not treated,
= (7-x)*28 + last dose date; for 1 ≤ x ≤ 6,
= 7th dose date; for x ≥7,
where x be the number of injections received.
4.6
Validity Review
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 Plan
16507: BAY 88-8223/16507
Page:
13 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
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.
4.6.1 Protocol Deviations
Assessment criteria, deviation definitions, are described in a separate Protocol Deviations 
document.   
4.7
Additional Statistical Considerations
4.7.1 Delayed Effect Efficacy Assumptions
Since the comparison between the “standard” and “extended” regimens involves identical 
treatment for the first 6 doses, the following assumptions were made:

Both regimens  have identical efficacy for the first 6 doses, and 

The efficacy would diverge at the time that extended-dosing subjects received their 7th
dose.  
This feature is consistent with a delayed effect as described in Fine (2007) [1] and Zhang and 
Quan (2009) [2]. To account for this delayed-effect feature, hazards were modeled using a 2-
compartment approach:

With the standard (Arm A) and high-dose (Arm B) regimens having constant 
hazards throughout the study, and 

The extended regimen (Arm C) initially having the same hazards as the standard 
regimen (Arm A) but having a fixed change point at Week 24, approximately the 
point at which the 7th dose would begin, with constant, reduced hazards thereafter. 
A sensitivity analysis using two-compartment Cox model will be performed by taking into 
account of this delayed-effect feature for Comparison 2. The details are specified in Section 
6.2.1.
5. Analysis Sets

Intent-to-treat (ITT): All randomized subjects.  The ITT population will be used in 
the analysis of efficacy endpoints for Comparison 1.  Subjects will be included in ITT 
analyses according to the treatment to which they were randomized as based on IXRS.
The randomization baseline will be used in the ITT analyses.

Week 24(W24): All ITT subjects in Arm A (standard dose) and Arm C (extended
dosing) treated with radium-223 dichloride and eligible for further treatment at W24 
(i.e., 7th injection).  Week 24 applies to subjects who received the 6th injection 
without any dose delays. As dose delays are allowed per protocol, 6th injection can 
occur after Week 24 for subjects who had dose delays. Hence, this population is 
defined based on the number of injections not based on the timing.  The W24 dataset 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
14 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
will be used for the analysis of efficacy endpoints  related to Comparison 2 and 
associated evaluations.  Subjects will be included in W24 analyses according to the 
treatment to which they were randomized. 

Safety (SAF): All subjects who have received at least one study drug administration.   
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.
6. Statistical Methodology
6.1
Population characteristics
6.1.1 Disposition of Subjects
The  number and percentage of subjects screened, randomized, and treated will be presented 
by treatment group and overall.  In addition, the number of subjects discontinued prior to 
receiving the 6th injection in Arm A and C will be tabulated. The reasons for subjects 
discontinuing from treatment will be summarized by treatment group. In addition, the number 
of subjects screened and included in each analysis population will be displayed overall and by 
country and investigator.
6.1.2 Demographic and Baseline Characteristics
Descriptive summaries of demographics and baseline characteristics will be presented by 
treatment group and overall for the ITT, Safety and W24 populations whenever applicable. 
Comparability of the treatment groups with respect to demographics and baseline 
characteristics will be assessed using descriptive summaries.
For these tables, the summaries refer to the randomization baseline by default, using the ITT 
or Safety population. Additional summaries for the W24 population, using week 24 baseline, 
are identified below as “(W24)”. ITT population tables will be reported both by treatment 
arm, and by pooled arms (A & C).
The following demographic data will be summarized:

Age (years)

Age category (< 65, 65 – 74,  75-84, ≥85 years)

Race and ethnicity

Height (cm)

Weight (kg) (W24)

Vital signs:  blood pressure (mm Hg), heart rate (bpm), respiratory rate (rpm), and 
temperature (°C)
The following baseline characteristics will be summarized:

Stage of prostate cancer at initial diagnosis (TNM)

Histology Stage of prostate cancer at study entry (TNM)


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
15 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5

Status of primary tumor at study entry

Gleason score at initial diagnosis of prostate cancer

PSA and total ALP(W24)

ECOG Performance Status (W24)

Number of bone lesions (1-5, 6-20, >20 but not a superscan vs. superscan at baseline)

Bone scan lesion area 

BPI-SF average WPS (W24)

Time from initial diagnosis to randomization for prostate cancer and bone metastases
(months)

Time from first progression to randomization for prostate cancer and bone metastases 
(months)

Time from most recent progression to randomization for prostate cancer and bone 
metastases (months

Time from first progression to most recent progression for prostate cancer and bone 
metastases (months)
Categorical summaries of each of three randomization stratification factors per IXRS: 

Use of prior chemotherapy (≤ 1 regimen versus > 1 regimen)

Total ALP (< 220 U/L versus ≥ 220 U/L) and 

Average worst pain score (WPS) of the BPI-SF at randomization (WPS≤ 4 versus 
WPS >4), will also be presented for the ITT and W24 populations. 
The discordance for each stratification factor between CRF and IXRS data will be presented 
in a shift table.
In addition, average WPS at randomization, as used to calculate the average WPS 
randomization stratification factor, will be summarized.
The following body descriptors will be summarized as described in Green and Duffull (2004) 
[3]:

Total body weight(TBW), defined as the weight (kg) used for calculating the first dose

Total body weight (W24), defined as the Week 24 baseline weight (kg)

Body Mass Index, and Body Mass Index (W24), calculated as:
 =
	
 ()
[	
 ()]

Ideal Body Weight(IBW) will be calculated as: 
IBW = 50.0 + [0.89 x (HT(cm)-152.4)] for male
Subjects will be classified by BMI as low weight (BMI < 18.5), normal weight (18.5 ≤BMI 
< 30), or high weight (BMI ≥30) at each baseline [4]. Baseline BMI will also be categorized 
as low versus normal/high. 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
16 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
6.1.3 Medical history
Medical history will be summarized by MedDRA body system organ class (SOC) and 
preferred term (PT) for the ITT population overall, by treatment group, and for pooled arms A 
& C.
6.1.4 Extent of Exposure
Extent of exposure will be summarized for the Safety population by treatment group, using 
descriptive statistics. 

Duration of study treatment will be calculated in days as the date of the last dose of 
study  – date of the first dose of study treatment + 1

Number of radium-223 dichloride injections received. Summary statistics will include 
both descriptive statistics of number of doses received, and number and percent of 
subjects by number of doses received

Total activity of radium-223 dichloride (sum of activity in all doses) in kBq and 
kBq/kg

Dose intensity of radium-223 dichloride calculated as total activity of radium-223 
dichloride/(duration of study treatment + 27), in kBq/day and KBq/kg/day

Number and percent of subjects with dose modifications (none, at least one 
interruption/delay)

Normalized dose for  total body weight (TBW) and ideal body weight (IBW) will be 
summarized by quartile:
Total body weight normalized dose=Activity in the first dose administered to subject 
/body weight used for first dose
Ideal body weight normalized dose= Activity in the first dose administered to subject 
/ideal body weight
All exposure summaries will be based on the old standard (50 or 80 kBq/kg). Hence, doses 
administered with the new standard (55 or 88 kBq/kg) will be converted to the old standard 
prior to any analyses as specified below. A country specific 2016 NIST implementation date 
will be utilized for this conversion.
Radioactivity will be calculated as follows:

Activity per injection (kBq) = Activity in syringe before injection (kBq) - activity in 
syringe after injection (kBq)

Activity adjusted 
1. If the dose date is prior to 2016 global NIST implementation date in the country, 
then Activity per injection = Activity per injection 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
17 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
2. If the dose date is after the 2016 global NIST implementation date in the country, 
then Activity per injection  = Activity per injection/1.1

Total activity injected (kBq) = Sum of (‘Activity per injection’)
6.1.5 Prior and Concomitant Medications
All investigator-reported non-study medications taken before and/or during the study will be 
coded using the Bayer modified version of 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 before and/or during the study will be categorized as prior 
medications, concomitant medications, and post treatment medications. 
Classifications of prior and concomitant medication as based on Table 6–1.
If a start date is missing,  the medication will be assumed to start prior to first dose of study 
drug. If the end date is unknown and ‘ongoing’ was not checked in CRF, the medication will 
be assumed to end at the last visit date, death date or withdrawal from study date, whichever 
is the latest. 
All concomitant medications will be listed, including verbatim descriptions and coded terms, 
and flags for prior/concomitant/post treatment medications. Prior, concomitant, and post 
treatment medications 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.
Summaries will also be produced for anti-cancer therapies (systemic therapy, radiotherapy as 
well as diagnostic and therapeutic procedures). These summaries will be created for ITT 
population and Week 24 population.
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


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
18 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
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
For Comparison 1, Arm A will be pooled with Arm C in the time-to-event analyses. Refer to 
censoring rules in Section 4.5 for the pooling algorithm. No pooling of Arm C subjects will 
occur in Comparison 1 for non-time-to-event endpoints (e.g. pain improvement rate).  
As sensitivity analyses, the analyses described for Comparison 1 will also be performed 
between Arm A and Arm B only (i.e., without pooling Arm C data).
Each efficacy endpoint will be defined separately for Comparison 1 and Comparison 2. For 
Comparison 1 analyses, endpoints will be defined following randomization baseline. For 
Comparison 2 analyses, endpoints will be defined following Week 24 baseline(the 6th dose 
date) unless otherwise specified.
Imaging endpoints based on tumor assessments, will not follow the Week-24 baseline for 
Comparison 2 analyses. The study did not plan to do Week 24 re-baseline for the site 
investigators. The site investigators would determine PD only based on the randomization 
baseline. Once a subject had a PD (or a confirmed PD for bone progression) based on 
randomization baseline, the subject will not be further followed for a second PD using Week-
24 assessment as the new baseline. Therefore, there will be no assessments after an 
observation of PD to perform re-reads of tumor assessments based on the Week-24 baseline 
by the central reviewer. This incomplete tumor assessments can lead to a biased analysis 
favoring one arm vs the other (i.e., the arm with more PDs based on randomization baseline 
could have more censored data for the analyses based on Week-24 baseline). Hence, the 
Comparison 2 analysis on the Week-24 population will only be performed based on the 
randomization baseline, not the Week-24 baseline for both investigator and centrally 
reviewed data.
6.2.1 Primary Efficacy Analysis
The primary efficacy endpoint, symptomatic skeletal event-free survival (SSE-FS), will be 
defined separately for each of the two efficacy evaluations described above, as follows: 
For Comparison 1, SSE-FS following randomization is defined in ITT subjects as the time
from randomization to an SSE or death, whichever occurs first.  Refer to Appendix 9.1.1 for 
censoring rules.
For Comparison 2, SSE-FS from 6th dose is defined in W24 subjects as the time from Week 
24 baseline (the 6th dose date) to an SSE or death, whichever occurs first.  Refer to Appendix
9.1.1 for censoring rules.


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
19 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
For both evaluations, a symptomatic skeletal event (SSE) is defined as follows:

The use of external beam radiotherapy (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.
The censoring rules for SSE-FS for each comparison are summarized in Table 9–1 and Table 
9–2 of Appendix 9.1.1.  Stratified statistical tests described in this section refers to two of the 
three randomization strata as determined by the IXRS: use of prior chemotherapy (≤ 1 
regimen versus > 1 regimen), and total ALP (< 220 U/L versus ≥ 220 U/L). Note that 
Average worst pain score (WPS) was included as one of stratification factor for 
randomization in order to balance the baseline pain across three arms. However, WPS will not 
be included in the analysis to avoid sparse cells due to relatively small sample size within 
each arm. 
Each analysis will use a stratified log-rank test.  A one-sided significance level of 0.10 will be 
used for interpretation of the results.  Additionally, the hazard ratio (respectively high 
dose/standard dose and extended dose/standard dose) will be computed together with the two 
sided -80% and -95% CIs using a stratified Cox regression model.  There will be no 
adjustment for multiple comparisons.
SSE-FS will also be summarized using Kaplan-Meier [5] estimates. Kaplan-Meier [5] curves 
will be generated, and median survival time together with the 25th and 75th percentiles and 
associated Brookmeyer-Crowley [6] 80% and 95% CIs will be presented separately for the 
two comparisons. Kaplan-Meier plots will be presented for the time from randomization for 
both Comparison 1 and 2. Additionally, similar descriptive summaries will be created for 
Week 24 population using the randomization baseline.
For each comparison, the contribution of each component of the SSE will be evaluated.
Descriptive statistics will be presented.
A Kaplan-Meier [5] curves will be generated for each BMI category ( < 18.5,  ≥ 18.5 - < 30), 
and  ≥ 30) by treatment group within the 2 comparisons. The effect of low baseline BMI 
status on efficacy will be addressed by including baseline BMI category as a binary covariate 
(low versus normal/high) in a stratified Cox proportional hazards model.
A 2-compartment Cox model will be fitted as a sensitivity analysis to explore differences 
between arms A and C for the two time periods before and after the 6th dose, with period as a 
time-varying covariate. Hazard ratio (and CIs) will be reported for each time period and 
treatment arm.


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
20 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Supportive analysis for SSE-FS will be performed for each comparison using a non-stratified 
log-rank test. The treatment effect (hazard ratio) will be estimated using an unstratified Cox 
model.
The comparison 2  for SSE-FS will be also performed using randomization baseline as 
supportive analysis. 
As an exploratory analysis, stratified Cox proportional hazards regression models may be 
fitted for each comparison including other applicable baseline covariates considered to be of 
prognostic importance.  Time-dependent covariates that may be investigated individually in 
the model include: non-study systemic anti-cancer therapy, increase in analgesics use,  
radiological progression, pain progression, and pain improvement.
6.2.2 Secondary Efficacy Analysis
6.2.2.1 Secondary efficacy endpoints
The secondary efficacy variables are specified below.  

Overall survival

Time to first SSE

Radiological progression-free Survival (rPFS)

Time to radiological progression (TTP)

Pain improvement rate

Time to pain progression
Overall survival is defined for each comparison as the time (days) from the applicable start 
date to the date of death due to any cause.  See Table 9–3 in Appendix 9.1.2 for detailed 
censoring rules.
Comparison 1:
Arm C subjects who have died or are known to be alive after ‘pooling cut-off date’ will be 
censored on the ‘pooling cut-off’ date. Refer to Section 4.5 for pooling cut-off date.
All other subjects in arms A, B and C, refer to Table 9–3 for censoring rules.
Overall Survival (OS) following randomization = End Date – Date of Randomization +1
Comparison 2:
For Comparison 2 eligible subjects, refer to Table 9–3 for censoring rules.
Overall Survival (OS) following Week 24 baseline = End Date – Date of Week 24
baseline(the 6th dose date) +1


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
21 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Time to first symptomatic skeletal event is defined for each comparison as the time (days) 
from the applicable start date to the date of the first SSE. See 
Table 9–4 in Appendix 9.1.3 for detailed censoring.
Time to radiological progression is defined for each comparison as the time (days) from the 
randomization date to the date of the first radiological progression.  Comparison 2 will not 
follow the Week-24 baseline and randomization baseline will be used instead. See Table 9–5  
and Table 9–6 in Appendix 9.1.4 for detailed censoring rules.  
The central reviewer will evaluate the radiological imaging produced by the investigator. 
Primary radiological progression endpoints will be based on the central radiological reviewer 
assessments.  Investigator assessments will be provided as a sensitivity analysis.
Radiological progression of soft-tissue disease is determined  according to modified RECIST 
criteria, version 1.1 (See Protocol Section 14.1) based on MRI / CT scans of the chest, 
abdomen, and pelvis.
Radiological progression of bone disease is determined  according to adapted PCWG2 criteria 
(see Protocol Section 14.2) based on whole body technetium-99 bone scans.
Radiological progression of bone disease requires confirmation.  A subject is considered to 
have progressed by bone scan if: 

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).
The date of progression of bone disease will be the date of the first observed bone 
progression, not the date that confirmed the bone progression.  
The date of radiological progression will be determined following the rules in Table 9–6.
Radiological progression-free survival is defined for each comparison as the time (days)
from the randomization baseline to the date of radiological disease progression or death from 
any cause (if death occurs without prior progression).  See Table 9–7 in Appendix 9.1.5 for 
detailed censoring rules for both Comparison 1 and Comparison 2. 
If data permits, unconfirmed radiological progression-free survival and time to unconfirmed 
radiological progression will be analyzed as sensitivity analyses based on central reviewer. 
Bone progression in this case does not require confirmation. 
Pain endpoints
The pain data collected from ePRO will be used for these analyses.
Worst pain score (WPS) at a given visit is defined for each subject as the mean of the 7 day
“worst pain score” assessments taken on or before each applicable visit. If less than 4 non-


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
22 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
missing WPS values are available for a given visit, then the weekly worst pain score will be
left missing for that visit. 
Timepoint pain improvement rate is defined with respect to each applicable baseline as the 
proportion of subjects with a 30% and 2-point decrease in WPS with respect to the applicable 
baseline assessment over 2 consecutive assessment periods conducted at least 3 weeks apart
among subjects with a WPS score ≥ 4 at the applicable baseline.  The first of the 2 
consecutive periods is taken to be the date of improvement.  
      Time to pain progression is defined for each comparison in subjects with a WPS of ≤ 7 
at the applicable baseline as the time from the applicable start date to an increase of 2 or 
more points in WPS (with respect to the applicable baseline). Refer to 
Table 9–4 in Appendix 9.1.3 for detailed censoring rules. 
6.2.2.2 Analysis of secondary efficacy endpoints
The following secondary efficacy time-to-event endpoints will have hypothesis testing 
performed for both Comparison 1 and Comparison 2: OS, time to first SSE, time to 
radiological progression, and rPFS.
A one-sided type I error rate of 0.10 will be  used for secondary efficacy endpoint hypothesis 
testing. 
Hypothesis tests for these endpoints will be performed using a stratified log-rank test 
accounting for the same two randomization stratification factors as for the primary endpoint 
analysis (See Section 6.2.1). The treatment effect (hazard ratio) will be estimated using the 
Cox proportional hazards regression model stratified by the above-mentioned two
randomization stratification factors. For rPFS and time to radiological progression, analyses 
will be done based on both the investigator’s and the independent assessments. Analysis 
based on the independent central review assessment will be considered the primary analysis 
for rPFS. 
Secondary efficacy time-to-event endpoints will be summarized using Kaplan-Meier [5]
estimates. Median survival time together with the 25th and 75th percentiles and associated 
80% and 95% Brookmeyer-Crowley [6] confidence intervals (CI) will be presented by group. 
Corresponding Kaplan-Meier [5] curves will be generated by group.  
Pain improvement rate will be calculated for each post-baseline timepoint, with exact 
binomial 80% ad 95% Clopper-Pearson [7] confidence intervals.   Pain improvement rate 
with exact binomial 80% and 95% CIs will also be plotted by timepoint. 
6.2.3 Exploratory Analysis
For exploratory radiological endpoints, only central reviewer assessments will be analyzed.
6.2.3.1 Exploratory endpoints
The exploratory variables are specified below: 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
23 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5

Time to radiological bone progression

Time to radiological soft-tissue progression

Patient bone scan lesion area (BSLA) 

Patient bone scan time point response rate (week 8, week 16 and week 24) and best 
overall response rate, based on central review

Total alkaline phosphatase (ALP) response rate

Time to total alkaline phosphatase (ALP) progression

Time to total alkaline phosphatase (ALP) progression without 12 week restriction

Percentage change in total alkaline phosphatase (ALP) at 12 and 24 weeks

Prostate specific antigen (PSA) response rate 

Time to PSA progression 

Time to PSA progression without 12 week restriction

Pain improvement rate without increase in analgesic use (week 12, week 24, EOT and 
overall) 

Time to pain progression or increase in analgesic use 

Change in analgesic use

Time to increase in analgesic use

NCCN-FACT FPSI-17 subscale scores 
o
FPSI Disease Related Symptoms – Physical (DRS-P) 
o
FPSI Disease Related Symptoms – Emotional (DRS-E) 
o
FPSI Treatment Side Effects (TSE) 
o
FPSI Function/Well Being (F/WB) 

Time to increase in physical symptoms of disease based on FPSI-DRS-P 

BPI-SF subscale scores and aggregate indices
o
BPI-SF Pain Severity Index 
o
BPI-SF Function Interference Index 

Average Pain Score (APS)
6.2.3.1.1 Exploratory endpoints
For all exploratory time-to-event endpoints, randomization baseline will be used for all the 
analyses unless otherwise specified.  Week 24 baseline will not be defined for exploratory 
endpoints. 
Radiological endpoints 
Only central reviewer assessments will be analyzed for exploratory radiological endpoints.
Time to radiological bone progression is defined for each comparison as the time (days) 
from randomization date to the date of confirmed radiological bone progression.  See Table 
9–5 in Appendix 9.1.4 for detailed censoring rules.  


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
24 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Time to radiological soft-tissue progression is defined as the time (days) from 
randomization date to the date of radiological soft tissue progression.   See Table 9–5 in 
Appendix 9.1.4 for detailed censoring rules.  
Quantitated bone scan endpoints 
Digitized images of whole body quantified technetium-99 bone scans will be evaluated by the 
central imaging reviewer using CAD system software using the method of Brown et al. 
(2012) [8], as described in the imaging charter. The central reviewer will use the CAD system 
software to evaluate each subject’s digitized whole body quantified technetium-99 scans at 
each timepoint.  The reviewer will identify the bone pixels, and determine the area (cm2) and 
disease status (bone lesion, not bone lesion) associated with each bone pixel [8].
The analysis timepoints for the analysis of quantitative bone scan endpoints are randomization 
baseline, Week 8, 16, 24, and every 12 weeks thereafter.
For analyses reported by visit, nominal visit per CRF will be used. 
Patient bone scan lesion area (BSLA) is defined for each subject at each assessment as the 
sum of the pixel areas (cm2) of the set of the whole body quantified technetium-99 bone scan 
imaging pixels identified as bone lesion, as determined by the central imaging reviewer using 
the CAD system software. 
Patient bone scan timepoint response rate (week 8, 16 and week 24) For each 
comparison, patient bone scan timepoint response with respect to the randomization baseline 
will be assessed according to the following criteria in Table 6–2:
Table 6–2 Patient Bone Scan Timepoint Response Criteria Following Randomization
Responder (R)
30% or greater resolution of the BSLA compared to baseline
Stable Disease (SD)
Not meeting the criteria for R, PD, or UE
Progressive Disease 
(PD)
Two or more new areas of radiotracer uptake attributable to metastatic 
disease in regions of bone that had not previously shown radiotracer uptake 
or greater than 30% increase from baseline in bone scan lesion area in areas 
attributable to metastatic disease.
Unable to Evaluate (UE)
Assigned if bone scan results cannot be interpreted due to inconsistent image 
acquisition parameters compared to the reference scan, incomplete imaging, 
or other similar technical deficiencies.
Subjects with no randomization baseline assessment or a baseline BSLA value of 0 will be 
assigned ‘UE’ values for all timepoints  for the comparison.  The response rate is the 
proportion of subjects with a response at the timepoint among the subjects evaluable for bone 
scan response at the randomization baseline.  


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
25 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Patient bone scan best overall response rate is defined for each comparison as the 
proportion of subjects having the best bone scan timepoint overall response as R, SD, PD, or 
UE among subjects with a non-zero BSLA measurement at the randomization baseline.
Overall response is judged on all responses observed during the post-baseline period, 
including unscheduled visits.  Responder and SD responses will only be reported if observed 
prior to PD.  No confirmation of R or PD status is required. 
Total ALP and PSA Endpoints 
Total ALP and PSA endpoints are determined based on the total ALP and PSA laboratory 
assessments collected as described in the schedule of procedures.
Total ALP response rate is defined as the proportion of subjects with a ≥30% reduction of 
the blood total-ALP level compared to the randomization baseline, confirmed by a second 
consecutive ALP value 4 or more weeks later but within 9 weeks, among evaluable subjects.  
PSA response rate is defined as the proportion of subjects with a ≥30% reduction of the 
blood PSA level, compared to the randomization baseline value, confirmed by a second 
consecutive  PSA value e  4 or more weeks later but within 9 weeks, among evaluable 
subjects.
In addition, percentage change from randomization baseline in Total ALP at weeks 12 
and 24 will be summarized for Comparison 1. 
Time to total ALP progression is defined as the time (days) from randomization date to the 
date of first total ALP progression.  A progression event is defined as 25% increase from 
randomization 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 consecutive value obtained 3 or more weeks later but within 9 weeks in subjects with 
an initial ALP decline from the baseline.
Time to total ALP progression without 12-week restriction is similar to the time to total 
ALP progression defined above except that 12-week rule is removed in subjects with no ALP 
decline from baseline.
See Table 9–4 in Appendix 9.1.3 for detailed censoring rules.
Time to PSA progression is defined as the time (days) from randomization baseline to the 
date of first PSA progression. A progression event is defined as 25% increase from 
randomization baseline value and an increase in absolute value of 2 ng/mL, at least 12 weeks 
from the applicable 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 
consecutive value obtained 3 or more weeks later but within 9 weeks in subjects with an 
initial PSA decline from the baseline.   
Time to PSA progression without 12 week restriction is similar to the time to PSA 
progression defined above except that 12-week rule is removed in subjects with no PSA 
decline from baseline.
See 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
26 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Table 9–4 in Appendix 9.1.3 for detailed censoring rules .
Analgesic Use and Related Endpoints
Analgesic use in this study will be captured via two 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.
Data from both sources will be used to identify strength of  each analgesic used by each 
subject at baseline and post-baseline visits.  The amount of medication a subject actually took 
cannot be calculated due to only prescribed information is collected on the eCRF. Hence, 
only drug name will be used in identifying non-, weak- or strong- opioids for analgesics 
related analyses. 
Analgesic names will be coded into standard terms using the World Health Organization Drug 
Dictionary (WHO-DD), Version 2005 Q3.
Each standardized analgesic name will be classified by strength type as non-opioid, weak 
opioid, or strong opioid. 
An increase in analgesic use following randomization baseline is defined in Table 6–3 below.
If a subject is using more than one type of analgesic, the strongest type will be used in the 
analysis.
Table 6–3 Increase in Analgesic Use Algorithm
Pain improvement rate without increase in analgesic use following baseline  is defined at 
each post-baseline assessment time point as the proportion of subjects with a 30% and 2-point 
decrease in average WPS over 2 consecutive assessment periods conducted at least 4 weeks 
apart, without a corresponding increase in analgesic use over those 2 periods.  The 
denominator is the number of subjects with a non-missing WPS of at least 4 at randomization.
Time to increase in analgesic use is defined as the time in days from randomization baseline
until the first increase in analgesic use for subjects with baseline average WPS of ≤ 7 and non-
missing baseline assessment of  analgesic use. See Table 9–5 in Appendix 9.1.4 for detailed 
censoring rules.
Baseline intake 
Post baseline
No analgesics or a 
non-opioid
Initiation of any opioid
Weak opioid 
Initiation of any strong opioid
or adding an additional weak 
opioid
Strong opioid
Initiation of an additional
strong opioid


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
27 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Pain progression or increase in analgesic use following baseline is defined as the time in 
days from randomization baseline until the earlier of pain progression or a first increase in 
analgesic use for subjects with a non-missing baseline average WPS of ≤ 7. See Table 9–4 in 
Appendix 9.1.3 for detailed censoring rules.
Change in analgesic use following baseline : A shift table will be presented to summarize 
the change in strength of analgesic use from randomization baseline to the strongest use at
post-baseline. The strength type will include: no analgesics or non-opioid, weak opioid, and 
strong opioid. 
NCCN-FACT FPSI-17 Endpoints
The NCCN-FACT FPSI-17 is a validated instrument that was developed to assess symptoms 
of prostate cancer, symptoms caused by the treatment of prostate cancer, and the health 
related quality of life of prostate cancer patients. [12] The instrument contains 17 items, each 
of which utilizes a Likert scale with 5 possible responses.  Ten 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 (FPSI-DRS-P, Disease Related Symptoms –
Physical),  One item represents emotional symptoms of disease and the response to that item 
is used to calculate a disease related emotional symptom subscale score (FPSI-DRS-E, 
Disease Related Symptoms – Emotional).  Four items represent treatment related symptoms 
and the responses to these items are summed to calculate a treatment side effect subscale 
score (FPSI-TSE,  Treatment Side Effects).  Finally, two items represent functional well-
being and the responses to those items are summed to calculate a functional/well-being 
subscale score (FPSI-F/WB, Function/Well Being).
The  NCCN-FACT FPSI-17 total score and each of its subscale scores, FPSI-DRS-P, FPSI-
DRS-E , FPSI-TSE, and FPSI-F/WB, will be summarized by visit.
Time to increase in physical symptoms of disease  based on FPSI-DRS-P will be 
evaluated based on the FPSI-DRS-P subscale score of the NCCN-FACT, as the time from 
treatment start to the first increase in physical symptoms of disease on-study. NCCN-FACT 
FPSI-17  was not collected prior to randomization, so baseline is the assessment collected 
prior to first dosing. An increase 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. See Table 
9–4 in Appendix 9.1.3 a for detailed censoring rules.
BPI Subscales
Each subject will fill out the complete 11-question BPI-SF using an ePRO device at the 
Treatment Day 1 visit and at each clinic visit thereafter through Week 48. For subjects in 
Arm A and Arm B, the modified complete BPI-SF will also be filled out on the day of 
telephone contacts scheduled for Weeks 28, 32, 40, and 44. The data will be collected for one 
week (6 days prior to the applicable visit and the morning of the visit) prior to each clinic visit 
or phone call follow-up. 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
28 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
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 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 sum of the 
four items on the pain intensity, and (2) Function interference index, using the sum of the 
seven pain interference items (at least 4 out of 7).  
Each BPI-SF subscale, and the two indices for pain severity and function interference, will be 
summarized using descriptive statistics.  
Weekly Average pain score (APS) is defined for each subject at baseline and at each post-
baseline date, as the mean of the “average pain score” values in the last 24 hours from the 
preceding 7 days before each applicable visit or telephone contact per the BPI-SF. 
Analysis of Exploratory Endpoints
Identical statistical methods for analyzing time-to-event secondary endpoints, as elucidated in 
section 6.2.2.2, will be applied to the analysis of time-to-event exploratory endpoints:

Time to radiological bone progression 

Time to radiological soft-tissue progression 

Time to total alkaline phosphatase (ALP) progression

Time to ALP progression without 12-week restriction

Time to PSA progression 

Time to PSA progression without 12-week restriction

Time to pain progression or increase in analgesic use following baseline 

Time to increase in analgesic use
Time to increase in physical symptoms of disease based on FPSI-DRS-P 
Descriptive statistics (n, nmiss, mean, std, median, interquartile range, range) will apply to 
other exploratory endpoints by timepoint:

Bone scan lesion area

Percent change in ALP from baseline 

NCCN-FACT FPSI-17 subscale scores and total score 

BPI-SF subscales and 2 indices (pain severity and function interference)
The following rates will be summarized using (n, %) with exact binomial 80% and 95% CIs 
using the method of Clopper and Pearson [7]

Timepoint and Best overall bone scan response rate


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
29 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5

ALP response rate

PSA response rate

Pain improvement rate without increase in analgesic use
o
Plots with 80% and 95% confidence intervals at each timepoint will also be 
provided.
A shift table will be presented to summarize the change in the strength of analgesic use from 
randomization baseline to the strongest use at post-baseline. 
Summary statistics on weekly worst pain score at baseline and at each post-baseline timepoint 
(n, nmiss, mean, std, median interquartile range, range) will be presented. 
6.3
Pharmacokinetics / pharmacodynamics
Not applicable.
6.4
Safety
No formal statistical tests will be done for the safety endpoints. 
A safety analysis will be performed at the same time as the final primary endpoint analysis.
This analysis will include treatment-emergent safety events as of database closure for primary 
endpoint completion. 
An updated analysis of safety events will be performed after the last followed patient 
completes active follow-up 2 years following the last dose of radium-223 dichloride 
treatment, which will be reported in a separate document from the Clinical Study report. In 
addition, safety events emerging during long-term follow-up conducted as part of this study 
will be reported in separate document(s) from the study Clinical Study Report.
6.4.1 Adverse events
All adverse events (AE) will be coded according to the latest Medical Dictionary for 
Regulatory Activities (MedDRA) Version as of database lock for the applicable analysis. The 
MedDRA version used will be documented in the CSR. The intensity of an AE will be 
documented using the NCI-CTCAE v4.03. 
Adverse Events of Interest
A summary table and a listing will be provided for subjects who experienced following  
adverse events:  pancytopenia and myelotoxicity including myelodysplastic syndrome, 
aplastic anemia and myelofibrosis. The events will be identified by medical reviewer based on 
verbatim recorded in database. 
Treatment Period Analyses


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
30 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
The treatment period for this study, for purposes of safety analyses, extends from the 
initiation of study treatment until 30 days after the last administration of radium-223 
dichloride. 
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 CTCAE
toxicity grade or became serious) during the treatment period. 
Treatment-emergent AEs
All AEs starting or worsening within the treatment period will be considered TEAEs,
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 treatment-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

any pre-treatment AEs TEAEs, or post-treatment AEs

any study treatment related TEAEs

any serious TEAEs, 

any serious treatment related TEAEs

any CTCAE Grade ≥3 TEAEs

any TEAEs leading to drug modification or discontinuation

any TEAEs leading to death

any AEs leading to drug modification or discontinuation
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. For post-standard treatment AE tables, 
only treatment-related AEs, serious treatment-related AEs will be reported. Subjects who 
received 6 or less doses from Arm A and C versus subjects received 7 or more doses in Arm 
C will also be summarized for evaluating potential cumulative toxicity of extended regimen.
The same summaries will be repeated for related TEAES, serious TEAEs, serious related 
TEAEs, CTCAE Grade ≥3 TEAEs, TEAEs leading to drug modification or discontinuation , 
TEAEs leading to death and any AEs leading to drug modification or discontinuation.
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.


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
31 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
The numbers of subjects experiencing TEAEs will be presented.
The analysis of TEAEs will be reported by treatment group as treated (Arm A, Arm B, and
Arm C ).
Long-Term Follow-Up AEs
Long-term follow-up AEs are AEs arising during the long-term follow-up period. LTFU AEs 
will not be included in safety analysis summary tables for this study, but will be included in 
listings.
AE Listings
Data listings will be produced for all AE recorded in the study. Verbatim descriptions and 
coded terms will be listed for all AEs. 
Serious adverse events (SAEs), deaths, AEs leading to discontinuation and AEs of interest 
will each have a separate listing.  
6.4.2 Deaths
Deaths reported during the study period will be tabulated by treatment group.
6.4.3 Clinical Laboratory Data
The following laboratory parameters will be summarized:

Complete blood count (CBC), including hematocrit, hemoglobin, red blood cell 
(RBC) count, mean corpuscular volume (MCV), mean corpuscular hemoglobin 
(MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cell 
(WBC) count, platelet count, and differential blood count reported as absolute count or 
percentage for neutrophils, lymphocytes, monocytes, eosinophils, and basophils

Chemistry panel, including serum creatinine, sodium, potassium, chloride, calcium, 
phosphorous, magnesium, total bilirubin, total ALP, AST, ALT, lactate 
dehydrogenase (LDH) (screening only), and albumin (screening only)

Other parameters: PSA, serum testosterone 
Hematological and biochemical laboratory values will be graded based on NCI CTCAE 
version 4.03. CTCAE severity grading for laboratory abnormalities are based on applicable 
laboratory threshold values outlined in NCI CTCAE v4.03. It should be noted that in the 
process of assigning toxicity grades of those lab parameters for which additional clinical 
information potentially can also influence the toxicity grade, this clinical information is in 
general not available and only the lab measurements are used for toxicity grading. 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
32 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Hematological and biochemical laboratory toxicities assigned by the investigator that include 
clinical assessments are available in Adverse Events database and are summarized in Adverse 
Event tables. 
Any additional specific handling of the CTCAE v4.03 toxicity grading assignments will be 
noted in the footnotes of the corresponding tables. 
Laboratory parameters will be evaluated for subjects in the safety (SAF) population by 
treatment group (Arm A, B, C). 
For each analysis, 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 change from baseline by group.  Box plots will
be generated for hematology parameters over all visits, by group, to investigate trends over 
time and outliers in the data. Graphs of hematological toxicity parameters (boxplots of mean 
and quartile values over time) will be produced. Similar graphs of chemistry and/or other lab 
parameters may also be produced. 
In addition, for each analysis, change from baseline will be summarized in shift tables 
according to CTCAE 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 not be 
included in the by visit summary tables, however will be included in the overall CTCAE 
grade tables. 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
33 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
6.4.4 New Primary Malignancies
The new primary malignancies will be summarized overall and by cancer type (n, percent), 
and reported through listings.
6.5
Analysis of Other Endpoints
6.5.1 ECOG Performance Status
For ITT subjects, the number and percentage of subjects in each category will be presented by 
treatment group. Changes from randomization baseline in PS on the ECOG scale will be 
summarized in shift tables by treatment group.
6.5.2 Quality of Life
Summaries of NCCN-FACT FPSI-17 questionnaire 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. Analyses of NCCN-FACT data are described in the 
sections on efficacy and exploratory endpoints.
6.5.3 Long Term Safety
Safety data arising during the long-term safety follow-up period in this study will be 
presented through listings. In the event subjects in this study transfer into a long term safety 
follow-up study for all or a portion of their long-term follow-up period, any data not collected 
in this study is outside the scope of this SAP. 
6.6
Examination of Subgroups
Subgroup analyses will be conducted for the primary efficacy endpoint SSE-FS following 
randomization based on the ITT population, and SSE-FS following Week 24 baseline on the 
W24 population, and for secondary endpoint OS. Subgroup analyses will be provided by 
subgroup within each respective pooled treatment grouping, as described for the primary 
analysis for each comparison. Descriptive statistics and hazard ratio estimates with 80% and 
95% CIs will be provided at least for the subgroups listed below, provided there is a sufficient 
number of events (at least 10 events) in total within the subgroup across the applicable pooled 
treatment groups.  Hazard ratios by subgroup with 80% and 95% CIs will be plotted using 
forest plots. 

ECOG performance status at baseline (0 vs 1)

Extent of Disease (number of bone lesions: <6, 6-20, >20 or superscan at baseline)

Race (White, Asian and Other)

Age group (<65, 65-74, 75-84, >=85 years)

Baseline Total Body Weight and Ideal Body Weight normalized dose quartiles 

Randomization stratification factors: 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
34 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
o
use of prior chemotherapy (≤ 1 regimen versus > 1 regimen)
o
total ALP (< 220 U/L versus ≥ 220 U/L)
o
average worst pain score (WPS) of the BPI-SF at screening assessment (WPS 
≤4 versus WPS >4).

BMI
o
Low, non-low (< 18.5 and ≥ 18.5)
o
Non-high, high (< 30 and ≥ 30) 

Gleason Score at the time of diagnosis (<8, ≥8, Missing)

Baseline PSA values by median(<median, ≥median)

Received prior anti-androgens at baseline: abiraterone or enzalutamide (Yes vs. No)
For time-to-event endpoints, Kaplan-Meier [5] estimates will be presented with  median, 25th, 
and 75th percentile survival time and associated 80% and 95% Brookmeyer-Crowley [6] 
confidence intervals (CI), and number and percentage of censored observations.
Corresponding Kaplan-Meier curves will also be plotted.  A Cox proportional hazards model 
will be fitted for each time-to-event secondary efficacy endpoint, with baseline BMI category 
coded as a binary covariate (low versus non-low).   
Safety analysis (i.e. AE) will be conducted based on age subgroup, and ideal body weight 
normalized dose quartiles. 
7. Document history and changes in the planned statistical analysis
•
SAP 21 February 2016 version 1.0
•
SAP 17May 2017  version 2.0
Table 7–1 The Changes Between SAP V1.0 and SAP V2.0
Endpoints/Definitions
SAP V1.0
SAP V2.0
Week 24 baseline
The Week 24 baseline 
assessment was defined as the  
assessment within the window 
(Day 127, Day 211) (Week 24
target – 14 through Day 28 
target + 14) closest to Day 169 
(Week 24 target date), selecting 
the earlier date in the event of a 
tie.
‘Week 24 baseline’ is defined as the last 
non-missing value on or before the date of 
the 6th injection for Arm A and Arm C. 
Time to radiologic 
progression / rPFS/Bone 
scan time point &overall 
response
All imaging-based endpoints 
will be based on week-24 
baseline for Comparison 2.
All imaging endpoints will be based on 
randomization baseline for Comparison 2. 
PSA progression 
Prostate specific antigen 
progression is defined with 
respect to each applicable 
baseline, as a ≥25% increase 
Will use the definition consistent with 
compound standard: Prostate specific 
antigen progression is defined as 25% 
increase from the baseline value and an 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
35 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
above the applicable nadir 
(lowest baseline or post-
baseline) value, and an increase 
in absolute value of ≥2 ng/mL 
above the nadir.
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 consecutive value 
obtained 3 or more weeks later but within 9 
weeks in subjects with an initial PSA decline 
from baseline.   
Total ALP progression
Total ALP progression is 
defined with respect to each 
applicable baseline, as a ≥25% 
increase above the applicable 
nadir (lowest respective 
baseline or post-baseline) value.
Will use the definition consistent with the 
compound standard: 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 consecutive value obtained 3 or 
more weeks later but within 9 weeks in 
subjects with an initial ALP decline from 
baseline.
ALP response
Total ALP response is defined 
with respect to each applicable 
baseline, as a ≥30% reduction 
of the blood total-ALP level 
compared to the baseline value.
Will use the definition consistent with the 
compound standard: Alkaline phosphatase 
response is defined as ≥30% reduction of the 
blood level, compared to the baseline value, 
confirmed by a second consecutive ALP 
value 4 or more weeks later but within 9 
weeks.
Increase in analgesic use 
algorithm
Use AQA score in the algorithm
Will be based on strength and type of 
analgesic use. No AQA score will be 
calculated.
Exploratory endpoint
analyses
Both randomization baseline 
and week 24 baseline will be 
used in the analyses
Only randomization baseline will be used. 
Endpoints with respect to Week 24 baseline 
will not be derived as formal statistical 
comparisons will not be made.
8. References
1. Fine, D. Consequences of delayed treatment effects on analysis of time-to-event 
endpoints. Drug Inform J. 41:535–539 (2007)
2. Zhang, D., and Quan, H. Power and sample size calculation for log-rank test with a 
time lag in treatment effect. Stat Med.  28: 864–879 (2009)
3. Green B. and Duffull S. What is the best size descriptor to use for pharmacokinetic 
studies in the obese? J Clin Pharmacol. Aug 2004; 58(2): 119–133.
4. World Health Organization. “Obesity: Preventing and Managing the Global Epidemic. 
Report of a WHO Consultation.” WHO Technical Report Series 894. Geneva: WHO; 
2000. 8-9. 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
36 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
5. Kaplan E and Meier P. Nonparametric estimation from incomplete observations. J 
Amer Statist Assn 53:457–481 (1958)
6. Brookmeyer R and Crowley J. A confidence interval for the median survival time. 
Biometrics 38:29-41 (1982)
7. Clopper C and Pearson E. The use of confidence or fiducial limits illustrated in the 
case of the binomial. Biometrika 26:404–413. (1934)
8. Brown M, et al. Computer-aided quantitative bone scan assessment of prostate cancer 
treatment response, Nucl Med Commun. 33:384-94 (2012)
9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology: Adult Cancer Pain. Version 2.2014.
10. Butler, SF, Budman, SH, Fernandez, KC, et al. Development and validation of the 
current opioid misuse measure. Pain 142:144-156 (2007)
11. Pereira, J, Lawlor, P, Vigano, A, et al. Equianalgesic dose ratios for opioids: a critical 
review and proposals for long-term dosing J Pain and Symptom Manage 22:672-687 
(2001). 
12. http://www.facit.org/FACITOrg/Questionnaires.


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
37 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
9. Appendices
9.1
Censoring Rules
9.1.1 Censoring rules for Symptomatic Skeletal Event-Free Survival (SSE-FS)
Comparison 1:

Arm C subjects who had SSE assessments or SSE event or death (in the absence of an SSE event) after
‘pooling cut-off date’ will be censored on last SSE assessment date prior to ‘pooling cut-off date’. Refer 
to Section 4.5 for pooling cut-off date.

All other subjects in arms A, B and C, refer to Table 9–1  for censoring rules.

Symptomatic Skeletal Event Free Survival (SSE-FS) following randomization = End Date – Date of 
Randomization +1 
Table 9–1 Comparison 1: Censoring for Symptomatic Skeletal Event Free Survival 
(SSE-FS) 
      
Situation
End Date 
Censored
Reason for Censoring
No post-randomization  SSE 
assessment and no death
Date of Randomization
Yes
No post-baseline SSE 
assessments and no 
death
Subject had a 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 by database
cutoff date
Last SSE assessment 
prior to database cutoff  
Yes
Neither SSE nor  death
*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-randomization SSE assessment.
Note: symptomatic skeletal events immediately after missing SSE assessments are still counted as events in 
the analysis of SSE-FS.
Comparison 2:

All subjects eligible for Comparison 2, refer to Table 9–2 for censoring rules.

Symptomatic Skeletal Event Free Survival (SSE-FS) following Week 24 baseline= End Date – Date of 
Week 24 baseline(the 6th dose date) +1 
Table 9–2 Comparison 2: Censoring for Symptomatic Skeletal Event Free Survival 
(SSE-FS) 
       
Situation
End Date 
Censored
Reason for Censoring
No SSE assessment or death 
following Week 24 baseline
Date of Week 24
baseline  
Yes
No post-Week 24
baseline SSE 
assessments and no 


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
38 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
death.
Had an SSE event between date 
of randomization and Week 24
baseline
Date of Week 24
baseline  
Yes
First event occurred 
between date of 
randomization and 
Week 24 baseline
Subject had a SSE event after 
Week 24 baseline 
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 by database
cutoff date
Last SSE assessment 
prior to database cutoff 
Yes
Neither SSE nor  death
*The earliest end date in the table is used in calculating the SSE-FS.
#: use Week 24 baseline date instead of last SSE assessment date if no post-Week 24 baseline  SSE 
assessment.
Note: symptomatic skeletal events immediately after missing SSE assessments are still counted as events in 
the analysis of SSE-FS.
9.1.2 Censoring rules for Overall Survival  (OS)
Comparison 1:

Arm C subjects who have died or are known to be alive after ‘pooling cut-off date’ will be censored on 
the ‘pooling cut-off’ date. Refer to Section 4.5 for pooling cut-off date.

All other subjects in arms A, B and C, refer to Table 9–3 for censoring rules.

Overall Survival (OS) following randomization = End Date – Date of Randomization +1 
Comparison 2 

For Comparison 2 eligible subjects, refer to Table 9-3 for censoring rules. 

Overall Survival (OS) following Week 24 baseline = End Date – Date of Week 24 baseline(the 6th dose 
date) +1 
Table 9–3 Overall Survival censoring rules
Situation
End Date 
Censored
Reason for Censoring
Death on or prior to database cut off date  
Date of Death
No
N/A
Not known to have died as of database cut 
off date   
Last known alive date 
(LKAD) on or prior to 
database cutoff 
Yes
No Death
Lost to follow-up prior to database cutoff 
Last known alive date 
(LKAD)
Yes
Lost to follow up
  


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
39 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
9.1.3 Censoring rules for other time-to-event endpoints 
Comparison 1:

Arm C subjects who had relevant event assessment or event after ‘pooling cut-off date’ will be censored 
on last assessment date prior to ‘pooling cut-off date’. Refer to Section 4.5 for pooling cut-off date.

All other subjects in arms A, B and C, refer to 

Table 9–4 for censoring rules.

Randomization baseline is used for this comparison 

Time-to-event following randomization = End date - date of randomization +1
Comparison 2:

Subjects who had a relevant event between date of randomization and Week 24 baseline will be censored 
at date of Week 24 baseline, with the reason ‘First event occurred between date of randomization and 
Week 24 baseline’. 

All other subjects refer to 

Table 9–4.

Week 24 baseline is used for this comparison for following endpoints: Time to first SSE and Time to Pain 
progression

Randomization baseline is used for this comparison for exploratory endpoints :Time to ALP progression, 
time to PSA progression, time to increase in analgesic use and time to pain progression or increase in 
analgesic use.

The assessment prior to treatment start is used as baseline for time to increase in physical symptoms of 
disease.

Time-to-event following Week 24 baseline = End date - date of week 24 baseline +1.
Table 9–4 applies to the following endpoints:

Time to First Symptomatic Skeletal Event

Time to Pain Progression

Time to ALP Progression

Time to ALP Progression without 12-week Restriction

Time to PSA Progression

Time to PSA Progression without 12-week Restriction

Time to Increase in Analgesic Use
o
Requires Baseline WPS ≤7 for inclusion in analysis

Time to Pain progression or increase in analgesic use
o
Requires Baseline WPS ≤7 for inclusion in analysis
o
The last assessment for censoring purposes refers to the latest date Pain Progression 
assessment. The earlier of the date of pain progression or increase in analgesic use is 
taken as the endpoint.    

Time to increase in physical symptoms of disease following start of treatment based on 
FPSI-DRS-P
Table 9–4 Time-to Event Censoring Rules 
Situation
End Date 
Censored
Reason for Censoring
No baseline assessment
Relevant Baseline Date
Yes
No baseline assessment.
No post baseline assessment
Relevant Baseline Date
Yes
No post-baseline 
assessment.
Subject had an event
Date of first event
No
N/A
No event by database cutoff 
Last assessment prior to 
Yes
No Event


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
40 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
database cutoff 
9.1.4 Censoring rules for time to radiological progression 
Note: ‘radiological’ in the tables refer to either ‘radiological soft tissue’ or ‘radiological bone’ as 
applicable to the endpoint.
Refer to Section 4.5.2 for pooling cut-off date.  
Table 9–5 applies to:

Time to radiological progression following randomization

Time to radiological bone progression following randomization and

Time to radiological soft tissue progression following randomization. 
                 The following censoring rules will be used for both Comparison 1 and Comparison 2. Randomization   
baseline is used for all comparisons.
Table 9–5 Censoring for Time to Radiological Bone/Soft Tissue Progression 
following randomization
Situation
End Date 
Censored
Reason for Censoring
No randomization baseline or post-
randomization baseline radiological 
assessment
Date of randomization
Yes
No baseline  or post-
baseline assessment.
Subject died without prior radiological 
progression  
Date of last radiological 
assessment before death
Yes
No progression before 
death or database cutoff
Subject survived without radiological 
progression as of database cutoff date
Date of last radiological 
assessment before data 
cutoff
Yes
Alive and no 
progression before  
database cutoff
Subject had a radiological assessment of PD 
(no two consecutive missed radiological 
assessments*)
Date of first PD
No
N/A
PD immediately after two or more 
consecutive  missed radiological  
assessments*
Date of last radiological
assessment before missed 
assessments
Yes 
Missed two or more 
consecutive tumor 
assessments
Subject discontinuation from study for 
reasons other than PD 
Last radiological
assessment date  
Yes
Subject discontinued 
from study due to a 
reason other than PD 
Subjects discontinued from study due to 
PD, but no documented date of PD
Date of last radiological 
assessment
Yes
Subjects discontinued 
from study due to PD, 
but no documented date 
of PD
New non-protocol permitted systemic 
anti-cancer treatment started
Date of last radiological 
assessment before 
starting new systemic 
anti-cancer treatment
Yes 
New anti-cancer
treatment started
*Two consecutive missing radiological assessments are defined as the time interval between two consecutive 
radiological assessments is more than 28 weeks =2 × (12+2) week, where 12-week is scheduled frequency for 
tumor assessment and 2-week is protocol-allowed window.


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
41 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Duration = End date – randomization date +1
There will be no Week 24 baseline censoring for Comparison 2. 
In addition to the rules in Table 9–5 the following rule will be applied to Comparison 1:
Situation
End Date 
Censored
Reason for Censoring
Arm C subject with no radiological 
progression event on or after pooling 
cutoff date
Last radiological progression
assessment on or before 
pooling cutoff date
Yes
Post Week 24 Arm C 
events censored at pooling 
cutoff date
When determining time to radiographic progression, the following rules will be applied by taking into 
consideration of both bone and non-bone disease status:
Table 9–6 Censoring for Time to Radiological Progression Following Randomization
Situation  
Event/Censor
Event/censor date
Combined Non-bone and Bone 
outcome
1
Bone
Event (PD)
Bone scan date
Event at min(Bone scan date, Non-
Bone assessment date)Event at 
min(Bone scan date, Non-Bone 
assessment)
Non-
Bone
Event (PD)
Non-Bone assessment 
date
2
Bone
Censor
Bone scan date
Censor at min(Non-Bone 
assessment date, Bone scan date)
Non-
Bone
Censor
Non-Bone assessment 
date
3
Bone
Censor
Bone scan date
Event at Non-Bone assessment date: 
if Non-Bone assessment date ≤ Bone
scan date ;
Else if Non-Bone assessment date > 
Bone scan date AND Difference < 
28weeks;
Else censor at bone scan Date;
Event at Non-Bone assessment 
Date: 
if Non-Bone assessment Date 
≤ Bone scan date 
Else if Non-Bone assessment 
Date > Bone scan date AND 
Difference < 28weeks
Else censor at bscan Date
Non-
Bone
Event(PD)
Non-Bone assessment 
date
4
Bone
Event(PD)
Bone scan date
Event at bone scan date: 
if Bone scan date ≤ Non-Bone 
assessment date 
Else if Bone scan date > Non-Bone 
assessment date AND Difference < 
28weeks;
Else censor at Non-Bone 
assessment date
Non-
Bone
Censor
Non-Bone assessment 
date


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
42 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
9.1.5 Censoring rules for radiological progression-free survival (rPFS)
The following censoring rules will be used for both Comparison 1 and Comparison 2. 
Table 9–7 Censoring for radiological progression-free survival following 
randomization
Situation
End Date 
Censored
Reason for Censoring
No randomization baseline or 
post-randomization baseline  
radiological progression 
assessments 
Date of Randomization
Yes
No baseline or post-
baseline assessment.
Subject had a radiological 
assessment of PD following 
randomization (no 2 consecutive 
missing radiological assessments*)
Date of first radiological 
event
No
N/A
Death or PD immediately after two 
or more consecutive  missed 
radiological  assessments*
Date of last radiological
assessment before missed 
assessments
Yes 
Missed two or more 
consecutive tumor 
assessments
Subject discontinued from study 
for other than PD or death
Last radiological
assessment date 
Yes
Subject discontinued 
from study due to a 
reason other than PD or 
death
Death during the study (no 2 
consecutive missing radiological 
assessments*) or before first 
radiological PD assessment
Date of Death
No
N/A
Subjects discontinued from study 
due to PD, but no documented date 
of PD
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
New non-protocol permitted 
systemic anti-cancer treatment 
started
Date of last radiological 
assessment before 
starting new systemic 
anti-cancer treatment
Yes 
New systemic anti-
cancer treatment started
*Two consecutive missing radiological assessments are defined as the time interval between two consecutive 
radiological assessments is more than 28 weeks =2 × (12+2) week, where 12-week is scheduled frequency for 
tumor assessment and 2-week is protocol-allowed window
Radiological progression date and status mentioned in above table  will be obtained following the 
rules specified in Table 9–6.
   
rPFS following randomization = End date – randomization date +1.
There will be no Week 24 baseline censoring for Comparison 2. Randomization baseline will be used 
for Comparison 2. 
In addition to the rules in Table 9–7, the following rule will be applied to Comparison 1:


Statistical Analysis Plan
16507: BAY 88-8223/16507
Page:
43 of
43
Reference Number: BPD-SOP-060
Supplement Version: 5
Situation
End Date 
Censored
Reason for Censoring
Arm C subject with no death or 
radiological progression event on 
or after pooling cutoff date
Last radiological 
progression assessment 
on or before pooling 
cutoff date
Yes
Post Week 24 Arm C 
events censored at 
pooling cutoff date


Supplement Statistical Analysis Plan
BAY 88-8223/16507
Page: 1 of 5:
Reference Number: RD-OI-0119
Supplement Version: 9.0
Title page
A three arm randomized, open-label Phase II study of radium-223 
dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update)  
versus 80 kBq/kg (88 kBq/kg after implementation of NIST update) , and 
versus 50 kBq/kg (55 kBq/kg after implementation of NIST update)  in an 
extended dosing schedule in subjects with castration-resistant prostate 
cancer metastatic to the bone
[Standard dose versus high dose and versus extended standard dose radium-223 
dichloride in castration-resistant prostate cancer metastatic to the bone]
Bayer study drug
BAY 88-8223 / Radium-223 dichloride / Xofigo
[Study purpose:]
Efficacy, dose-finding
Clinical study 
phase:
II
Date:
02 July 2018
Study No.:
BAY 88-8223 / 
16507
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 88-8223/16507>
Page: 2 of 5:
Reference Number: RD-OI-0119
Supplement Version: 9.0
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 2
1.
Introduction....................................................................................................................... 2
2.
Study Objectives................................................................................................................ 2
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 4
5.
Analysis Sets ...................................................................................................................... 4
6.
Statistical Methodology .................................................................................................... 4
6.1
Population characteristics ................................................................................................ 4
6.1.1
Additional Summary of Baseline Characteristics......................................................... 4
6.1.2
Additional Summary of Prior/Concomitant Bone Health Agent (BHA) use ............... 4
6.2
Efficacy............................................................................................................................ 4
6.3
Exploratory variables and analyses.................................................................................. 5
6.4
Pharmacokinetics............................................................................................................. 5
6.5
Safety ............................................................................................................................... 5
6.5.1
Adverse Events............................................................................................................. 5
7.
Document history and changes in the planned statistical analysis............................... 5
8.
References .......................................................................................................................... 5
Abbreviations
AE
Adverse event
BHA
Bone health agent
CI
Confidence interval
CSR
Clinical Study Report
SAP
Statistical Analysis Plan
1.
Introduction
This Supplemental Statistical Analysis Plan (SAP) describes analyses that were not included 
in the main SAP but may be used for submission purposes or CSR. 
This Supplemental SAP version 1.0 is a supplement of SAP version 2.0 dated 17 May 2017.  
2.
Study Objectives
Co-primary objectives:


Statistical Analysis Plan
Protocol No.: < BAY 88-8223/16507>
Page: 3 of 5:
Reference Number: RD-OI-0119
Supplement Version: 9.0

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 doses 
compared to radium-223 dichloride 80 kBq/kg (88 kBq/kg after implementation of 
NIST update); and

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 additional 
doses compared to no further radium-223 dichloride treatment in subjects with CRPC 
metastatic to the bone who previously received radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 doses, and 
survived SSE free and are eligible for further radium-223 dichloride treatment.
Secondary objectives:

To evaluate safety and tolerability

To evaluate overall survival (OS)

To evaluate pain improvement rate

To evaluate time to pain progression

To evaluate time to first SSE

To evaluate time to radiological progression

To evaluate radiological progression-free survival (rPFS)
Exploratory objectives:

To evaluate quantitated whole body technetium-99 bone scan tumor burden area and 
index, and determine bone tumor response

To explore the impact of patient body size on the efficacy and safety of radium-223 
dichloride

Time to increase in physical symptoms of disease based on the NCCN FACT-P 
Symptom Index-17 (NCCN-FACT FPSI-17) physical disease related symptoms 
(FPSI-DRS-P) subscale score measured up to Week 48 after the start of treatment

To evaluate laboratory indicators of efficacy, including:
o
PSA response
o
Time to PSA progression
o
ALP response
o
Time to ALP progression
o
Percentage change in ALP from baseline

To evaluate change in analgesic use.


Statistical Analysis Plan
Protocol No.: < BAY 88-8223/16507>
Page: 4 of 5:
Reference Number: RD-OI-0119
Supplement Version: 9.0
3.
Study Design
Refer to the main SAP v2.0 dated 17 MAY 2017.
4.
General Statistical Considerations
Refer to the main SAP v2.0 dated 17 MAY 2017.
5.
Analysis Sets
Refer to the main SAP v2.0 dated 17 MAY 2017.
6.
Statistical Methodology
Refer to the main SAP v2.0 dated 17 MAY 2017.
6.1
Population characteristics
Refer to the main SAP v2.0 dated 17 MAY 2017.
6.1.1
Additional Summary of Baseline Characteristics
The following baseline cancer characteristics will be summarized for ITT and week 24 
analysis set:

The summary of patients with vertebral bone metastasis at baseline

The number of subjects with prior local radiotherapy on prostate and prostate gland by 
intent.
6.1.2
Additional Summary of Prior/Concomitant Bone Health Agent (BHA) 
use
The number of subjects who used BHA at baseline and during treatment period will be 
summarized for ITT and week 24 analysis set.
6.2
Efficacy
Refer to the main SAP v2.0 dated 17 MAY 2017.
Pain improvement rate at week 12, week 24, EOT, and overall will  be summarized by 
including all subjects in ITT population as denominator. Same analyses will be repeated for 
week 24 analysis set. 


Statistical Analysis Plan
Protocol No.: < BAY 88-8223/16507>
Page: 5 of 5:
Reference Number: RD-OI-0119
Supplement Version: 9.0
6.3
Exploratory variables and analyses
Refer to the main SAP v5.0 dated 17 NOV 2017.
6.4
Pharmacokinetics
Not Applicable.
6.5
Safety
Refer to the main SAP v2.0 dated 17 MAY 2017.
6.5.1
Adverse Events
Additional analyses of Adverse Events of 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 the last visit date during treatment period. 
Time to fracture will be summarized using Kaplan-Meier estimates.  Median survival time 
together with the 25th and 75th percentiles and associated 80% and 95%  Brookmeyer-
Crowley confidence intervals (CI) will be presented by treatment arm.  Corresponding 
Kaplan-Meier curves will be generated by treatment arm.   
Time to fracture will also be summarized for subjects with/without use of concomitant  anti-
androgen, enzalutamide  and abiraterone  during the treatment period using same approach 
mentioned  above, respectively. 
A subject listing of fractures will be provided.
7.
Document history and changes in the planned statistical analysis

Main SAP v2.0 dated 17 MAY 2017.
8.
References
Refer to the main SAP v2.0 dated 17 MAY 2017.


Supplement Statistical Analysis Plan
BAY 88-8223/16507
Page: 1 of 6:
Reference Number: RD-OI-0119
Supplement Version: 9.0
Title page
A three arm randomized, open-label Phase II study of radium-223 
dichloride 50 kBq/kg (55 kBq/kg after implementation of NIST update)  
versus 80 kBq/kg (88 kBq/kg after implementation of NIST update) , and 
versus 50 kBq/kg (55 kBq/kg after implementation of NIST update)  in an 
extended dosing schedule in subjects with castration-resistant prostate 
cancer metastatic to the bone
[Standard dose versus high dose and versus extended standard dose radium-223 
dichloride in castration-resistant prostate cancer metastatic to the bone]
Bayer study drug
BAY 88-8223 / Radium-223 dichloride / Xofigo
[Study purpose:]
Efficacy, dose-finding
Clinical study 
phase:
II
Date:
08 Oct 2018
Study No.:
BAY 88-8223 / 
16507
Version:
2.0
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 88-8223/16507>
Page: 2 of 6:
Reference Number: RD-OI-0119
Supplement Version: 9.0
Table of Contents
Title page................................................................................................................................... 1
Abbreviations............................................................................................................................ 2
1.
Introduction....................................................................................................................... 2
2.
Study Objectives................................................................................................................ 3
3.
Study Design ...................................................................................................................... 4
4.
General Statistical Considerations .................................................................................. 4
5.
Analysis Sets ...................................................................................................................... 4
6.
Statistical Methodology .................................................................................................... 4
6.1
Population characteristics ................................................................................................ 4
6.1.1
Additonal Summary of Disposition of Subjects........................................................... 4
6.1.2
Additional Summary of Baseline Characteristics......................................................... 4
6.1.3
Additional Summary of Prior/Concomitant Bone Health Agent (BHA) use ............... 5
6.1.4
Additional Summary of  Post-treatment Bone Radiotherapy  Use............................... 5
6.2
Efficacy............................................................................................................................ 5
6.3
Exploratory variables and analyses.................................................................................. 5
6.4
Pharmacokinetics............................................................................................................. 5
6.5
Safety ............................................................................................................................... 5
6.5.1
Adverse Events............................................................................................................. 5
6.5.2
Long Term Adverse Events.......................................................................................... 6
6.5.3
Long Term Safety......................................................................................................... 6
7.
Document history and changes in the planned statistical analysis............................... 6
8.
References .......................................................................................................................... 6
Abbreviations
AE
Adverse event
BHA
Bone health agent
CI
Confidence interval
CSR
Clinical Study Report
SAP
Statistical Analysis Plan
1.
Introduction
This Supplemental Statistical Analysis Plan (SAP) describes analyses that were not included 
in the main SAP but may be used for submission purposes or CSR. 
This Supplemental SAP version 1.0 is a supplement of SAP version 2.0 dated 17 May 2017.  


Statistical Analysis Plan
Protocol No.: < BAY 88-8223/16507>
Page: 3 of 6:
Reference Number: RD-OI-0119
Supplement Version: 9.0
2.
Study Objectives
Co-primary objectives:

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 doses 
compared to radium-223 dichloride 80 kBq/kg (88 kBq/kg after implementation of 
NIST update); and

To evaluate efficacy as measured by SSE-FS of radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 additional 
doses compared to no further radium-223 dichloride treatment in subjects with CRPC 
metastatic to the bone who previously received radium-223 dichloride 50 kBq/kg (55 
kBq/kg after implementation of NIST update) every 28 days for up to 6 doses, and 
survived SSE free and are eligible for further radium-223 dichloride treatment.
Secondary objectives:

To evaluate safety and tolerability

To evaluate overall survival (OS)

To evaluate pain improvement rate

To evaluate time to pain progression

To evaluate time to first SSE

To evaluate time to radiological progression

To evaluate radiological progression-free survival (rPFS)
Exploratory objectives:

To evaluate quantitated whole body technetium-99 bone scan tumor burden area and 
index, and determine bone tumor response

To explore the impact of patient body size on the efficacy and safety of radium-223 
dichloride

Time to increase in physical symptoms of disease based on the NCCN FACT-P 
Symptom Index-17 (NCCN-FACT FPSI-17) physical disease related symptoms 
(FPSI-DRS-P) subscale score measured up to Week 48 after the start of treatment

To evaluate laboratory indicators of efficacy, including:
o
PSA response
o
Time to PSA progression
o
ALP response
o
Time to ALP progression
o
Percentage change in ALP from baseline


Statistical Analysis Plan
Protocol No.: < BAY 88-8223/16507>
Page: 4 of 6:
Reference Number: RD-OI-0119
Supplement Version: 9.0

To evaluate change in analgesic use.
3.
Study Design
Refer to the main SAP v2.0 dated 17 MAY 2017.
4.
General Statistical Considerations
Refer to the main SAP v2.0 dated 17 MAY 2017.
5.
Analysis Sets
Refer to the main SAP v2.0 dated 17 MAY 2017.
6.
Statistical Methodology
Refer to the main SAP v2.0 dated 17 MAY 2017.
6.1
Population characteristics
Refer to the main SAP v2.0 dated 17 MAY 2017.
6.1.1
Additional Summary of Disposition of Subjects
The  number and percentage of subjects entered long-term follow up, completed and 
discontinued and reason for discontinuation will be presented by treatment group and overall
for both ITT and safety analysis set. 
6.1.2
Additional Summary of Baseline Characteristics
The following baseline cancer characteristics will be summarized for ITT and week 24 
analysis set:

The summary of patients with vertebral bone metastasis at baseline

The number of subjects with prior local radiotherapy on prostate and prostate gland by 
intent.
The following summary tables will be provided for subjects who entered long-term follow up
in safety analysis set. 

Demographics

Baseline prostate cancer characteristics


Statistical Analysis Plan
Protocol No.: < BAY 88-8223/16507>
Page: 5 of 6:
Reference Number: RD-OI-0119
Supplement Version: 9.0
6.1.3
Additional Summary of Prior/Concomitant Bone Health Agent (BHA) 
use
The number of subjects who used BHA at baseline and during treatment period will be 
summarized for ITT and week 24 analysis set. The same summary tables will also be 
provided for subjects who entered long-term follow up period in safety analysis set. 
6.1.4
Additional Summary of  Post-treatment Bone Radiotherapy  Use
The number of subjects who received bone radiotherapy after last dose of Radium-223 will be 
summarized for subjects who entered long-term follow up period in safety analysis set.
6.2
Efficacy
Refer to the main SAP v2.0 dated 17 MAY 2017.
Pain improvement rate at week 12, week 24, EOT, and overall will  be summarized by 
including all subjects in ITT population as denominator. Same analyses will be repeated for 
week 24 analysis set. 
6.3
Exploratory variables and analyses
Refer to the main SAP v5.0 dated 17 NOV 2017.
6.4
Pharmacokinetics
Not Applicable.
6.5
Safety
Refer to the main SAP v2.0 dated 17 MAY 2017.
6.5.1
Adverse Events
Additional analyses of Adverse Events of 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 either end of treatment (EOT) visit date or 
the last visit date before the start of active follow-up Period if no EOT visit was recorded.
Time to fracture will be summarized using Kaplan-Meier estimates.  Median survival time 
together with the 25th and 75th percentiles and associated 80% and 95%  Brookmeyer-
Crowley confidence intervals (CI) will be presented by treatment arm.  Corresponding 
Kaplan-Meier curves will be generated by treatment arm.   
Time to fracture will also be summarized for subjects with/without BHA use at baseline, 
with/without concomitant  use of anti-androgen, enzalutamide,  and abiraterone by same 
approach mentioned  above, respectively. 


Statistical Analysis Plan
Protocol No.: < BAY 88-8223/16507>
Page: 6 of 6:
Reference Number: RD-OI-0119
Supplement Version: 9.0
A subject listing of bone fractures occurred after first dose will be provided.
6.5.2
Long Term Adverse Events
All Bone fracture and bone events occurred after patients entering long-term follow up period 
will be summarized by NCI-CTCAE toxicity criteria. Same summary will also be provided 
for serious bone fracture and bone events during long-term follow up period.  A listing of 
bone fracture and bone events will be provided for entire study period and during follow-up 
period, respectively.
6.5.3
Long Term Safety
All Safety data arising during the long-term safety follow-up period in this study will be 
presented through listings.
7.
Document history and changes in the planned statistical analysis

Main SAP v2.0 dated 17 MAY 2017.

SAP supplement v1.0 dated 02JUN 2018
8.
References
Refer to the main SAP v2.0 dated 17 MAY 2017.