Conditions: Breast Neoplasms
Keywords: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 99
Healthy volunteers: no

Brief summary:
The objective of this study was to assess efficacy and safety of radium-223 dichloride in subjects with human epidermal growth factor receptor 2 negative (HER2 negative) hormone receptor positive breast cancer with bone metastases treated with hormonal treatment background therapy

Detailed description:

Arms:
arm 1: Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks arm 2: Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks

Interventions: intervention 1: Radium-223 dichloride (Xofigo, BAY88-8223) intervention 2: Placebo (saline) intervention 3: Background hormonal therapy
Intervention descriptions: intervention 1: Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of National Institute of Standards and Technology \[NIST\] update) intervention 2: Up to 6 cycles of saline injection intervention 3: Prescribed by PI and was provided as long as patient can tolerate treatment. It must be prescribed as per local label in country participating.

Protocol document:
Prot_001.pdf: 
 
Document 
Type: 
Study Protocol 
Official Title: 
A phase II randomized, double-blind, placebo-controlled trial 
of radium-223 dichloride versus placebo when administered to 
metastatic HER2 negative hormone receptor positive breast 
cancer subjects with bone metastases treated with hormonal 
treatment background therapy 
NCT Number: 
NCT02258464 
Document Date: 
03 Apr 2018 
 


Integrated Clinical Study Protocol 
BAY 88-8223/ 16298 
03 APR 2018 
Version no. 8.0 
Page:  1 of 281 
Cover page of the integrated clinical study protocol 
A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride 
versus placebo when administered to metastatic HER2 negative hormone receptor 
positive breast cancer subjects with bone metastases treated with hormonal treatment 
background therapy 
For this study, the protocol and subsequent protocol amendment were released as follows: 

Original protocol, Version 1.0, dated 13 MAY 2014

Amendment 1 (global amendment described in Section 15.1) forming integrated
protocol Version 2.0, dated 16 DEC 2014

Amendment 2 (global amendment described in Section 15.2) forming integrated
protocol Version 3.0, dated 29 APR 2015

Amendment 3 (local amendment France only) dated 29 APR 2015

Amendment 4 (global amendment described in Section 15.3) forming integrated
protocol Version 4.0, dated 29 JUL 2015.

Amendment 5 (global amendment described in Section 15.4) forming integrated
protocol Version 5.0, dated 11 MAR 2016.

Amendment 6 (global amendment described in Section 15.5) forming integrated
protocol Version 6.0, dated 11 JUL 2016.

Amendment 7 (global amendment described in Section 15.6) forming integrated
protocol Version 7.0, dated 23 MAY 2017.

Amendment 8 (global amendment described in Section 15.7) forming current
integrated protocol Version 8.0, dated 03 APR 2018
This document integrates the original protocol and all global amendments. 


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


 
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2. 
Synopsis 
 
Title 
 
 
A phase II randomized, double-blind, placebo-controlled 
trial of radium-223 dichloride versus placebo when 
administered to metastatic HER2 negative hormone receptor 
positive breast cancer subjects with bone metastases treated 
with hormonal treatment background therapy 
Short title 
Study of radium-223 dichloride versus placebo with hormonal 
treatment as background therapy in subjects with bone 
predominant HER2 negative hormone receptor positive 
metastatic breast cancer  
Short title section modified by Amendment 1. 
Clinical study phase 
2 
Study objectives 
The objective of this study is to assess the efficacy and safety of 
radium-223 dichloride in subjects with human epidermal growth 
factor receptor 2 negative (HER2 negative), hormone receptor 
positive breast cancer with bone metastases treated with 
hormonal treatment background therapy.  
The primary endpoint is: 
1. Symptomatic skeletal event-free survival (SSE-FS) 
The secondary endpoints are: 
2. Overall survival 
3. Time to opiate use for cancer pain 
4. Time to pain progression (only in subjects with baseline 
worst pain score ≤8) 
5. Time to cytotoxic chemotherapy 
6. Radiological progression-free survival (rPFS) 
7. Pain improvement rate 
8. Safety, acute and long term, including new primary 
malignancies and hematopoietic reserve for tolerability of 
subsequent chemotherapy 
The study will also include the following exploratory 
endpoints: 
9. Time to first on-study symptomatic skeletal event (SSE) 
10. Time to bone alkaline phosphatase (ALP) progression 


 
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11. Bone ALP response at Week 12 and end of 
treatment (EOT) 
12. Bone-specific rPFS 
13. Resource utilization 
14. Biomarker assessments 
15. Time to visceral metastases onset 
Study objectives section modified by Amendment 4. 
Test drug 
BAY 88-8223 
Name of active ingredient 
Radium-223 dichloride  
Dose 
50 kBq/kg (55 kBq/kg after implementation of National Institute 
of Standards and Technology [NIST] update) body weight every 
4 weeks for 6 cycles 
Dose section modified by Amendment 4. 
Route of administration 
Intravenous injection (slow bolus)  
Duration of treatment 
6 cycles at 4-week intervals (24 weeks) 
Reference drug 
Matching placebo (normal saline) 
Name of active ingredient 
Not applicable 
Background treatment 
All study subjects will receive local standard of care hormonal 
treatment, and best supportive care 
Indication 
Subjects with HER2 negative, hormone receptor positive breast 
cancer with bone metastases treated with a single hormonal 
agent as background therapy 
 


 
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Diagnosis and main criteria 
for inclusion and 
exclusion 
Subjects must meet the following criteria for inclusion in the 
study: 
1. Have provided written informed consent.  Subjects must 
be able to understand and be willing to sign the written 
informed consent.  A signed informed consent form must 
be appropriately obtained prior to the conduct of any 
study-specific procedure. 
2. Documentation of histological or cytological confirmation 
of estrogen receptor positive (ER+) and HER2 negative 
adenocarcinoma of the breast must be available.  HER2 
status should be determined by an accredited/Ministry of 
Health approved laboratory by immunohistochemistry 
(IHC), fluorescence in situ hybridization (FISH), 
chromogenic in situ hybridization (CISH) or other 
validated in situ hybridization (ISH) assay for detection 
of HER2 gene expression.  
3. Tumors (from either primary or metastatic sites) must be 
ER+ defined as ≥10% positive tumor nuclei in the 
analyzed sample. ER+/progesterone receptor positive 
(PR+) and ER+/ progesterone receptor negative (PR-) 
subjects are eligible whereas estrogen receptor negative 
(ER-)/PR+ and ER-/PR- disease will not be eligible. 
4. Women (≥18 years of age) with metastatic breast cancer 
not amenable to curative treatment by surgery or 
radiotherapy.  Women of reproductive potential and their 
male partners must agree to use adequate contraception 
during treatment and for 6 months following the 
completion of treatment with radium-223 
dichloride/placebo. 
5. Documentation of menopausal status: post-menopausal 
or pre-menopausal subjects are eligible. 
 
Note: In premenopausal subjects, ovarian radiation or 
treatment with a luteinizing hormone-releasing hormone 
(LH-RH) agonist/antagonist is permitted for induction of 
ovarian suppression if the plasma/serum estradiol assay 
is within local laboratory postmenopausal range at 
screening, performed within 7 days of randomization. 
 Pre-menopausal subjects with or without ovarian 
radiation or concomitant treatment with an LH-RH 


 
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agonist/antagonist must have a negative pregnancy 
test at screening and agree to use an adequate 
method of contraception as recommended by their 
treating physicians 
 Post-menopausal status is defined either by:  
o age ≥55 years and one year or more of 
amenorrhea,  
o age <55 years and one year or more of 
amenorrhea with a plasma/serum estradiol 
assay within local laboratory postmenopausal 
range, performed within 7 days of 
randomization, 
o bilateral ovariectomy.  
6. Subjects with bone dominant disease with at least 
2 skeletal metastases identified at baseline by bone 
scintigraphy and confirmed by computed tomography 
(CT)/magnetic resonance imaging (MRI).  Presence of 
metastases in soft tissue (skin, subcutaneous, muscle, fat, 
lymph nodes) and/or visceral metastases is allowed. 
7. Measurable or non-measurable disease (but radiologically 
evaluable) according to Response Evaluation Criteria in 
Solid Tumors v1.1 criteria.  All disease burden must be 
assessed at baseline by CT or MRI of chest, pelvis and 
abdomen and any additional fields as needed.  A bone 
scan should also be done at baseline for all subjects. 
CT/MRI done as part of the standard of practice within 
3 weeks prior to randomization and standard of care bone 
scans done within 3 weeks prior to randomization are 
acceptable. 
F-18 fluorodeoxyglucose (FDG) positron emission 
tomography (PET) scan, if performed as part of standard 
of care imaging, can be used as an adjunct to CT/MRI in 
line with RECIST 1.1 guidelines. If FDG PET/CT scan, 
the CT component of the scan can be used for tumor 
measurements only if the site can document that the CT is 
of identical diagnostic quality to a diagnostic CT (See 
also Appendix 16.2). 
FDG PET/CT or NaF PET/CT scan is acceptable as an 
alternative to technetium-99m bone scintigraphy if it is 
the standard of care at the institution, provided the same 


 
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bone imaging modality is used throughout the study. 
8. Subjects must have received at least one line of hormonal 
therapy in the metastatic setting.  
 
Note: A change of the hormone agent due to progression 
(as per the Investigator assessment) is counted as a new 
line of therapy.  A switch of hormone therapy from one 
agent to another due to toxicity or other reasons (e.g., 
subject’s preference), in absence of progressive disease 
at the time of the switch, will be counted as one line 
although 2 different agents have been administered. 
9. Subjects who are eligible for further standard of care 
endocrine treatment with any of the following 
administered as in second line or greater of hormone 
therapy in metastatic setting:  
 Selective estrogen receptors modulators such as 
tamoxifen and toremifene  
 Non-steroidal aromatase inhibitors such as 
anastrozole and letrozole  
 Steroidal aromatase inhibitors such as exemestane 
 Estrogen receptor down-regulators such as 
fulvestrant  
Subjects enrolled in the current study must start treatment 
with the single hormone agent either within 15 days prior 
to randomization or after randomization (before or 
simultaneously to the first injection of radium-223 
dichloride/placebo).   
10. Subjects must have experienced no more than 
2 skeletal-related events (SREs) prior to study entry 
defined as: Need for external beam radiotherapy (EBRT) 
to bone, pathological bone fracture (excluding major 
trauma), spinal cord compression, and/or orthopedic 
surgical procedure.  Subjects with no prior SREs are not 
permitted.  
Note: All prior SRE-related procedures (i.e., orthopedic 
surgery, EBRT) must be administered prior to 
randomization. Separate SRE events are the ones that 
occur at least 21 days apart from each other to ensure 
that linked events (e.g., surgery to repair a fracture or 
multiple doses of radiation during a course of treatment) 
are not counted as separate events. In case of bone pain 


 
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that occurs in several anatomical locations and requires 
separate EBRT sessions, it should be counted as one event 
if the EBRT sessions are administered within a period of 
21 days. 
11. Subjects must be on therapy with bisphosphonate or 
denosumab and are required to have been on such 
therapy for at least 1 month before the start of study 
treatment. 
12. Eastern Cooperative Oncology Group (ECOG) 
Performance Status 0 or 1 
13. Life expectancy 6 months  
14. Laboratory requirements:  
 Absolute neutrophil count 1.5 x 109/L  
 Platelet count 100 x 109/L without platelet 
transfusion within 4 weeks prior to randomization 
 Hemoglobin 9.0 g/dL (90 g/L; 5.6 mmol/L) 
without transfusion or erythropoietin within 
4 weeks prior to randomization 
 Total bilirubin ≤1.5 x institutional upper limit of 
normal (ULN) (except for subjects with 
documented Gilbert’s disease) 
 Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) ≤2.5 x institutional ULN. 
 Creatinine ≤1.5 x ULN 
o Estimated glomerular filtration rate 
≥30 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease 
abbreviated formula (Note: please refer to 
local labelling for administration of full dose 
of bisphosphonates) 
o International normalized ratio of prothrombin 
time (INR) and partial thromboplastin time 
(PTT) or activated PTT ≤1.5 x ULN at study 
entry.  Subjects treated with warfarin, heparin, 
enoxaparin, rivaroxaban, dabigatran, 
apixaban, or aspirin (e.g. ≤100 mg daily) will 
be allowed to participate in the study if no 
underlying abnormality in coagulation 
parameters exists per prior history; weekly 


 
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evaluation of INR/PTT will be required until 
stability is achieved for anticoagulants that 
require their monitoring as per local label. 
 Serum albumin >30 g/L 
 Pulse oximetry O2 saturation >92% if lung 
metastases are present  
15. Able to swallow oral medication  
Exclusion criteria 
Eligible subjects must not meet any of the exclusion criteria 
listed below: 
1. HER2-positive breast cancer (IHC=3+, positive 
FISH/CISH/other ISH validated assay); equivocal or 
unknown HER2 status 
Note: Subjects with 3+ by IHC cannot be chosen 
regardless of their FISH/CISH/other ISH validated assay 
status and those with positive FISH/CISH/other ISH 
validated assay cannot be chosen either, regardless of 
the IHC findings.  Subjects with 2+ by IHC will not be 
eligible if no negative FISH/CISH/other ISH validated 
assay for detection of HER2 gene expression is available. 
2. Subjects considered by the treating Investigator to be 
appropriate candidates for treatment with everolimus as 
current treatment for their metastatic breast cancer 
3. Subjects with inflammatory breast cancer 
5. Subjects who have either received chemotherapy for 
metastatic disease or are considered by the treating 
Investigator to be appropriate candidates for 
chemotherapy as current treatment for metastatic breast 
cancer are excluded.  Chemotherapy administered for 
adjuvant/neo-adjuvant disease is acceptable. 
6. Subjects with any previous untreated or concurrent 
cancer that is distinct in primary site or histology from 
the cancer under study, except treated basal cell 
carcinoma or superficial bladder tumor (Ta and Tis, 
American Joint Committee on Cancer, 7th edition).  
Subjects surviving a cancer that was curatively treated 
and without evidence of disease for more than 3 years 
before enrollment are allowed.  All cancer treatments 
must be completed at least 3 years prior to study entry 
(i.e., signature date of informed consent form). 


 
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7. Subjects with known or history of brain metastases or 
leptomeningeal disease: subjects with neurological 
symptoms must undergo a contrast CT scan or MRI of the 
brain within 28 days prior to randomization to exclude 
active brain metastasis.  Imaging of the central nervous 
system is otherwise not required. 
8. 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. 
9. Prior treatment with radium-223 dichloride 
10. Prior hemibody external radiotherapy.  Subjects who 
received other types of prior external radiotherapy are 
allowed provided that bone marrow function is assessed 
and meets the protocol requirements for hemoglobin, 
absolute neutrophil count, and platelets. 
11. Prior systemic radiotherapy with strontium-89, 
samarium-153, rhenium-186, or rhenium-188 
12. ECOG Performance Status ≥2 
13. Blood transfusions, platelet transfusions or use of 
erythropoietin within 4 weeks prior to randomization.   
14. Use of biologic response modifiers, such as granulocyte 
macrophage-colony stimulating factor or granulocyte- 
colony stimulating factor, within 4 weeks prior to 
randomization. 
15. Treatment with an investigational drug or with any 
anti-cancer treatments not permitted by the protocol, 
within 4 weeks prior to randomization 
16. Chronic conditions associated with non-malignant 
abnormal bone growth (e.g., confirmed Paget’s disease of 
bone) 
17. 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 


 
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 Bone marrow dysplasia 
18. Previous assignment to treatment in this study 
19. Breastfeeding women 
20. Known hypersensitivity to the active substance or to any 
of the excipients of radium-223 dichloride 
21. Known presence of osteonecrosis of jaw 
22. Patients with immediately life-threatening visceral 
disease, for whom chemotherapy is the preferred 
treatment option. 
23. Lymphangitic carcinomatosis. 
24. Patients with ascites requiring paracentesis within 
2 weeks prior to study entry (signature of informed 
consent) and during the screening period. 
All local label specific criteria for the standard of care hormonal 
treatment as well as denosumab and bisphosphonates apply.  
Subjects must be treated according to the local standard of care 
requirements. 
Diagnosis and main criteria for inclusion and exclusion section 
modified by Amendments 1, 2, 4, 5, and 6. 
Study design 
International, phase II, double-blind, randomized, 
placebo-controlled, parallel-group study.  Randomization will be 
stratified by: 
 Geographical regions (Europe/North America 
[including Israel] versus Asia) 
 Previous lines of hormone therapy in metastatic 
setting (1 versus 2 or more): for the purpose of 
counting the number of prior lines of hormone 
therapy, only a change of the hormone agent due to 
progression is counted as a new line of therapy.  
Switch of hormone therapy from one agent to 
another due to toxicity or other reasons (e.g., 
subject’s preference) in absence of progressive 
disease at the time of switch will be counted as one 
line, although 2 different agents have been 
administered. 
 Prior SREs (1 versus 2): for the purpose of prior 
SREs stratification, separate SREs are those that 
occur at least 21 days apart from each other. Any 
procedure which is related to an SRE, such as 


 
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orthopedic surgery to treat a pathological bone 
fracture or multiple doses of radiation during a 
course of treatment, should not be counted as a 
separate event. In case of bone pain that occurs in 
several anatomical locations and requires separate 
EBRT sessions, it should be counted as one event if 
the EBRT sessions are administered within a period 
of 21 days. 
Study design section modified by Amendment 4. 
Methodology 
The study will comprise 4 periods: screening, randomization, 
treatment, and the follow-up period (active follow-up with clinic 
visits and active follow-up without clinic visits). 
 
Screening period:  
All trial related procedures and evaluations will only be 
performed after the subject has agreed to participate and has 
signed the informed consent form.  The screening period will 
consist of multiple evaluations that will take place within 
3 weeks prior to randomization to ensure that all eligibility 
criteria are met.  
 
Randomization:  
After all screening assessments have been completed and the 
subject’s eligibility has been confirmed and documented, eligible 
subjects will be randomized in a ratio of 1:1 to treatment with 
radium-223 dichloride (Arm A - investigational arm) or placebo 
(Arm B - control arm).  All subjects receive hormonal treatment 
and supportive care as background treatment according to the 
local standard of practice. 
 
Treatment period:  
Investigational treatment consists of up to 6 cycles of 
radium-223 dichloride 50 kBq/kg (55 kBq/kg after 
implementation of NIST update) body weight (Arm A) or 
placebo (Arm B) each separated by an interval of 4 weeks.  
All ongoing subjects at the time of study termination will finish 
study treatment with radium-223 dichloride or placebo as part of 
the study. 
All subjects will receive hormonal treatment with a single agent 
and supportive care as background treatment according to the 


 
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local standard of practice.  Subjects enrolled in the current study 
must start treatment with the single hormone agent either within 
15 days prior to randomization or after randomization either 
before or simultaneously to the first injection of radium-223 
dichloride or placebo.  For subject’s convenience, injections of 
fulvestrant may be scheduled on the same day of the radium-223 
dichloride or placebo injection. 
These treatments will also continue after completion of 
radium-223 dichloride or placebo. 
Subjects who discontinue treatment with radium-223 
dichloride/placebo prior to experiencing an SSE or radiological 
progression will enter the follow-up period and will be followed 
up for SSEs and radiological progression. 
In case an SSE is not defined as progression, the subject will 
continue to be followed as per protocol until radiological 
progression.  
All subjects will continue to receive standard of care hormonal 
treatment background therapy.  Hormonal treatment may also be 
changed according to the local standard of practice, including 
exemestane in combination with everolimus.  For the purpose of 
this study, only a new hormonal treatment initiated due to 
disease progression will be considered a new anti-cancer 
therapy. 
If radium-223 dichloride/placebo treatment is still ongoing but 
the hormonal treatment is no longer considered a treatment 
option and the subject must start cytotoxic treatment, the subject 
will terminate radium-223 dichloride/placebo treatment.   
If radium-223 dichloride/placebo treatment is still ongoing but 
the background treatment is no longer considered a treatment 
option and the subject must start another protocol permitted 
concomitant systemic anticancer treatment, the subject can 
continue radium-223 dichloride/placebo until completion or until 
any withdrawal criteria are met. 
If however, the background hormonal treatment or further 
standard of care protocol permitted concomitant systemic 
anticancer therapy are discontinued, radium-223 
dichloride/placebo must also be discontinued. 
Subjects will continue to be followed up for SSEs and 
radiological progression.  Symptomatic skeletal events should be 
recorded until end of active follow-up, independent of whether 
patient starts a new anticancer therapy (i.e. chemotherapy, 


 
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other).  
Subject management unless otherwise defined by this protocol 
will be in accordance to the local standard of practice.  
The radium-223 dichloride/placebo administration should be 
discontinued as per the withdrawal criteria described in 
Section 6.3.1 of the protocol (e.g., subject experiences 
unacceptable toxicities, delays in radium-223 dichloride/placebo 
> 4 weeks, subject enters the active follow-up without clinic 
visits as she can no longer travel to the clinical site, and if in the 
Investigator’s opinion, continuation of the study treatment would 
be harmful to the subject’s well-being).  
Subjects who experience an SSE during radium-223 
dichloride/placebo treatment may continue treatment until 
completion or until any withdrawal criteria are met, if in the 
opinion of the Investigator the subject continues to derive 
benefit.  In case an SSE is not defined as progression, the subject 
will continue to be followed as per protocol until radiological 
progression. 
Subjects will be assessed for efficacy and safety endpoints at 
each treatment visit and will be evaluated every 12 weeks for 
radiological progression. 
Subjects who did not experience either an SSE or radiological 
progression during the treatment period will enter, at the end of 
the treatment period, the Active Follow-up with clinic visits 
where they will continue to be followed up for these events. 
Subjects who experience an SSE and radiological progression 
during the protocol defined treatment period will enter, at the 
end of the treatment period, the active follow-up without clinic 
visits. 
Subjects who can no longer travel to the clinical site will be 
discontinued from the radium-223 dichloride/placebo study 
treatment and will enter the active follow-up without clinic 
visits.  During this time subjects will continue to receive 
hormonal background treatment as per local standard of practice. 
Subjects who missed 2 consecutive treatment visits will be 
considered unable to travel to the site, will be discontinued from 
study treatment and will enter the active follow-up without clinic 
visits. 
The total treatment period is defined from the day of 
randomization of subject in the interactive voice/web response 
system until 4 weeks after the last administration of radium-223 


 
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dichloride/placebo.  
A specific interval, depending on country specific drug order 
lead time between the date of randomization and the first 
radium-223 dichloride/placebo administration will be necessary 
for the study drug shipment/availability.  Randomized subjects 
who never received treatment will not be included in the safety 
analysis.  An end of treatment (EOT) electronic case report form 
should be completed for these subjects to document the reason 
for discontinuation. 
Follow-up period: 
The active follow-up has 2 distinct periods based on whether the 
subject can travel to the clinic site: the active follow-up with 
clinic visits for subjects who can travel and the active follow-up 
without clinic visits for subjects who cannot travel.  Once a 
subject switches from active follow-up with clinic visits to active 
follow-up without clinic visits, the subject will not be allowed to 
switch back.  
All subjects, regardless of reaching a study endpoint (on-study 
SSE or radiological progression), will enter the follow-up period 
in order to collect the required long-term safety information. 
Active follow-up period with clinic visits: 
Subjects who discontinued or completed the radium-223 
dichloride or placebo treatment did not experience an SSE and 
radiological progression during the treatment period, had an 
EOT visit, and can travel to the clinic will enter an active 
follow-up period with clinic visits.  During this period, clinic 
visits are to occur as follows: 
 For subjects who have not experienced an SSE during the 
treatment period, visits will continue with the same 
frequency as during treatment (every 4 weeks ±7 days) 
until the subject has an SSE.  After the occurrence of the 
SSE, the subjects will be switched to a frequency of visits 
every 12 weeks ±7 days at the next scheduled visit.  
 For subjects who experienced an SSE during the 
treatment or this period, visits will occur every 12 weeks 
±7 days.  The subjects will continue to be followed for 
radiological progression and long-term safety. 
 Subjects who miss 2 consecutive follow-up visits will be 
considered unable to travel to the site and will enter the 
active follow-up without clinic visits.  


 
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Radiological tumor assessment will be performed every 
12 weeks, independently of the frequency of the visits, until 
radiological disease progression is documented. 
Symptomatic skeletal events should be recorded until end of 
active follow-up, independent of whether patient starts a new 
anticancer therapy (i.e. chemotherapy, other).  
The active follow-up period with clinic visits extends from the 
EOT visit until the subject can no longer travel to the clinic, 
experiences an SSE and radiological progression, 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 until study termination. 
These subjects will be evaluated for pain endpoints, radiological 
progression, SSEs, survival, treatment-related adverse events 
(AEs) and serious adverse events (SAEs), and 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 any additional 
malignancies, including acute myelocytic leukemia (AML), and 
hematological conditions, such as myelodysplastic syndromes 
(MDS), aplastic anemia, or myelofibrosis must be reported as 
SAEs, regardless of the Investigator’s causality assessment.  All 
bone fractures and bone associated events (e.g., osteoporosis) 
should be collected as either AEs or SAEs if the criteria of SAE 
were met, regardless of the investigator’s causality assessment. 
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 or 
those who experienced an SSE and radiological progression will 
be followed for survival, treatment-related AEs and SAEs, the 
initiation of other anti-cancer therapies, and SSEs with phone 
calls as follows: 
 For subjects that did not experience an SSE during 
treatment or the previous follow-up period, the frequency 
of the phone calls will be every 4 weeks ±7 days until the 
subject has an SSE.  After the occurrence of the SSE, the 
subjects will be switched to a frequency of phone calls 
every 12 weeks ±7 days at the next scheduled phone call. 
 For subjects who experienced an SSE during treatment or 


 
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the previous follow-up period, the frequency of the phone 
calls will be every 12 weeks ±7 days.   
Symptomatic skeletal events should be recorded until end of 
active follow-up, independent of whether patient starts a new 
anticancer therapy (i.e. chemotherapy, other). 
The active follow-up period without clinic visits extends from 
the EOT visit or the end of active follow-up with clinic visits 
until the subject 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 until study 
termination. 
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 any additional 
malignancies, including AML, and hematological conditions, 
such as MDS, aplastic anemia or myelofibrosis must be reported 
as SAEs, regardless of the Investigator’s causality assessment.  
All bone fractures and bone associated events (e.g., osteoporosis) 
should be collected as either AEs or SAEs if the criteria of SAE 
were met, regardless of the investigator’s causality assessment. 
Subject treatment management will be in accordance with 
routine clinical practice, at the discretion of the Investigator.  
Survival will also be updated for all subjects in the active 
follow-up period at the time of final analysis of the primary 
endpoint. 
Long-term follow-up – Extension study: 
All ongoing study subjects who have completed at a minimum 
the EOT visit or 30 days from last study treatment dose, 
whichever is latest, may be transitioned into a separate long-term 
follow-up study (BAY 88-8223 study 16996 / NCT02312960). 
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 primary objective 
of this study is to define the long-term safety profile of 
radium-223 dichloride. 
All subjects who transition into this separate long-term follow-
up study will require a separate signed informed consent. 
This study will end when all subjects have transitioned into the 
long-term follow-up study or discontinued from this study for 


 
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another reason (e.g., death, consent withdrawn and active 
objection for further data collection, lost to follow-up). Until the 
transition to the long-term follow up study, subjects will 
continue to follow all the protocols required procedures and 
visits in the current protocol. 
Methodology section modified by Amendments 1, 2, 4, and 8. 
Type of control 
Placebo-control arm 
Number of subjects 
227 subjects in total (with 1:1 randomization) 
Primary variable 
Symptomatic skeletal event-free survival (SSE-FS) 
Time point/frame of 
measurement for 
primary variable(s) 
The primary variable/endpoint, SSE-FS, is defined as the time 
from randomization to the occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone 
fractures (vertebral or non-vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
(2) Death from any cause  
Note: All prior SRE-related procedures (i.e., orthopedic surgery, 
EBRT) must be administered prior to randomization.  
Plan for statistical analysis 
The analysis of efficacy will be performed using the 
intent-to-treat population, defined as all subjects who are 
randomized.  
The primary efficacy analysis of SSE-FS will be performed 
using a log-rank test, stratified by the same factors as the 
randomization factors (i.e., geographic region, prior lines of 
hormone therapy in metastatic setting, and prior SREs).  A 
one-sided alpha of 0.1 will be used for the analysis of SSE-FS.  
Assuming a one-sided alpha of 0.1, power of 90%, a 
randomization ratio of 1:1 between treatments, and the median 
SSE-FS for the control group to be 7 months, approximately 
119 events will be required to detect a 60% increase in SSE-FS 
for a total of 227 subjects in the 2 treatment groups combined. 
The secondary and exploratory time-to-event efficacy endpoints 
will be analyzed using a log-rank test, stratified by the same 


 
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factors as the randomization factors.  
The analysis of safety will be descriptive only (no statistical test 
will be applied). 
 


 
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Table of contents 
 
Cover page of the integrated clinical study protocol ............................................................ 1 
1. 
Title page ........................................................................................................................... 2 
Signature of the sponsor’s medically responsible person ..................................................... 3 
Signature of principal investigator ......................................................................................... 4 
2. 
Synopsis ............................................................................................................................. 5 
Table of contents .................................................................................................................... 22 
Table of tables ........................................................................................................................ 26 
Table of figures ....................................................................................................................... 26 
List of abbreviations .............................................................................................................. 27 
Definitions of terms ................................................................................................................ 30 
3. 
Introduction .................................................................................................................... 31 
3.1 
Metastatic breast cancer ............................................................................................. 31 
3.2 
HER2 negative and hormone receptor-positive metastatic breast cancer .................. 32 
3.3 
Bone metastasis in HER2-negative and hormone receptor-positive metastatic 
breast cancer ............................................................................................................... 33 
3.4 
Study medications ...................................................................................................... 35 
3.4.1 
Radium-223 dichloride ....................................................................................... 35 
3.4.1.1 
Drug development...............................................................................................35 
3.4.1.2 
Benefits and risks ................................................................................................37 
3.4.1.3 
Dosing rationale ..................................................................................................37 
3.4.2 
Standard of care hormonal treatments ................................................................ 38 
3.5 
Study rationale ............................................................................................................ 39 
4. 
Study objectives .............................................................................................................. 40 
5. 
Study design .................................................................................................................... 41 
5.1 
Design overview ......................................................................................................... 41 
5.1.1 
Study periods and duration ................................................................................. 42 
5.1.2 
Study endpoints ................................................................................................... 48 
5.2 
Primary variables ........................................................................................................ 49 
5.3 
End of study ................................................................................................................ 49 
6. 
Study population............................................................................................................. 49 
6.1 
Inclusion criteria ......................................................................................................... 50 
6.2 
Exclusion criteria ........................................................................................................ 53 
6.3 
Withdrawal of subjects from study............................................................................. 55 
6.3.1 
Withdrawal .......................................................................................................... 55 
6.3.1.1 
Withdrawal from treatment period (collection of follow-up data) .....................56 
6.3.1.2 
Withdrawal from treatment period and/or all follow-up (no further 
data collection) ....................................................................................................57 
6.3.2 
Replacement ........................................................................................................ 57 
6.4 
Subject identification .................................................................................................. 57 
7. 
Treatments ...................................................................................................................... 58 
7.1 
Treatments to be administered.................................................................................... 58 


 
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7.2 
Identity of study treatment.......................................................................................... 59 
7.2.1 
Investigational medicinal product ....................................................................... 59 
7.2.1.1 
Radium-223 dichloride .......................................................................................59 
7.2.1.2 
Saline ..................................................................................................................60 
7.2.2 
Non-investigational medicinal products ............................................................. 60 
7.2.2.1 
Background treatment with standard of care hormonal treatment ......................60 
7.2.2.2 
Bone-targeted agents, bisphosphonates and denosumab ....................................60 
7.3 
Treatment assignment ................................................................................................. 60 
7.4 
Dosage and administration ......................................................................................... 61 
7.4.1 
Dose calibration .................................................................................................. 61 
7.4.2 
Radium-223 dichloride dose handling ................................................................ 62 
7.4.3 
Radium-223 dose calculation .............................................................................. 63 
7.4.4 
Study drug dose preparation ............................................................................... 63 
7.4.5 
Dose administration ............................................................................................ 64 
7.4.6 
Dose adjustments, delays, and treatment discontinuations ................................. 65 
7.4.7 
Supportive care guidelines .................................................................................. 66 
7.5 
Blinding ...................................................................................................................... 67 
7.6 
Drug logistics and accountability ............................................................................... 68 
7.7 
Treatment compliance ................................................................................................ 69 
8. 
Non-study therapy .......................................................................................................... 69 
8.1 
Prior and concomitant therapy.................................................................................... 69 
8.1.1 
Prohibited concomitant therapy .......................................................................... 70 
8.1.2 
Permitted concomitant therapy ........................................................................... 70 
8.2 
Post-study treatment therapy ...................................................................................... 72 
9. 
Procedures and variables ............................................................................................... 72 
9.1 
Tabular schedule of evaluations ................................................................................. 72 
9.2 
Visit description.......................................................................................................... 78 
9.2.1 
Screening period (Visits 0 to 1) .......................................................................... 78 
9.2.2 
Randomization .................................................................................................... 80 
9.2.3 
Treatment period ................................................................................................. 80 
9.2.3.1 
Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) .82 
9.2.3.2 
Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits ...............................................................................................84 
9.2.3.3 
End of treatment visit ..........................................................................................85 
9.2.4 
Active follow-up ................................................................................................. 86 
9.2.4.1 
Active follow-up with clinic visits......................................................................86 
9.2.4.2 
Active follow-up without clinic visits ................................................................89 
9.2.4.3 
End of active follow-up ......................................................................................90 
9.2.5 
End of Study ....................................................................................................... 92 
9.2.6 
Radiological assessment: tumor and response evaluation .................................. 93 
9.3 
Population characteristics ........................................................................................... 94 
9.3.1 
Demographic ....................................................................................................... 94 
9.3.2 
Medical history ................................................................................................... 94 
9.3.3 
Other baseline characteristics ............................................................................. 95 
9.4 
Efficacy....................................................................................................................... 95 


 
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9.4.1 
Efficacy variables................................................................................................ 95 
9.4.2 
Definition of efficacy variables .......................................................................... 96 
9.4.2.1 
Primary endpoint.................................................................................................96 
9.4.2.2 
Secondary efficacy endpoints .............................................................................96 
9.4.2.3 
Exploratory efficacy endpoints ...........................................................................97 
9.5 
Pharmacokinetics ........................................................................................................ 98 
9.6 
Safety .......................................................................................................................... 98 
9.6.1 
Adverse events .................................................................................................... 99 
9.6.1.1 
Definitions ..........................................................................................................99 
9.6.1.2 
Classifications for adverse event assessment ....................................................101 
9.6.1.3 
Assessments and documentation of adverse events ..........................................103 
9.6.1.4 
Reporting of serious adverse events ..................................................................104 
9.6.1.5 
Expected adverse events ...................................................................................105 
9.6.2 
Pregnancies ....................................................................................................... 105 
9.7 
Other procedures and variables ................................................................................ 106 
9.7.1 
Resource utilization .......................................................................................... 106 
9.7.2 
Biomarker assessments ..................................................................................... 106 
9.7.2.1 
Urine, plasma, and serum based biomarker analysis ........................................106 
9.7.2.2 
Collection of circulating tumor cells for biomarker analyses ...........................107 
9.7.3 
Analysis of the impact of body weight on SSE-FS and AEs ............................ 107 
9.8 
Appropriateness of procedures/measurements ......................................................... 107 
10. Statistical methods and determination of sample size .............................................. 107 
10.1 
General considerations ............................................................................................. 107 
10.2 
Analysis sets ............................................................................................................. 108 
10.3 
Efficacy variables and planned statistical analyses .................................................. 108 
10.3.1 
Primary efficacy analysis .................................................................................. 109 
10.3.2 
Secondary efficacy analysis .............................................................................. 109 
10.3.3 
Exploratory efficacy analysis ............................................................................ 109 
10.3.4 
Safety analysis .................................................................................................. 109 
10.4 
Determination of sample size ................................................................................... 109 
10.5 
Planned interim data review ..................................................................................... 110 
11. Data handling and quality assurance ......................................................................... 110 
11.1 
Data recording .......................................................................................................... 110 
11.2 
Monitoring ................................................................................................................ 111 
11.3 
Data processing ........................................................................................................ 111 
11.4 
Missing data.............................................................................................................. 111 
11.5 
Audit and inspection ................................................................................................. 111 
11.6 
Archiving .................................................................................................................. 112 
12. Premature termination of the study ........................................................................... 112 
13. Ethical and legal aspects .............................................................................................. 113 
13.1 
Investigators and other study personnel ................................................................... 113 
13.1.1 
Independent data monitoring committee .......................................................... 113 
13.1.2 
Independent radiological review ....................................................................... 114 
13.1.3 
Independent Data Review Committee (IDRC) ................................................. 114 
13.2 
Funding and financial disclosure .............................................................................. 114 


 
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13.3 
Ethical and legal conduct of the study ...................................................................... 114 
13.4 
Subject information and consent .............................................................................. 115 
13.5 
Publication policy and use of data ............................................................................ 116 
13.6 
Compensation for health damage of subjects/insurance .......................................... 116 
13.7 
Confidentiality .......................................................................................................... 116 
14. Reference list ................................................................................................................. 118 
15. Protocol amendments ................................................................................................... 123 
15.1 
Amendment 1 ........................................................................................................... 123 
15.1.1 
Overview of changes to the study ..................................................................... 124 
15.1.2 
Changes to the protocol text ............................................................................. 130 
15.2 
Amendment 2 ........................................................................................................... 152 
15.2.1 
Overview of changes to the study ..................................................................... 154 
15.2.2 
Changes to the protocol text ............................................................................. 160 
15.3 
Amendment 4 ........................................................................................................... 182 
15.3.1 
Overview of changes to the study ..................................................................... 183 
15.3.2 
Changes to the protocol text ............................................................................. 189 
15.4 
Amendment 5 ........................................................................................................... 213 
15.4.1 
Overview of changes to the study ..................................................................... 214 
15.4.2 
Changes to the protocol text ............................................................................. 219 
15.5 
Amendment 6 ........................................................................................................... 242 
15.5.1 
Overview of changes to the study ..................................................................... 242 
15.5.2 
Changes to the protocol text ............................................................................. 245 
15.6 
Amendment 7 ........................................................................................................... 254 
15.6.1 
Overview of changes to the study ..................................................................... 254 
15.6.2 
Changes to the protocol text ............................................................................. 256 
15.7 
Amendment 8 ........................................................................................................... 260 
15.7.1 
Overview of changes......................................................................................... 260 
15.7.1.1 
Modification 1...................................................................................................260 
15.7.1.2 
Modification 2...................................................................................................261 
15.7.1.3 
Modification 3...................................................................................................261 
15.7.1.4 
Modification 4...................................................................................................261 
15.7.1.5 
Minor clarifications...........................................................................................261 
15.7.2 
Changes to the protocol text ............................................................................. 262 
16. Appendices .................................................................................................................... 263 
16.1 
National Cancer Institute-Common Terminology Criteria, version 4.03 ................. 263 
16.2 
Response Evaluation Criteria in Solid Tumors (RECIST 1.1) ................................. 264 
16.3 
Calculation for glomerular filtration rate ................................................................. 272 
16.4 
New York Heart Association Functional Classification .......................................... 273 
16.5 
ECOG performance status ........................................................................................ 274 
16.6 
BPI-SF ...................................................................................................................... 275 
16.7 
Resource utilization questionnaire ........................................................................... 279 
16.8 
Patient Reported Questionnaire Information Sheet .................................................. 281 
 


 
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Table of tables 
 
Table 9–1:  Schedule of assessments ....................................................................................... 73 
Table 16–1:  Target lesion response ...................................................................................... 267 
Table 16–2:  Non-target lesion response ............................................................................... 268 
Table 16–3:   Visit Response:  Subjects with target lesions (with or without non-target 
lesions) .............................................................................................................. 270 
Table 16–4:  Time Point Response:  Subjects with non-target lesions only .......................... 271 
 
Table of figures 
 
Figure 5–1:  Study design schematic ....................................................................................... 47 
Figure 9–1:  Radiological tumor evaluation schedule ............................................................. 93 


 
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List of abbreviations 
Section modified by Amendment 4 (Section 15.3), Amendment 5 (Section 15.4), and 
Amendment 7 (Section 15.6). 
AE 
Adverse event 
AI 
Aromatase inhibitor 
ALP 
Alkaline phosphatase 
ALSYMPCA 
Alpharadin in Symptomatic Prostate Cancer 
ALT 
Alanine aminotransferase 
AML 
Acute myelocytic leukemia 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BCE 
Bone collagen equivalents 
BPI-SF 
Brief Pain Inventory-Short Form  
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CI 
Confidence interval 
CISH 
Chromogenic in situ hybridization 
Cl 
Chloride 
CR 
Complete response 
CRO 
Contract research organization 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTC 
Circulating tumor cell 
CTCAE  
Common Terminology Criteria for Adverse Events; version 4.03 
Cx 
Cycle x 
DK 
Decay correction factor 
DNA 
Deoxyribonucleic acid 
EBRT 
External beam radiotherapy 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of study 
EOT 
End of treatment 
ER 
Estrogen receptor 
ER- 
Estrogen receptor negative 


 
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ER+ 
Estrogen receptor positive 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FDG 
Fluorodeoxyglucose 
FISH 
Fluorescence in situ hybridization 
G-CSF 
Granulocyte-colony stimulating factor 
GCP 
Good clinical practice 
GFR 
Glomerular filtration rate 
GM-CSF 
Granulocyte macrophage-colony stimulating factor 
GMP 
Good Manufacturing Practice 
Hb 
Hemoglobin 
HER2 
Human epidermal growth factor receptor 2 
HR 
Hazard ratio 
HRQoL 
Health-related quality of life 
IB 
Investigator’s Brochure 
IBW 
Ideal body weight 
ICF 
Informed consent form 
ID 
Identification number 
IDRC 
Independent Data Review Committee  
IEC 
Independent Ethics Committee  
IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
INR 
International normalized ratio of prothrombin time 
IPM 
Increase in pain management 
IRB 
Institutional Review Board 
ISH 
In situ hybridization 
ITT 
Intent-to-treat 
IV 
Intravenous 
IXRS 
Interactive voice/web response system 
K 
Potassium 
kBq 
KiloBecquerel; SI unit of radioactivity 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LH-RH 
Luteinizing hormone-releasing hormone 
mCi 
Millicuries 
MDRD 
Modification of Diet in Renal Disease 
MDS 
Myelodysplastic syndromes 


 
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mg 
Milligram 
mL 
Milliliter 
mRECIST 1.1 
Modified Response Evaluation Criteria in Solid Tumors version 1.1 
MRI 
Magnetic resonance imaging 
Na 
Sodium 
NCI 
National Cancer Institute 
NE 
Non-evaluable 
NIST 
National Institute of Standards and Technology 
NSAI 
Non-steroidal aromatase inhibitor 
NTX 
N-terminal telopeptide 
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Progressive response 
PR- 
Progesterone receptor negative 
PR+ 
Progesterone receptor positive 
PRD 
Patient ready dose 
PS 
Performance status 
PSA 
Prostate specific antigen 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
q 
Every 
QoL 
Quality of life 
RANKL 
Receptor activator of NF–κB ligand 
RAVE 
Medidata Rave; electronic data capture tool 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
Radiological progression-free survival 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
SAS Institute Inc. 
SC 
Subcutaneously 
SD 
Stable disease 
SPECT 
Single photon emission tomography 
SRE 
Skeletal-related event 


 
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SSE 
Symptomatic skeletal event 
SSE-FS 
Symptomatic skeletal event-free survival 
SUSAR 
Suspected unexpected serious adverse reaction 
TBW 
Total body weight 
TTP 
Time to progression 
tx 
Treatment 
ULN 
Upper limit of normal 
US 
United States 
W/O 
Without 
WBC 
White blood cell 
wk 
Week 
WPS 
Worst pain score 
 
Definitions of terms 
Radium-223 
dichloride  
The investigational product, a targeted alpha particle emitting 
radiopharmaceutical, is a ready-to-use solution for intravenous injection 
containing the drug substance radium-223 dichloride.  The active moiety is 
the alpha particle emitting nuclide radium-223, present as a divalent cation 
(223Ra2+).  
Dose  
Doses are given as kiloBecquerel (kBq) per kilogram body weight, with the 
corresponding dose given in millicurie (mCi) per kilogram in parenthesis.  
The term “dose” is used to describe the quantity of radioactivity from 
radium-223 administered.  
 


 
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3. 
Introduction 
3.1 
Metastatic breast cancer 
Breast cancer is by far, the most common cancer among women worldwide with an estimated 
1.67 million new cancer cases diagnosed in 2012 (25% of all cancers).  It is the most frequent 
cause of cancer death in women in less developed regions (324,000 deaths, 14.3% of total) 
and the second cause of cancer death in more developed regions (198,000 deaths, 15.4%) 
after lung cancer.(1) 
Despite recent progress in diagnostic and therapeutic approaches of early breast cancer, a 
significant proportion of patients relapse following adjuvant treatment and approximately 5% 
to 6% of women present with metastatic disease at the time of their initial diagnosis.  
The clinical presentation in the metastatic setting may range from an aggressive clinical 
course in patients with multiple and/or extensive organ involvement to a rather indolent 
clinical course in those with a solitary or only few metastatic lesions (oligometastatic 
disease).  
Depending on the extent of metastatic involvement, the prognosis is variable ranging from a 
median overall survival (OS) time of 26 months, in patients with bone metastases only, to 
21 months, in patients with bone and visceral metastases, and 18 months, in patients with 
visceral metastases only.(2) 
Patients with metastatic disease are unlikely to be cured with actual available therapies.  As 
cure is unlikely in the metastatic setting, prolongation of survival, disease control, 
improvement/maintenance of quality of life (QoL) and palliation of cancer-related symptoms 
are reasonable goals of therapy.  
Various therapeutic approaches are available; however, there are few widely accepted 
standards.  Most patients will receive systemic therapies such as chemotherapy, endocrine 
therapy, biologic/targeted molecular therapies, bone-targeted agents, as well as supportive 
care.  The selection of a certain type of therapy over the other depends upon factors, such as 
tumor/disease characteristics (hormone receptor status, human epidermal growth factor 
receptor 2 [HER2] status, extent of metastatic involvement, disease clinical behavior, etc.), 
prior therapies and disease response to prior therapies, patient characteristics (i.e., 
comorbidities, estimated treatment tolerability, menopausal status), availability and costs of 
therapeutic agents and, last but not least, patient preference.  
Participation in well-designed clinical studies should always be considered in patients with 
metastatic breast cancer.  
Patients with rapidly progressing or symptomatic or visceral disease as well as those patients 
with hormone receptor–negative tumors or with disease that is resistant to hormonal therapy 
are candidates for chemotherapy. 
Patients with HER2/neu positive disease are candidates for anti-HER2-targeted agents (i.e., 
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3.2 
HER2 negative and hormone receptor-positive metastatic breast cancer 
Presence of estrogen receptor (ER) and/or progesterone receptor (PR) is one of the most 
important prognostic/predictive factors in breast cancers.  Approximately 70% to 75% of 
patients with invasive breast cancer have hormone receptor (ER and/or PR) positive disease 
at the time of diagnosis.(3) 
Patients with hormone receptor positive disease and HER2-negative disease are candidates 
for endocrine therapy unless one of the factors described above would prompt the selection of 
another type of therapy (i.e., chemotherapy in a patient with an aggressive clinical course and 
rapid pace of progression).  Endocrine therapy will very likely have a beneficial effect in 
these patients and fewer side effects in comparison with chemotherapy.(4,5) 
Selection of the first line endocrine agent is generally based on the menopausal status, type of 
endocrine agent in the adjuvant setting, timing of relapse following treatment in the adjuvant 
setting, and tolerability.  First line endocrine therapy is usually continued until the patient 
experiences disease progression or unacceptable toxicity.  
Additional lines of therapy may include another endocrine agent (not previously 
administered) or another type of therapy such as cytotoxic therapy.  There are no widely 
accepted standards/definitive recommendations for a specific treatment sequence, number of 
lines of endocrine therapy, and the therapeutic decision should be again based on the factors 
described above. 
Endocrine therapy exerts its action either by reducing estrogen production or by interacting 
with ERs.  
Various endocrine agents are currently in use including:  
 Selective estrogen receptor modulators (SERMs):  Tamoxifen and toremifene.  
SERMs act by antagonizing the action of estrogen in breast tissue.  At the same time, 
they also mimic the action of estrogen in other tissues, such as bone and 
endometrium.(6)   
 Third generation aromatase inhibitors (AIs) block peripheral estrogen synthesis by 
inhibiting aromatase, the enzyme responsible for the peripheral conversion of 
androgens to estrogen.(7)  Currently available third generation AI are the nonsteroidal 
AIs (NSAIs), anastrozole and letrozole and the steroidal AI, exemestane.  In the 
first-line setting, large phase III studies have shown that all 3, anastrozole, letrozole, 
and exemestane are equivalent or superior to tamoxifen in women with metastatic 
disease.(8,9,10,11) 
 Estrogen receptor down-regulators:  Fulvestrant is a competitive ER antagonist.  It 
blocks the actions of estrogens at the level of the receptor without any known partial 
agonist (estrogen-like) activity.  Fulvestrant has been approved by the United States 
(US) Food and Drug Administration (FDA) and European Medicines Agency (EMA) 
for the treatment of hormone receptor positive metastatic breast cancer in post-


 
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menopausal women with disease progression following prior anti-estrogen therapy 
based on results of published clinical studies.(12,13,14) 
 Luteinizing hormone-releasing hormone (LH-RH) analogues: Goserelin, leuprorelin, 
triptorelin.  
 Other: estrogens, progestins, anabolic steroids 
Recently published data from a phase II study shows that addition of everolimus to tamoxifen 
in hormone receptor positive, HER2 negative patients who progressed on prior AI treatment 
significantly improved the clinical benefit rate, time to progression.(15) 
In addition to this, data from the phase III BOLERO-2 study showed that the addition of 
everolimus to exemestane significantly improved progression-free survival (PFS) compared 
with single-agent exemestane in estrogen receptor positive (ER+), HER2 negative patients 
whose metastatic disease was refractory to prior treatment with letrozole or anastrozole.(16)  
This led to the recent marketing approval of everolimus by the FDA and EMA for the 
treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in 
combination with exemestane, in post-menopausal women without symptomatic visceral 
disease after recurrence or progression following an NSAI. 
3.3 
Bone metastasis in HER2-negative and hormone receptor-positive 
metastatic breast cancer 
Bone is a frequent site of metastatic spread with approximately 65% to 75% of patients with 
metastatic breast cancer having skeletal involvement.(17)  The skeleton is the first site of 
distant spread in 46% to 47% of patients with breast cancer.  The presence of skeletal 
metastases correlates significantly with ER and PR positivity.(18,19)  Bone-only metastases 
have been reported to occur in 17% to 37% of women with metastatic breast 
cancer.(20,21,22) 
Results of a recent meta-analysis from 41 randomized studies that compared bisphosphonates 
to no bisphosphonates and including data from 17,751 breast cancer patients suggests that 
adjuvant bisphosphonates reduce bone recurrences and improve breast cancer survival in 
post-menopausal women.  Reductions in bone recurrence for post-menopausal women were 
similar independent of ER status, nodal involvement, bisphosphonate type, treatment 
schedule, or use of concomitant chemotherapy.(23) 
Prognosis of patients with metastases confined to bone only seems to be better compared to 
patients with visceral involvement with median survival times from the diagnosis of 
metastatic disease to death between 24 to 36 months as reported per different 
publications.(2,21,22,24,25)  Occurrence of osseous metastases interferes with normal bone 
homeostasis and impacts the normal remodeling process by disrupting the fine balance 
between new bone formation and bone resorption processes.  This, finally results in loss of 
bone integrity and loss of function.  
The most common sites of bone involvement are axial bones; however, other locations may 
also be encountered although with a lower frequency.  Bone lesions may be of osteolytic, 
osteoblastic, or mixed phenotype as per the radiographic appearance of the lesions.  It is well 


 
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known that bone metastases from breast cancer usually show osteolytic changes.  However, 
interestingly, as per a retrospective study, when comparing the morphology of breast cancer 
bone metastases by computed tomography (CT) in the time period 1996 to 2000 versus 2001 
to 2005, a higher prevalence of osteoblastic metastases was observed in the later period (1996 
to 2000: osteolytic 53.7%, osteosclerotic 32.1%, mixed type 14.3%; 2001 to 2005: osteolytic 
9.4%, osteosclerotic 71.9%, mixed type 18.7%).  This might be due to the application of 
systematic bisphosphonate treatment.(26)   
Due to the disrupted bone remodeling process, patients with metastatic bone lesions are at 
risk of increased morbidity including skeletal related events (SRE), such as bone pain 
requiring intervention (i.e., radiotherapy or surgery), pathologic fractures, spinal cord 
compression, as well as symptomatic hypercalcemia and bone marrow infiltration.  These 
events will ultimately impair the patient’s QoL and functional independence.   
A multidisciplinary therapeutic approach is generally recommended in patients presenting 
with bone metastases.  Current therapeutic options include systemic therapies such as 
endocrine therapies, chemotherapy, and bone-targeted agents (i.e., bisphosphonates, 
denosumab).  Local therapies such as external beam radiotherapy (EBRT) as well as other 
supportive interventions (i.e., orthopedic interventions for prevention/correction of 
pathological fractures) are also an important part of the therapeutic management for symptom 
palliation. 
Use of systemic bone targeted agents, such bisphosphonates, as well as the newer anti-
receptor activator of NF–κB ligand (RANKL) antibody, denosumab demonstrated a 
beneficial effect in patients with metastatic bone disease.  While bisphosphonates inhibit 
osteoclast-mediated bone resorption, denosumab, a monoclonal antibody, inhibits key 
pathways in the vicious cycle of bone metastases by binding to RANKL, a mediator that 
stimulates increased osteoclast activity.  
Several clinical studies have demonstrated the efficacy of bisphosphonates in women with 
bone metastases from breast cancer.(27,28,29,30) 
More recently, denosumab has been found to be more effective than zoledronic acid as 
measured by the time to first and subsequent on-study SREs in patients with bone 
metastases.(31,32)  The median time to the first on-study SRE was 26.4 months for 
zoledronic acid and was not yet reached for denosumab at time of reporting.  Denosumab was 
approved for the treatment of patients with bone metastases from solid tumors, including 
breast cancer.  
A recent review of 34 studies performed in this patient population provided further 
confirmation that the use of bisphosphonates or denosumab (in addition to their other cancer 
treatments) reduces the risk of developing SREs and delay the time to SREs.  However, 
questions on the optimal timing and duration of treatment with these agents in patients with 
bone metastases from breast cancer remain unanswered.(33)  Bone-targeted agent therapy 
(i.e., bisphosphonates or denosumab) is actually recommended for patients with breast cancer 
with evidence of bone metastases.(34)  


 
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Patients with multiple, mainly osteoblastic lesions and pain syndrome may also benefit from 
treatment with radionuclide therapy.  Bone-seeking radionuclides have been developed for 
palliation of bone pain from metastases.(35) 
Metastron (strontium-89) and Quadramet (samarium-153 ethylene diamine tetramethylene 
phosphonate) have been approved in several countries for symptom palliation in patients with 
bone metastases.(36)  The bone-seeking nature of these agents results in direct delivery of 
beta radiation to the sites of disease.  Due to the long range of the beta particles from these 
radioisotopes, the major dose-limiting factor with this treatment modality is toxicity to the 
bone marrow cells, limiting the use of these agents to pain palliation only as they have not 
demonstrated an OS benefit.  This toxicity has seriously limited their clinical use. 
The limited hematological toxicity resulting from the short particle range of new alpha 
emitter radiopharmaceutical radium-223 dichloride may allow an easier integration with 
background anti-cancer therapies.  Beside pain palliation effect, the high absorbed dose 
delivered by alpha-emitting radionuclides might have a direct anti-tumor effect in bone. 
Multimodality therapy such as bisphosphonate/denosumab and radiopharmaceutical agents in 
addition to the standard background treatment might offer superior symptom control and even 
prolonged PFS and OS. 
3.4 
Study medications 
3.4.1 
Radium-223 dichloride 
3.4.1.1 
Drug development 
Radium-223 dichloride solution for injection is a novel alpha particle-emitting 
radiopharmaceutical.  The bone targeting property of radium-223 is similar to that of other 
earth alkaline elements, like calcium or strontium-89.  However, the radiation characteristics 
of an alpha particle-emitting radionuclide appear to be more advantageous than of a beta-
emitting radionuclide.  Radium-223, with a physical half-life of 11.4 days, emits high linear 
energy transfer alpha radiation, with a range limited to less than 100 micrometers.  The high 
linear energy transfer of alpha emitters (80 keV/micrometer) leads to a high frequency of 
double-strand deoxyribonucleic acid (DNA) breaks in adjacent cells, resulting in an 
anti-tumor effect on bone metastases.  The alpha particle range from radium-223 dichloride is 
less than 100 micrometers (less than 10 cell diameters), which limits damage to the 
surrounding normal tissue. 
Biodistribution studies have shown that radium-223 is selectively concentrated in bone 
compared to soft tissues, and that radium-223 is retained in the bone matrix.(37,38)  Due to 
increased bone metabolism in skeletal metastases, preferential uptake in these lesions 
compared to normal bone is observed.  A significant radium-223 anti-tumor effect has been 
demonstrated in an experimental skeletal metastases model in nude rats.(38) 
The clinical development of radium-223 dichloride was initiated in August 2001.  A phase I 
clinical study in subjects with skeletal metastases from breast and prostate cancer was 
performed in order to evaluate whether the product could be administered safely at 


 
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therapeutically relevant doses.  A total of 31 subjects were enrolled.  Twenty-five subjects 
received a single intravenous (IV) injection in the dose escalating part of the study, with 
5 subjects at each dose level of 46, 93, 163, 213, and 250 kBq/kg body weight radium-223 
dichloride.  The results of this phase I study were encouraging (low toxicity, significant pain 
relief, and decreased serum alkaline phosphatase [ALP]); thus, a phase II study (BC1-02 
study) for castration-resistant prostate cancer (CRPC) was conducted,(37) where subjects 
received multiple doses of either 50 kBq/kg body weight radium-223 dichloride or saline 4 
times at 4-week intervals.  In both studies, the results showed modest dose-dependent 
reversible hematological toxicity.  No significant deleterious changes in chemistry parameters 
were seen, and the most frequent adverse event (AE) was transient diarrhea, which responded 
well to medication.  In terms of efficacy, the BC1-02 phase II results showed a significant 
improvement in serum bone markers, i.e., bone ALP (a primary efficacy endpoint) and, 
perhaps more importantly, a delayed time to prostate specific antigen (PSA) progression.  
Median OS at 2 years was 65.3 weeks for radium-223 dichloride and 46.3 weeks for placebo 
(hazard ratio [HR]=2.1; p=0.017 based on an intent-to-treat [ITT] population and adjusting 
for baseline covariates).  
Following the positive results of the phase II study, the phase III, double-blind, randomized, 
BC1-06, ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) study was started in 
2008.  A total of 922 subjects with CRPC and symptomatic bone metastases were 
randomized to receive 6 injections of radium-223 dichloride (50 kBq/kg IV) or matching 
placebo every 4 weeks.  Based on data of an interim analysis (n=809), the study was 
unblinded in June 2011, since radium-223 dichloride significantly improved OS compared to 
placebo (the median OS was 14.0 versus 11.2 months, respectively; HR= 0.695; p=0.00185).  
Symptomatic skeletal events (SSE) were lower in the radium-223 dichloride arm, and time to 
first SSE was significantly delayed (the median time to SSE was 13.6 months, versus 
8.4 months, respectively; HR=0.610; p=0.00046).  A low incidence of myelosuppression was 
observed, with Grade 3/4 events of neutropenia (1.8%) and thrombocytopenia (6.2%).  
Adverse events of any grade were described in 88% of the subjects who received radium-223 
dichloride versus 94% in the placebo arm (Grade 3/4 AEs were described for 51% and 59%, 
respectively).  The updated analysis (performed in June 2012) also showed that radium-223 
dichloride significantly improved OS compared to placebo (median OS 14.9 versus 
11.3 months, respectively; HR=0.695; p=0.00007).(39)  
In an open-label, multicenter, single-arm, phase IIa study (BC1-09), 23 subjects with 
metastatic breast cancer with bone dominant disease were administered 4 injections of 
radium-223 dichloride (50 kBq/kg IV) every 4 weeks.  Bone markers were assessed at 
baseline, prior to every treatment, and thereafter at each follow-up visit.  The primary 
efficacy endpoints were the change in urine levels of N-terminal telopeptide (NTX) and bone 
ALP from baseline at Week 16.  Median urine NTX levels were reduced by 20% (from 36 to 
29 nmo1 bone collagen equivalents [BCE]/mmo1 creatinine; p=0.03) and 33% (from 36 to 
23 nmo1 BCE/mmo1 creatinine; p=0.0124) at Week 8 and Week 16, respectively; 17/23 and 
9/13 subjects (for whom data were available) had a decrease in urine NTX at Week 8 and 
Week 16, respectively.  Median bone ALP levels were reduced by 33% (from 22.1 to 
12.1 ng/mL; p=0.0001) at Week 8 and 42% (from 22.1 to 10.94 ng/mL; p=0.04) at Week 16.  
Bone ALP levels were reduced in 20/22 subjects at Week 8 and in 10/12 subjects (for whom 


 
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data were available) at Week 16.  Radium-223 dichloride was found to be safe and well 
tolerated.  Three subjects had serious AEs (SAEs), none related to study drug; 1 of them died 
due to disease progression.(40) 
Further details can be found in the Investigator's Brochure (IB), which contains 
comprehensive information on the study drug. 
3.4.1.2 
Benefits and risks 
Anticipated benefits of treatment with radium-223 dichloride include prolongation of 
symptomatic skeletal event-free survival (SSE-FS), OS, and radiological progression-free 
survival (rPFS), delay of SSEs, palliation of bone pain, and improvement in QoL. 
The risk profile attributed to radium-223 dichloride is favorable compared with available 
products for the treatment of metastatic breast cancer.  The anticipated risks attributed to 
radium-223 dichloride include the following AEs: gastrointestinal (constipation, transient but 
treatable diarrhea, nausea, and vomiting); hematological (transient reduction in neutrophil 
count, mild to moderate myelosuppression, low grade thrombocytopenia).  Due to its 
radioactive nature, radium-223 dichloride has the potential of inducting long-term toxicities 
such as other primary cancers.  Current ongoing studies have an increased follow-up of 
7 years in order to assess this potential. 
3.4.1.3 
Dosing rationale 
Section modified by Amendment 2 (Section 15.2) and Amendment 4 (Section 15.3). 
The proposed dosing regimen in this phase II study is 50 kBq/kg body weight (55 kBq/kg 
after implementation of NIST update) every 4 weeks for a 6-month treatment period 
(6 injections).  In the completed phase I safety, tolerability, and pharmacokinetic clinical 
study (ATI-BC-1), subjects diagnosed with prostate or breast carcinoma and skeletal 
metastases were administered radium-223 dichloride in single doses of 46, 93, 163, 213, or 
250 kBq/kg body weight (25 subjects) or multiple doses of 5 administrations of 50 kBq/kg 
body weight at 3-week intervals (3 subjects) or 2 administrations of 125 kBq/kg body weight 
at 6-week intervals (3 subjects).  In the completed phase II study, 64 subjects with CRPC and 
painful skeletal metastases, received 4 injections of 50 kBq/kg body weight radium-223 
dichloride (33 subjects) or placebo (31 subjects) at 4-week intervals to examine the effects of 
radium-223 dichloride on biomarkers of disease progression, SSEs, pain palliation, survival, 
and safety parameters.  The completed phase III study, ALSYMPCA, enrolled 922 subjects 
diagnosed with CRPC and symptomatic bone metastases who received 6 injections of 
radium-223 dichloride (50 kBq/kg IV) in 4-week intervals.  Endpoints included OS, time to 
disease-related events, time to progression (TTP) as measured by serum PSA and total ALP 
concentrations, pain palliation, acute and long-term safety profile, and health-related quality 
of life (HRQoL).  The efficacy and safety data from the ALSYMPCA study support the 
selection of a dosing regimen of 6 doses of 50 kBq/kg body weight (55 kBq/kg after 
implementation of NIST update) of radium-223 dichloride at 4-week intervals.  This dose and 
schedule was determined to be efficacious, with only minor side effects and no indication of 
cumulative effect on bone marrow suppression following multiple administrations of radium-
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Currently, no data are available to assess if similar effects could be achieved with a dose 
lower than 50 kBq/kg body weight (55 kBq/kg after implementation of NIST update). 
The same dose was used in a phase II breast cancer study BC1-09 which provided 
preliminary evidence of the effects of radium-223 on bone markers, BPI score, and tumor 
metabolism assessed by serial F-18 fluorodeoxyglucose (FDG) positron emission 
tomography (PET) imaging and supports further investigations to confirm effectiveness of 
radium-223 in treating bone metastases in patients with breast cancer and bone-dominant 
disease.  Data were communicated at the San Antonio Breast Cancer Symposium 2011 and 
published in 2014.(40)  The study results are presented in detail in Section 3.4.1.1. 
3.4.2 
Standard of care hormonal treatments 
Patients with hormone receptor positive disease and HER2-negative disease are generally 
considered good candidates for endocrine therapy unless other factors would prompt the 
choice of another type of therapy (i.e., chemotherapy in a patient with an aggressive clinical 
course and rapid pace of progression). 
Results of previous randomized studies and a meta-analysis suggest that AIs are more 
effective than tamoxifen for first-line therapy in post-menopausal women whose tumors have 
not become previously resistant to these drugs.(41)  The choice of initial, first line, endocrine 
therapy depends on the endocrine agent used in the adjuvant setting and timing of 
recurrence/relapse.  In first line setting, anastrozole was shown to be superior to tamoxifen 
for TTP but not for OS.  Letrozole significantly prolonged TTP compared with tamoxifen 
but, again, had no significant difference in OS; exemestane had similar OS compared with 
tamoxifen using the log-rank test and significant improvement in PFS when using the 
Wilcoxon test.(42,43,44)  Based on these results, NSAIs are currently considered the most 
effective first-line treatment of post-menopausal patients with metastatic breast cancer.  
However, tamoxifen remains a standard first-line agent for pre-menopausal women, as well 
as for post-menopausal women who have relapsed shortly following completion of adjuvant 
therapy with an AI (i.e., during or within 12 months).  
The first line endocrine therapy is generally continued until disease progression.  Responding 
patients, as well as those with very slowly progressing disease (i.e., no disease progression 
within 6 months of starting therapy), may be further treated, following progression, with 
several different endocrine agents that are generally tried in sequence.  
There is, however, limited data from randomized clinical studies concerning the best 
sequence of endocrine therapies in patients with metastatic breast cancer and no definitive 
recommendations can be made.(41)  
Examples of further line endocrine therapy in post-menopausal women include selective AIs 
(if not used in first line), such as anastrozole, letrozole, or exemestane; fulvestrant, megestrol 
acetate; estrogens; and androgens.   
Side effects associated with the use of endocrine therapies include, but are not limited to, hot 
flashes, vaginal discharge, menstrual irregularities, sexual dysfunction, thromboembolic 
events, increased risk of uterine cancer (tamoxifen), decrease in bone mineral density, bone 
fracture, and hypercholesterolemia. 


 
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However, endocrine therapy will very likely have a beneficial effect and fewer side effects in 
comparison with chemotherapy. 
3.5 
Study rationale 
The treatment options for patients with bone predominant metastasis of breast cancer are still 
limited.  
Radium-223 dichloride has shown significant anti-tumor activity in phase II and phase III 
studies in subjects with bone predominant metastatic CRPC and in the phase II metastatic 
breast cancer study. 
The safety profile and tolerability for radium-223 dichloride appear to be acceptable in this 
study population. 
This study is blinded, randomized, and placebo controlled for radium-223 dichloride, and it is 
unblinded for standard of care hormonal treatment that will be received by all subjects (both 
arms).  Best supportive care will also be received by both arms. 
The mode of action differs for all involved compounds, as hormonal treatment targets the 
estrogens which promote the growth of hormone sensitive breast cancers.  Tamoxifen and 
toremifene bind specifically to ERs, competitively with estradiol, and inhibit 
estrogen-induced stimulation of DNA synthesis and cell replication.  Fulvestrant is a 
competitive ER antagonist with an affinity comparable to estradiol.   
The NSAIs, anastrozole and letrozole, are competitive inhibitors of the aromatase enzyme 
system at the primary sites of estrogen synthesis, which in post-menopausal women, are 
peripheral tissues, whereas exemestane binds irreversibly to the active site of the enzyme 
aromatase, causing its inactivation.  Radium-223 dichloride delivers alpha radiation to bone 
lesions of breast cancer.  Based upon these individual effects, it is expected that radium-223 
dichloride treatment will prolong symptomatic SSE-FS compared to placebo, when 
administered to HER2 negative, hormone receptor positive metastatic breast cancer patients 
with bone metastases who receive standard of care hormonal treatment as background 
therapy.  
Primary efficacy endpoints 
Symptomatic skeletal event-free survival is defined as the time from randomization to the 
occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
(2) Death from any cause 


 
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Since the definition for measuring skeletal events will not use pre-specified imaging 
assessments, the use of imaging to identify a fracture or spinal cord compression will be 
triggered by symptoms.  As such, only symptomatic events will be captured; asymptomatic 
radiographic events are not included in this composite endpoint.  A delay or a reduction of 
SSEs represents an immediate clinical benefit, as it will delay or reduce bone pain, functional 
impairment, and the need for surgical intervention.  
In ALSYMPCA, treatment with radium-223 dichloride increased the time to first SSE from 
9.8 to 15.6 months (HR=0.658, p=0.00037, data on file).  
The median SSE-FS in ALSYMPCA was 9.0 and 6.4 months with and without radium-223 
dichloride, respectively (HR=0.685, p=0.00004).  An ad-hoc analysis (data on file) in 
subjects who did not receive docetaxel prior to radium-223 dichloride indicated that the 
median duration of SSE-FS is preserved in this subgroup of 395 subjects (SSE-FS was 
9.5 months with and 6.7 months without radium-223 dichloride). 
The occurrence of SREs in breast cancer patients with bone metastases is associated with 
worse functional, physical and emotional status and a decreased overall QoL.(45,46)  
Prevention of SREs, is therefore, an important aim in the therapeutic management of these 
patients.  Bone-targeted agents, such as bisphosphonates and denosumab, have been reported 
to delay the time to SRE and reduce the risk of developing SREs.  In addition, they also 
reduced bone pain and showed an improvement in QoL.(32, 33,46,47,48,49)  As per the 
American Society of Clinical Oncology treatment guidelines, they are both recommended in 
patients with breast cancer with evidence of bone metastases.(34) 
A recent study in patients with bone metastases also reported that patients rated chronic pain 
as their main symptom and the most relevant HRQoL issue related to their disease.  This was 
followed by difficulty in carrying out their usual tasks and worries about loss of 
independence and mobility.(50) 
The high incidence of bone metastases, as well as the prognostic relevance of bone 
involvement, definitely suggests that improvements in bone-targeted therapeutic approach 
could provide further patient benefit. 
In conclusion, SSE-FS is an objective variable that is likely to predict clinical benefit in the 
proposed study population. 
4. 
Study objectives 
Section modified by Amendment 4 (Section 15.3). 
The objective of this study is to assess the efficacy and safety of radium-223 dichloride in 
subjects with HER2 negative, hormone receptor positive breast cancer with bone metastases 
treated with hormonal treatment background therapy. 
The primary endpoint is: 
 SSE-FS 
The secondary endpoints are: 


 
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 OS 
 Time to opiate use for cancer pain 
 Time to pain progression (only in subjects with baseline worst pain score (WPS) ≤8) 
 Time to cytotoxic chemotherapy 
 rPFS 
 Pain improvement rate 
 Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy 
The study will also include the following exploratory endpoints: 
 Time to first on-study SSE 
 Time to bone ALP progression 
 Bone ALP response at Week 12 and end of treatment (EOT) 
 Bone-specific rPFS 
 Resource utilization 
 Biomarker assessments 
 Time to visceral metastases onset 
5. 
Study design 
5.1 
Design overview 
Section modified by Amendment 1 (Section 15.1) and Amendment 4 (Section 15.3). 
This study is an international phase II, randomized, double-blind, placebo-controlled, 
parallel-group study of radium-223 dichloride versus placebo administered on top of the 
hormonal treatment and supportive care as background treatment in subjects with HER2 
negative, hormone receptor positive breast cancer with bone metastases.  Randomization will 
be stratified by: 
 Geographical regions (Europe/North America [including Israel] versus Asia) 
 Previous lines of hormone therapy in metastatic setting (1 versus 2 or more): for the 
purpose of counting the number of prior lines of hormone therapy, only a change of 
the hormone agent due to progression is counted as a new line of therapy.  A switch of 
hormone therapy from one agent to another due to toxicity or other reasons (e.g., 
subject’s preference) in absence of progressive disease (PD) at the time of switch will 
be counted as one line, although 2 different agents have been administered. 
 Prior SREs (1 versus 2): for the purpose of prior SREs stratification, separate SREs 
are those that occur at least 21 days apart from each other. Any procedure which is 
related to an SRE, such as orthopedic surgery to treat a pathological bone fracture or 


 
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multiple doses of radiation during a course of treatment, should not be counted as a 
separate event. In case of bone pain that occurs in several anatomical locations and 
requires separate EBRT sessions, it should be counted as one event if the EBRT 
sessions are administered within a period of 21 days. 
This study will be conducted at approximately 160 investigative study sites and 
approximately 227 subjects will be enrolled. 
5.1.1 
Study periods and duration 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), Amendment 5 (Section 15.4), Amendment 8 (Section 15.7.1.1 and 
Section 15.7.1.2). 
The study will comprise 4 periods: screening, randomization, treatment, and the follow-up 
period (active follow-up with clinic visits and active follow-up without clinic visits).   
Screening period:  
All trial related procedures and evaluations will only be performed after the subject has 
agreed to participate and has signed the informed consent form (ICF).  The screening period 
will consist of multiple evaluations that will take place within 3 weeks prior to randomization 
to ensure that all eligibility criteria are met (Section 6). 
Randomization:  
After all screening assessments have been completed and the subject’s eligibility has been 
confirmed and documented, eligible subjects will be randomized in a ratio of 1:1 to treatment 
with radium-223 dichloride (Arm A - investigational arm) or placebo (Arm B - control arm).  
All subjects will receive treatment with a single hormonal agent and supportive care as 
background treatment, as per the local/institutional standard of practice. 
Treatment period:  
Investigational treatment consists of up to 6 cycles of radium-223 dichloride 50 kBq/kg body 
weight (55 kBq/kg after implementation of NIST update) (Arm A - investigational arm) or 
placebo (Arm B - control arm), each separated by an interval of 4 weeks.   
All ongoing subjects at the time of study termination will finish study treatment with 
radium-223 dichloride or placebo as part of the study. 
All subjects will receive hormonal treatment with a single agent and supportive care as 
background treatment according to the local standard of practice. Subjects enrolled in the 
current study must start treatment with the single hormone agent either within 15 days prior 
to randomization or after randomization (either before or simultaneously to the first injection 
of radium-223 dichloride or placebo).  For subject’s convenience, injections of fulvestrant 
may be scheduled on the same day of the radium-223 dichloride or placebo injection.  
These treatments will also continue after completion of radium-223 dichloride or placebo.  


 
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Subjects who discontinue treatment with radium-223 dichloride/placebo prior to experiencing 
an SSE or radiological progression will enter the follow-up period and will be followed up 
for SSEs and radiological progression. 
In case an SSE is not defined as progression, the subject will continue to be followed as per 
protocol until radiological progression.  
All subjects will continue to receive standard of care hormonal treatment background 
therapy.  Hormonal treatment may also be changed according to the local standard of 
practice, including exemestane in combination with everolimus.  For the purpose of this 
study, only a new hormonal treatment initiated due to disease progression will be considered 
a new anti-cancer therapy. 
Radium-223 dichloride/placebo administration should be discontinued as per the withdrawal 
criteria described in Section 6.3.1 (e.g., subject experiences unacceptable toxicities, delays in 
radium-223 dichloride/placebo >4 weeks, subject enters the active follow-up without clinic 
visits as she can no longer travel to the clinical site, and if in the Investigator’s opinion, 
continuation of the study treatment would be harmful to the subject’s well-being). 
If radium-223 dichloride/placebo treatment is still ongoing but the hormonal treatment is no 
longer considered a treatment option and the subject must start cytotoxic treatment, the 
subject will terminate radium-223 dichloride/placebo treatment.   
If radium-223 dichloride/placebo treatment is still ongoing but the background treatment is 
no longer considered a treatment option and the subject must start another protocol permitted 
concomitant systemic anticancer treatment, the subject can continue radium-223 
dichloride/placebo until completion or until any withdrawal criteria are met. 
If however, the background hormonal treatment or further standard of care protocol permitted 
concomitant systemic anticancer therapy are discontinued, radium-223 dichloride/placebo 
must also be discontinued. 
Subjects will continue to be followed up for SSEs and radiological progression.   
Subject management unless otherwise defined by this protocol will be in accordance to the 
local standard of practice.  
Symptomatic skeletal events should be recorded until end of active follow-up, independent of 
whether the subject starts a new anti-cancer therapy (i.e., chemotherapy, other). 
Subjects who experience an SSE during radium-223 dichloride/placebo treatment may 
continue treatment until completion or until any withdrawal criteria are met, if in the opinion 
of the Investigator the subject continues to derive benefit.  In case an SSE is not defined as 
progression, the subject will continue to be followed as per protocol until radiological 
progression. 
Subjects who did not experience either an SSE or radiological progression during the 
treatment period will enter, at the end of the treatment period, the active follow-up with clinic 
visits where they will continue to be followed up for these events. 


 
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Subjects who experience an SSE and radiological progression during the protocol-defined 
treatment period will enter, at the end of the treatment period, the active follow-up without 
clinic visits. 
Subjects who can no longer travel to the clinical site will be discontinued from radium-223 
dichloride/placebo study treatment and will enter the active follow-up without clinic visits.  
During this time subjects will continue to receive hormonal background treatment as per local 
standard of practice. 
Subjects who missed 2 consecutive treatment visits will be considered unable to travel to the 
site, will be discontinued from study treatment and will enter the active follow-up without 
clinic visits. 
Subjects will be assessed for efficacy and safety endpoints at each treatment visit and will be 
evaluated every 12 weeks for radiological progression.  
The total treatment period is defined from the day of randomization of the subject in the 
interactive voice/web response system (IXRS) until 4 weeks after the last administration of 
radium-223 dichloride or placebo.  
A specific interval, depending on country specific drug order lead time between the date of 
randomization and the first radium-223 dichloride/placebo administration will be necessary 
for the study drug shipment/availability.  Randomized subjects who never received treatment, 
will not be included in the safety analysis.  An end of treatment (EOT) electronic case report 
form (eCRF) should be completed for these subjects to document the reason for 
discontinuation.   
Follow-up period: 
The active follow-up has 2 distinct periods based on whether the subject can travel to the 
clinic site: the active follow-up with clinic visits for subjects who can travel and the active 
follow-up without clinic visits for subjects who cannot travel.  Once a subject switches from 
active follow-up with clinic visits to active follow-up without clinic visits, the subject will not 
be allowed to switch back.  
All subjects, regardless of reaching a study endpoint (on-study SSE or radiological 
progression), will enter the follow-up period in order to collect the required long-term safety 
information. 
Active follow-up period with clinic visits: 
Subjects who discontinued or completed the radium-223 dichloride or placebo treatment, did 
not experience an SSE and radiological progression during the treatment period, had an EOT 
visit, and can travel to the clinic will enter an active follow-up period with clinic visits.  
During this period, clinic visits are to occur as follows: 
 For subjects who have not experienced an SSE during the treatment period, visits will 
continue with the same frequency as during treatment (every 4 weeks ±7 days) until 
the subject has an SSE.  After the occurrence of the SSE, the subjects will be switched 
to a frequency of visits every 12 weeks ±7 days at the next scheduled visit.  


 
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 For subjects who experienced an SSE during the treatment or this period, visits will 
occur every 12 weeks ±7 days.  The subjects will continue to be followed for 
radiological progression and long-term safety. 
 Subjects who miss 2 consecutive follow-up visits will be considered unable to travel 
to the site and will enter the active follow-up without clinic visits.  Symptomatic 
skeletal events should be recorded until end of active follow-up, independent of 
whether patient starts a new anticancer therapy (i.e. chemotherapy, other). 
Radiological tumor assessment will be performed every 12 weeks, independently of the 
frequency of the visits, until radiological disease progression is documented. 
The active follow-up period with clinic visits extends from the EOT visit until the subject can 
no longer travel to the clinic, experiences SSE and radiological progression, 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 until study termination. 
These subjects will be evaluated for pain endpoints, radiological progression, SSEs, survival, 
treatment-related AEs and SAEs, and 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 any additional malignancies, including acute 
myelocytic leukemia (AML), and hematological conditions, such as myelodysplastic 
syndromes (MDS), aplastic anemia, or myelofibrosis, must be reported as SAEs, regardless 
of the Investigator’s causality assessment.  All bone fractures and bone associated events 
(e.g., osteoporosis) should be collected as either AEs or SAEs if the criteria of SAE were met, 
regardless of the investigator’s causality assessment. 
Subject treatment management will be in accordance with routine clinical practice, at the 
discretion of the Investigator. 
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 clinic site or those who experienced an SSE and radiological 
progression will be followed for survival, treatment-related AEs and SAEs, and the initiation 
of other anti-cancer therapies, and SSEs, with phone calls as follows: 
 For subjects who did not experience an SSE during treatment or the previous 
follow-up period, the frequency of the phone calls will be every 4 weeks ±7 days until 
the subject has an SSE.  After the occurrence of the SSE, the subjects will be switched 
to a frequency of phone calls every 12 weeks ±7 days at the next scheduled phone 
call. 
 For subjects who experienced an SSE during treatment or the previous follow-up 
period, the frequency of the phone calls will be every 12 weeks ±7 days.  
Symptomatic skeletal events should be recorded until end of active follow-up, 


 
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independent of whether patient starts a new anticancer therapy (i.e. chemotherapy, 
other). 
The active follow-up period without clinic visits extends from the EOT visit or the end of 
active follow-up with clinic visits until the subject 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 until study termination. 
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 any additional malignancies, including AML, and 
hematological conditions, such as MDS, aplastic anemia, or myelofibrosis, must be reported 
as SAEs, regardless of the Investigator’s causality assessment.  All bone fractures and bone 
associated events (e.g., osteoporosis) should be collected as either AEs or SAEs if the criteria 
of SAE were met, regardless of the investigator’s causality assessment. 
Subject treatment management will be in accordance with routine clinical practice, at the 
discretion of the Investigator.  Survival will also be updated for all subjects in the active 
follow-up period at the time of final analysis of the primary endpoint. 
Long-term follow-up – Extension study 
All ongoing study subjects who have completed at a minimum the EOT visit or 30 days from 
last study treatment dose, whichever is latest, may be transitioned into a separate long-term 
follow-up study (BAY 88-8223 study 16996 / NCT02312960). 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 primary objective of this study is 
to define the long-term safety profile of radium-223 dichloride. 
All subjects who transition into this separate long-term follow-up study will require a 
separate signed informed consent. 
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., death, consent withdrawn and active 
objection for further data collection, lost to follow-up). Until the transition to the long-term 
follow up study, subjects will continue to follow all the protocols required procedures and 
visits in the current protocol. 
A schematic of the study design is presented in Figure 5–1. 


 
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Figure 5–1:  Study design schematic  
 
 
ACTIVE FOLLOW-UP PERIOD WITHOUT CLINIC VISITS 
Same as the active follow-up period with clinic visits with the exception for the ability of subjects to 
travel to the clinic site, phone calls will be performed to collect information instead of clinic visits. 
During this period, phone calls are to occur as follows:  every 4 weeks ±7 days for subjects who have 
not experienced an SSE during the treatment period or previous follow-up period and every 12 weeks 
±7 days for subjects who have experienced an SSE during the treatment or previous period.   
Subjects will be evaluated for survival, treatment-related AEs and SAEs, the initiation of other anti-
cancer therapies and SSEs. 
INFORMED CONSENT
SCREENING
Subject fulfills eligibility criteria
Subject inclusion 
1:1 RANDOMIZATION and STRATIFICATION by
• Geographical regions (Europe/North America [including Israel] versus Asia 
• Previous lines of hormone therapy in metastatic breast cancer (1 versus 2 or more)
• Prior SREs (1 versus 2)
Arm A:  TREATMENT PERIOD
Radium -223 dichloride IV every 4 weeks for 
6 cycles + standard of care treatment with single 
hormonal agent and best supportive care
Subjects evaluated for efficacy and safety at each 
4-week visit
Hormonal treatment and supportive care
Arm B:  TREATMENT PERIOD
Placebo (saline) IV every 4 weeks for 
6 cycles + standard of care treatment with single 
hormonal agent and best supportive care
Subjects evaluated for efficacy and safety at each 
4-week visit
Hormonal treatment and supportive care
ACTIVE FOLLOW -UP PERIOD WITH CLINIC VISITS
Subjects who discontinue treatment, had an EOT visit, and can travel to the investigational site 
will be followed until the subject can no longer travel to the clinic, experiences a SSE and 
radiological progression, dies, is lost to follow up, or withdrawals informed consent and 
actively objects to collection of further data. The maximum duration of the active follow up is 
until study termination. 
During this period, clinic visits are to occur as follows:  every 4 weeks ± 7 days for subjects 
who have not experienced an SSE during the treatment period and every 12 weeks ± 7 days for 
subjects who have experienced an SSE during the treatment period. Subjects will be evaluated 
for pain endpoints, radiological progression, SSEs, survival, treatment-related AEs and SAEs, 
and anticancer therapies.  


 
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5.1.2 
Study endpoints 
Section modified by Amendment 4 (Section 15.3). 
Primary Endpoint: The primary endpoint is SSE-FS.  
SSE-FS is defined as the time from randomization to the occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
(2) Death from any cause 
Note: Any EBRT or orthopedic surgery related to a previous SSE but administered after 
signature of the ICF will not be counted as an on-study SSE. 
Secondary Endpoints  
 OS 
 Time to opiate use for cancer pain 
 Time to pain progression (only in subjects with baseline WPS ≤8) 
 Time to cytotoxic chemotherapy 
 rPFS 
 Pain improvement rate 
 Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy 
Exploratory Endpoints: 
 Time to first on-study SSE 
 Time to bone ALP progression 
 Bone ALP response at Week 12 and EOT 
 Bone-specific rPFS 
 Resource utilization 
 Biomarker assessments 
 Time to visceral metastases onset 


 
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5.2 
Primary variables 
The primary variable is SSE-FS.  The definition for this variable is provided in Section 5.1.2. 
5.3 
End of study 
Section modified by Amendment 8 (Section 15.7.1.2). 
All ongoing study subjects who have completed at a minimum the EOT visit or 30 days from 
last study treatment dose, whichever is latest, may be transitioned into a separate long-term 
follow-up study (BAY 88-8223 study 16996 / NCT02312960). 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 primary objective of this study is 
to define the long-term safety profile of radium-223 dichloride. 
All subjects who transition into this separate long-term follow-up study will require a 
separate signed informed consent. 
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., death, consent withdrawn and active 
objection for further data collection, lost to follow-up). Until the transition to the long-term 
follow up study, subjects will continue to follow all the protocols required procedures and 
visits in the current protocol. 
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 in any site 
has occurred.  
6. 
Study population 
Section modified by Amendment 1 (Section 15.1), Amendment 4 (Section 15.3) and 
Amendment 5 (Section 15.4). 
Approximately 227 subjects with HER2 negative, hormone receptor positive breast cancer 
with bone metastases will be randomized. 
Eligibility 
Eligibility is confirmed at the end of the screening period.  At that time, the subject is 
randomized and enters the treatment period.  Laboratory values will be verified prior to first 
study drug administration as per protocol.  Hematological support will be provided as needed 
according to the protocol guidance during the treatment period.  
Rescreening 
Rescreening of screen failed subjects may only be allowed after discussion with the medical 
monitor of the sponsor and after his/her approval.  Sponsor approval of rescreening must be 
documented.  Rescreening may be considered under the following circumstances: 
 Subjects who underwent screening procedures (i.e., scans and laboratory work) that 
expired (are outside of the 21-day window) may need the screening procedures to be 
repeated in order to be within the window required prior to randomization.  However, 


 
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rescreening is not permitted in cases in which the initial laboratory test results do not 
support eligibility. 
 Rescreening is also permitted where the screening procedures for subject’s eligibility 
expired due to completion of washout periods as per protocol (e.g., 4 weeks from 
treatment with an investigational drug), in case of expiry of investigational product 
that requires replacement, or for extraordinary logistical issues. 
The subjects who need to repeat the screening procedures will be asked to repeat the 
consenting process for study participation. 
6.1 
Inclusion criteria 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), Amendment 5 (Section 15.4), and Amendment 6 (Section 15.5). 
Subjects must meet the following criteria for inclusion in the study: 
1. Have provided written informed consent.  Subjects must be able to understand and be 
willing to sign the written informed consent.  A signed ICF must be appropriately 
obtained prior to the conduct of any study-specific procedure. 
2. Documentation of histological or cytological confirmation of ER+ and HER2 negative 
adenocarcinoma of the breast must be available.  HER2 status should be determined 
by an accredited/Ministry of Health approved laboratory by immunohistochemistry 
(IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization 
(CISH) or other validated in situ hybridization (ISH) assay for detection of HER2 
gene expression.  
3. Tumors (from either primary or metastatic sites) must be ER+ defined as ≥10% 
positive tumor nuclei in the analyzed sample.  ER+/ progesterone receptor positive 
(PR+), ER+/ progesterone receptor negative (PR-) subjects are eligible whereas 
estrogen receptor negative (ER-)/PR+ and ER-/PR- disease will not be eligible. 
4. Women (≥18 years of age) with metastatic breast cancer not amenable to curative 
treatment by surgery or radiotherapy.  Women of reproductive potential and their 
male partners must agree to use adequate contraception during treatment and for 
6 months following the completion of treatment with radium-223 dichloride/placebo. 
5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects 
are eligible. 
 
Note: In premenopausal subjects, ovarian radiation or treatment with an LH-RH 
agonist/antagonist is permitted for induction of ovarian suppression if the 
plasma/serum estradiol assay is within local laboratory postmenopausal range at 
screening, performed within 7 days of randomization. 
o Pre-menopausal subjects with or without ovarian radiation or concomitant 
treatment with an LH-RH agonist/antagonist must have a negative 
pregnancy test at screening and agree to use an adequate method of 


 
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contraception as recommended by their treating physicians (please refer to 
Section 8.1.2) 
o Post-menopausal status is defined either by:  
 age ≥55 years and one year or more of amenorrhea,  
 age <55 years and one year or more of amenorrhea with a 
plasma/serum estradiol assay within local laboratory postmenopausal 
range, performed within 7 days of randomization, 
 bilateral ovariectomy. 
6. Subjects with bone dominant disease with at least 2 skeletal metastases identified at 
baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging 
(MRI). Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph 
nodes) and/or visceral metastases is allowed. 
7. Measurable or non-measurable disease (but radiologically evaluable) according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.  All disease 
burden must be assessed at baseline by CT or MRI of chest, pelvis, and abdomen and 
any additional fields as needed.  A bone scan should also be done at baseline for all 
subjects. 
CT/MRI done as part of the standard of practice within 3 weeks prior to 
randomization and standard of care bone scans done within 3 weeks prior to 
randomization are acceptable. 
FDG PET scan, if performed as part of standard of care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See also 
Appendix 16.2).  
 
FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
8. Subjects must have received at least one line of hormonal therapy in the metastatic 
setting.  
 
Note: A change of the hormone agent due to progression (as per the Investigator 
assessment) is counted as a new line of therapy.  A switch of hormone therapy from 
one agent to another due to toxicity or other reasons (e.g., subject’s preference), in 
absence of PD at the time of the switch, will be counted as one line although 
2 different agents have been administered. 


 
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9. Subjects who are eligible for further standard of care endocrine treatment with any of 
the following administered as in second line or greater of hormone therapy in 
metastatic setting:    
o SERMs such as tamoxifen and toremifene  
o NSAIs such as anastrozole and letrozole  
o Steroidal AIs such as exemestane 
o ER down-regulators such as fulvestrant  
 
Subjects enrolled in the current study must start treatment with the single hormone 
agent either within 15 days prior to randomization or after randomization (before or 
simultaneously to the first injection of radium-223 dichloride/placebo).   
10. Subjects must have experienced no more than 2 SREs prior to study entry defined as: 
Need for EBRT to bone, pathological bone fracture (excluding major trauma), spinal 
cord compression, and/or orthopedic surgical procedure.  Subjects with no prior SREs 
are not permitted.  
Note: All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) must be 
administered prior to randomization. Separate SRE events are the ones that occur at 
least 21 days apart from each other to ensure that linked events (e.g., surgery to 
repair a fracture or multiple doses of radiation during a course of treatment) are not 
counted as separate events. In case of bone pain that occurs in several anatomical 
locations and requires separate EBRT sessions, it should be counted as one event if 
the EBRT sessions are administered within a period of 21 days. 
11. Subjects must be on therapy with bisphosphonate or denosumab and are required to 
have been on such therapy for at least 1 month before the start of study treatment. 
12. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 
13. Life expectancy ≥6 months  
14. Laboratory requirements:  
o Absolute neutrophil count (ANC) ≥1.5 x 109/L  
o Platelet count ≥100 x 109/L without platelet transfusion within 4 weeks 
prior to randomization 
o Hemoglobin ≥9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or 
erythropoietin within 4 weeks prior to randomization 
o Total bilirubin level ≤1.5 x institutional upper limit of normal (ULN) 
(except for subjects with documented Gilbert’s disease) 
o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 x institutional ULN. 
o Creatinine ≤1.5 x ULN 


 
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o Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73m2 according 
to the Modification of Diet in Renal Disease (MDRD) abbreviated formula 
(Note: please refer to local labelling for administration of full dose of 
bisphosphonates) 
o International normalized ratio of prothrombin time (INR) and partial 
thromboplastin time (PTT) or activated PTT ≤1.5 x ULN at study entry.  
Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, 
dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to 
participate in the study if no underlying abnormality in coagulation 
parameters exists per prior history; weekly evaluation of INR/PTT will be 
required until stability is achieved for anticoagulants that require their 
monitoring as per local label. 
o Serum albumin >30 g/L 
o Pulse oximetry O2 saturation >92% if lung metastases are present 
15. Able to swallow oral medication  
6.2 
Exclusion criteria 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 5 
(Section 15.4), Amendment 6 (Section 15.5) 
Eligible subjects must not meet any of the exclusion criteria listed below: 
1. HER2-positive breast cancer (IHC=3+, positive FISH/CISH/other ISH validated 
assay); equivocal or unknown HER2 status 
Note: Subjects with 3+ by IHC cannot be chosen regardless of their 
FISH/CISH/other ISH validated assay status and those with positive 
FISH/CISH/other ISH validated assay cannot be chosen either, regardless of the 
IHC findings.  Subjects with 2+ by IHC will not be eligible if no negative 
FISH/CISH/other ISH validated assay for detection of HER2 gene expression is 
available. 
2. Subjects considered by the treating investigator to be appropriate candidates for 
treatment with everolimus as current treatment for their metastatic breast cancer 
3. Subjects with inflammatory breast cancer 
5. Subjects who have either received chemotherapy for metastatic disease or are 
considered by the treating Investigator to be appropriate candidates for 
chemotherapy as current treatment for metastatic breast cancer are excluded.  
Chemotherapy administered for adjuvant/neo-adjuvant disease is acceptable. 
6. Subjects with any previous untreated or concurrent cancer that is distinct in 
primary site or histology from the cancer under study, except treated basal cell 
carcinoma or superficial bladder tumor (Ta and Tis, American Joint Committee on 
Cancer, 7th edition).  Subjects surviving a cancer that was curatively treated and 
without evidence of disease for more than 3 years before enrollment are allowed.  


 
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All cancer treatments must be completed at least 3 years prior to study entry (i.e., 
signature date of ICF). 
7. Subjects with known or history of brain metastases or leptomeningeal disease: 
subjects with neurological symptoms must undergo a contrast CT scan or MRI of 
the brain within 28 days prior to randomization to exclude active brain metastasis.  
Imaging of the central nervous system is otherwise not required 
8. 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. 
9. Prior treatment with radium-223 dichloride 
10. Prior hemibody external radiotherapy.  Subjects who received other types of prior 
external radiotherapy are allowed provided that bone marrow function is assessed 
and meets the protocol requirements for hemoglobin, ANC, and platelets. 
11. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or 
rhenium-188 
12. ECOG Performance Status ≥2 
13. Blood transfusions, platelet transfusions or use of erythropoietin within 4 weeks 
prior to randomization.   
14. 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 randomization 
15. Treatment with an investigational drug or with any anti-cancer treatments not 
permitted by the protocol, within 4 weeks prior to randomization 
16. Chronic conditions associated with non-malignant abnormal bone growth (e.g., 
confirmed Paget’s disease of bone) 
17. Any other serious illness or medical condition such as, but not limited to: 
o Any uncontrolled infection 
o Cardiac failure New York Heart Association Class III or IV 
o Crohn’s disease or ulcerative colitis 
o Bone marrow dysplasia 
18. Previous assignment to treatment in this study 
19. Breastfeeding women 
20. Known hypersensitivity to the active substance or to any of the excipients of 
radium-223 dichloride 
21. Known presence of osteonecrosis of jaw 


 
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22. Patients with immediately life-threatening visceral disease, for whom 
chemotherapy is the preferred treatment option. 
23. Lymphangitic carcinomatosis. 
24. Patients with ascites requiring paracentesis within 2 weeks prior to study entry 
(signature of informed consent) and during the screening period. 
All local label specific criteria for the standard of care hormonal treatment as well as 
denosumab and bisphosphonates apply.  Subjects must be treated according to the local 
standard of care requirements. 
6.3 
Withdrawal of subjects from study 
6.3.1 
Withdrawal 
The study will comprise the following 4 periods: 
1. Screening 
2. Randomization 
3. Treatment period  
4. Active follow-up period with or without clinic visits  
Note: Study drug (radium-223 dichloride/placebo) discontinuation (i.e., discontinuation 
during the treatment period) does not constitute withdrawal from the study.  Every effort 
should be made to retain subjects who discontinue the treatment period for any reason.  These 
subjects are to be encouraged to remain on the study for follow-up of primary, secondary, and 
exploratory endpoints (i.e., continue in the active follow-up period with or without clinic 
visits). 
Subjects are expected to participate in the follow-up unless they explicitly object.  
Withdrawal of consent should be documented in the subject’s medical file.  If the subject 
does not wish to be followed up further, she should sign the “Declaration of Objection to the 
Collection of Study Data after Withdrawal of Consent” form.  
A “dropout” is defined as a subject who has been randomized and discontinues study 
participation prematurely for any reason. 
A “screening failure” is defined as a subject who has signed informed consent and terminates 
the study for any reason (e.g., failure to satisfy the selection criteria) before randomization.  
Any subject removed from the study will remain under medical supervision until discharge or 
transfer is medically acceptable. 
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject’s 
medical records (consent withdrawal [due to AE or for other reason], lost to follow-up, or 
death). 
When a subject is withdrawn from the study, i.e., is not attending follow-up visits, the EOS 
page in the eCRF is to be completed.  


 
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6.3.1.1 
Withdrawal from treatment period (collection of follow-up data) 
Section modified by Amendment 1 (Section 15.1) and Amendment 2 (Section 15.2). 
The treatment period starts with the date of randomization and ends 4 weeks (±7 days) after 
the last administration of radium-223 dichloride/placebo.  
Subjects must be withdrawn from the radium-223 dichloride/placebo treatment for the 
following reasons: 
 If, in the Investigator's opinion, continuation of the radium-223 dichloride/placebo 
treatment would be harmful to the subject's well-being 
 If the subject experiences unacceptable toxicities to radium-223 dichloride/placebo 
 If a subject experiences National Cancer Institute (NCI)-Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 3 to 4 anemia, neutropenia, or 
thrombocytopenia lasting >2 weeks despite adequate supportive care treatment 
 If a subject experiences any non-hematological CTCAE Grade 4 toxicity lasting 
>1 week despite adequate treatment 
 Delay in radium-223 dichloride/placebo administration of >4 weeks (maximum of 
8 weeks between 2 injections of radium-223 dichloride/placebo) 
 If the subject starts treatment with a prohibited metastatic breast cancer therapy 
(Section 8.1) 
 If background hormonal treatment or further standard of care protocol permitted 
concomitant systemic anti-cancer therapy are discontinued, radium-223 
dichloride/placebo must also be discontinued.   
 If the subject can no longer travel to the clinical site, she will be discontinued from 
radium-223 dichloride/placebo study treatment and will enter the active follow-up 
without clinic visits.  Subjects who missed 2 consecutive treatment visits will be 
considered unable to travel to the site, will be discontinued from study treatment, and 
will enter the active follow-up without clinic visits.  Subject treatment management 
will be in accordance with routine clinical practice, at the discretion of the 
Investigator. 
 At her own request or at the request of her legally acceptable representative 
 At the specific request of the sponsor and in liaison with the Investigator (e.g., 
obvious non-compliance, safety concerns) 
Subjects who experience an SSE during study treatment may continue to receive radium-223 
dichloride (or placebo) until completion or until any of the above withdrawal criteria are met, 
if the Investigator feels the subject will receive clinical benefit. 
Subjects who experience disease progression (bone or non-bone) may continue to receive 
radium-223 dichloride (or placebo) until completion or until any of the above withdrawal 
criteria are met, if the Investigator feels the subject will receive clinical benefit.  These 
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concomitant systemic anticancer treatments according to the local standard of care.  If, 
however, chemotherapy is required as the next line of treatment, study treatment will be 
permanently discontinued, as concurrent chemotherapy administration is an exclusion 
criterion. 
Note:  Radium-223 dichloride/placebo treatment discontinuation (i.e., withdrawal from 
treatment period) does not constitute withdrawal from the study.  Every effort should be made 
to retain subjects who discontinue the treatment period.  These subjects are to be encouraged 
to remain on the study for follow-up of primary, secondary, and exploratory endpoints (i.e., 
continue in the active follow-up period with or without clinic visits). 
6.3.1.2 
Withdrawal from treatment period and/or all follow-up (no further 
data collection) 
Subjects must be withdrawn from the study treatment and/or procedures and no further data 
will be collected for the following reasons: 
 Subject withdraws consent from study treatment and/or study procedures.  A subject 
must be removed from the study at her own request or at the request of her legally 
acceptable representative.  At any time during the study and without giving reasons, a 
subject may decline to participate further.  The subject’s rights will be protected. 
 Subject is lost to follow-up 
 Death 
Note:  Withdrawal of consent should be documented in the subject’s medical file.  If the 
subject does not wish to be followed up further, she should sign the “Declaration of 
Objection to the Collection of Study Data after Withdrawal of Consent” form.  
6.3.2 
Replacement 
Withdrawn subjects will not be replaced. 
6.4 
Subject identification 
A subject number (a unique identification number) will be assigned via an IXRS when a 
subject signs the ICF and is evaluated for inclusion into the study.  When the subject is 
eligible for the study, the study site will send an order (using the IXRS) to the manufacturer 
for drug shipment based on the planned visit date of the subject.  See Section 7.3. 


 
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7. 
Treatments 
7.1 
Treatments to be administered 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), and 
Amendment 4 (Section 15.3). 
Investigational medicinal product (IMP): Radium-223 dichloride, 50 kBq/kg body weight 
(55 kBq/kg after implementation of NIST update) will be administered IV as a slow bolus 
injection for a maximum of 6 cycles at intervals of 4 weeks. 
Reference therapy: A solution of isotonic saline (0.9% sodium chloride solution for 
injection) will be administered IV as a slow bolus injection 6 times at intervals of 4 weeks. 
Non-investigational medicinal products: 
 Background treatment with standard of care hormonal treatment: Subjects will 
receive drugs from the following classes of agents administered as a single agent: 
o SERMs, such as tamoxifen and toremifene  
o NSAIs, such as anastrozole and letrozole  
o Steroidal AIs, such as exemestane 
o ER down-regulators such as fulvestrant 
Subjects enrolled in the current study must start treatment with the single hormone 
agent either within 15 days prior to randomization or after randomization (either 
before or simultaneously to the first injection of radium-223 dichloride or placebo).  
For subject’s convenience, injections of fulvestrant may be scheduled on the same day 
of the radium-223 dichloride/placebo injection.   
These treatments will be administered according to the local labels and in line with 
standard practice guidelines. 
 Bone-targeted agents: bisphosphonates or denosumab: Eligible subjects are required 
to be on therapy with bisphosphonates or denosumab at time of study entry (for at 
least 1 month prior to the start of investigational study treatment, radium-223 
dichloride/placebo).  Subjects should be maintained on bisphosphonate or denosumab 
therapy throughout the study, unless, in the Investigator’s opinion, these treatments 
need to be discontinued.  Bisphosphonates or denosumab should be administered as 
per the local label instructions and according to local standard of care.  Changes in 
therapy should be done as per the Investigator decision. 
 Other therapies: Supportive care therapies should be administered in line with local 
standard of care.  
Please refer to the section on prior and concomitant therapy concerning prohibited and 
allowed concomitant treatments during the radium-223 dichloride/placebo administration (see 
Section 8.1). 


 
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7.2 
Identity of study treatment 
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 provided by the sponsor, a system of numbering in accordance with all 
requirements of Good Manufacturing Practices (GMP) will be used, ensuring that each dose 
of study drug can be traced back to the respective bulk ware of the ingredients.  Lists linking 
all numbering levels will be maintained by the sponsor’s clinical supplies quality assurance 
group.  For all sponsor supplied study drugs, lists linking all numbering levels will be 
maintained by the sponsor. 
7.2.1 
Investigational medicinal product 
7.2.1.1 
Radium-223 dichloride 
Section modified by Amendment 4 (Section 15.3) and Amendment 5 (Section 15.4). 
The alpha particle-emitting radiopharmaceutical BAY 88-8223 is a ready-to-use, sterile, 
non-pyrogenic, clear and colorless aqueous solution of radium-223 dichloride for IV 
administration.  Radium-223 dichloride is an alpha particle emitter with a physical half-life of 
11.4 days.  The product is isotonic and has a pH of 6.0 to 8.0.  The radioactive concentration 
at the reference date is 1000 kBq/mL (1100 kBq/ mL after implementation of NIST update).  
The product has a pre-calibration of 14 days.  When administered on a day other than the 
reference day, the volume should be corrected according to the physical decay table supplied 
with each shipment.  
The sponsor will provide radium-223 dichloride which is manufactured by Bayer HealthCare.  
Radium-223 dichloride is produced according to GMP and will be delivered in a glass vial, 
ready-to-use with a certified activity.  This alpha particle-emitting radiopharmaceutical is 
shipped in a lead container and a Type A radioactive package according to international 
transportation guidelines for radioactive materials. 
The volume per vial is 6 mL, corresponding to 6 MBq (6.6 MBq after implementation of 
NIST update), at the calibration reference day.  Radium-223 dichloride has a shelf life of 28 
days from production day, when stored at ambient temperature.  The shelf life has been 
demonstrated for temperatures from cold storage (2 to 8°C) up to 40°C.  In addition, it has 
been shown that the product quality is not jeopardized upon freezing.  
For study sites in the US, it is possible to have a patient ready dose (PRD) prepared by a 
radiopharmacy.  Doses will be delivered to the sites in pre-filled syringes.  Cardinal Health is 
the radiopharmacy that will dispense the PRD in the US. 
It is important to note that, in general (unless otherwise agreed), in cases where study drug 
has been ordered, the time window for administration should be within 3 days of the planned 
treatment day.  If administration must be postponed more than 3 days, replacement of the 
drug order is required.  


 
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7.2.1.2 
Saline 
Isotonic saline (0.9% sodium chloride solution for injection) will be provided by the study 
site.  Traceability of the respective manufacturers and batches will be maintained in the 
respective preparation documentation and drug accountability logs. 
For saline solution and background treatment which will be provided to the subjects from the 
study site's commercial supply it is required at minimum that the assignment, batch numbers, 
and expiry dates are recorded.  The use of saline is to be recorded and documentation retained 
at the study site with a copy provided for the sponsor study file. 
7.2.2 
Non-investigational medicinal products 
7.2.2.1 
Background treatment with standard of care hormonal treatment 
The background standard of care hormonal treatment will be administered according to the 
local labels in each of the participating countries.  These treatments will be captured in the 
eCRFs. 
Hormonal treatment as well as bisphosphonates or denosumab will be supplied by study site 
and administered as part of the standard of care for the subject according to the local label. 
7.2.2.2 
Bone-targeted agents, bisphosphonates and denosumab 
Bisphosphonates (diphosphonates) are a class of drugs that prevent the loss of bone mass, 
used to treat osteoporosis and similar diseases including bone metastases.  Whichever 
bisphosphonate is selected for use as background therapy should be stored and administered 
according to the local label. 
Denosumab (Xgeva®), a RANKL inhibitor, is indicated for the prevention of SREs in 
subjects with bone metastases from solid tumors.  It is supplied as a single-use vial at a 
suspension of 120 mg/1.7 mL and should be stored in a refrigerator at 2 to 8°C (36 to 46°F) 
in the original carton.  Xgeva must not be exposed to temperatures above 25°C/77°F or direct 
light and must be used within 14 days, as directed in the label. 
Bisphosphonates or denosumab will be supplied by the study site and administered as part of 
the standard of care for the subject according to the local label. 
7.3 
Treatment assignment 
Section modified by Amendment 5 (Section 15.4). 
To accomplish random assignment of radium-223 dichloride/placebo treatment, a 
computer-generated randomization list will be prepared by the sponsor and provided to the 
IXRS.  The IXRS will assign each eligible subject a randomization number and the respective 
treatment in a ratio of 1:1 to radium-223 dichloride or placebo.  In addition, randomization 
will be stratified by geographical regions (Europe/North America [including Israel] versus 
Asia), previous lines of hormone therapy in metastatic setting (1 versus 2 or more), and prior 
SREs (1 versus 2). 


 
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The IXRS will provide only the randomization number to the caller, i.e., blinded personnel, 
but not the assigned treatment.  A confirmation e-mail containing randomization number will 
be sent to the unblinded personnel who will have to log into IXRS in order to know the 
treatment arm assigned to the patient.  The unblinded personnel will be responsible for 
preparing the study drug for the subject for the first administration.  For US only, if a subject 
is allocated to radium-223 dichloride, the unblinded personnel will fax shipment request to 
Cardinal Health for pre-filled syringe.  The timing for the drug order should be based on the 
planned subject visit date.  If the subject is allocated to placebo, the unblinded person at the 
study site will be responsible for providing saline corresponding to the IXRS treatment day.  
This should not be made available before to avoid unblinding the subject and blinded study 
personnel.  
Subsequent orders for each study drug administration will be made by calling the IXRS from 
the study site on the date of the previous injection.  If after ordering, the order needs to be 
cancelled or amended, the Investigator should contact their monitor immediately. 
7.4 
Dosage and administration  
Written information about radium-223 dichloride and instruction about handling and injection 
of radioactive material will be provided to study personnel. 
In general, the administration of radioactive drugs involves a potential risk for third parties, 
due to radiation from the subject and due to possible contamination by spilling urine or feces.  
When radium-223 dichloride has been injected intravenously into a subject, the risk for 
external radiation exposure to third parties is extremely low, due to the short range of the 
alpha particles (<100 μm) and the low portion of beta and gamma radiation.  For these 
reasons the product can be administered on an out-patient basis.  To minimize the risk of 
contamination, the subject and her caregivers will receive oral and written instructions 
regarding hygiene precautions to abide by after receiving the radioactive drug according to 
the investigational study site radiation protection guidelines.  These instructions will be given 
to all subjects, as neither the Principal Investigator nor subject will know the assignment to 
radium-223 dichloride or placebo injections. 
7.4.1 
Dose calibration 
Section modified by Amendment 4 (Section 15.3). 
Radium-223 dichloride can be measured in a normal dose calibrator instrument.  When all the 
required written approvals for the use and handling of radium-223 dichloride from the 
Radiation Protection Agency/Agencies for the specific site have been received by the 
sponsor, a vial of radium-223 dichloride for technical use will be sent to the study site.  
Different clinical study sites possess dose calibrators from various suppliers; thus, the isotope 
calibration factor may differ from site to site.  Consequently, each site must perform the 
radium-223 dial setting on their relevant dose calibrator(s), if no isotope calibration factor for 
radium-223 is being provided by the vendor of the dose calibrator.  For dial setting, the 
clinical study site will receive a sealed vial or a prefilled syringe containing a radium-223 
solution for calibration only.  The vial or syringe is identical to the vials/syringes used for 


 
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study treatment.  The amount of radium-223 in the vial/syringe will be stated on the label.  
Instructions for the dial setting, including the calibration log form, will be enclosed with the 
dispatch of the calibration sample. 
As of Amendment 4, 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 [52]) 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 [53]), 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 [53]) in place at the time of implementation.  The 
current dial setting (NIST 2010 [52]) 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 
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. 
7.4.2 
Radium-223 dichloride dose handling 
At least 2 unblinded personnel should be nominated at each study site (Section 7.5).  The 
primary dedicated unblinded person (“the unblinded person”), who has the responsibility 
delegated from the Principal Investigator, will be responsible for the safe handling and 
storage of radium-223 dichloride and placebo control.  The unblinded person also has the 
responsibility of correctly receiving and recording the delivery of radium-223 dichloride in 
accordance with this protocol.  At least one deputy unblinded person should also be 
nominated.  Radium-223 dichloride should be handled by individuals who are qualified by 
training and experience in the safe handling of radionuclides.  
The radium-223 dichloride vials or PRDs must be stored inside their lead container in a 
secure facility.  The study drug should be used within 28 days of production or prior to the 
expiry date specified for PRDs.  


 
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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.  Since PRDs will be prepared at the country depot, relevant procedures are 
recorded by the country depot staff.  All administrations of radium-223 dichloride will be 
based on the certified activity of radium-223 at the reference date.  Please note that all 
documentation that contains unblinded information should be kept by the unblinded person(s) 
and not shared with the other study site personnel during the conduct of the study. 
7.4.3 
Radium-223 dose calculation 
Section modified by Amendment 4 (Section 15.3). 
The dosage of radium-223 dichloride is 50 kBq/kg body weight (55 kBq/kg after 
implementation of NIST update).  The total activity to be injected will be calculated 
volumetrically using the subject’s body weight within 5 days of injection (kg), the 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) dosage level, and the decay correction 
factor (DK) to correct for physical decay of radium-223.  A table with DKs according to 
physical decay of the study medication will be provided with each vial of radium-223 
dichloride.  The total amount (volume to be drawn into the syringe) to be administered to a 
subject should be calculated according to the recommended formula below: 
Body weight (kg) x 50 kBq/kga = volume to be injected (mL) 
 
 
 
DK x 1000 kBq/mLb 
a 55 kBq/kg after implementation of NIST update 
b 1100 kBq/mL after implementation of NIST update  
 
Site specific volume calculation methods are acceptable as well provided that the patient dose 
is 50 kBq/kg (55 kBq/kg after implementation of NIST update).  
Data regarding activity, calculations, and volume to be injected must be recorded in the IMP 
preparation log and in the study electronic data capture tool (Medidata Rave; RAVE) by the 
unblinded person.  This applies to both doses that are prepared at the study site and doses that 
are prepared by an off-site vendor.  
For subjects in Arm B (placebo injection), the volume of saline to be injected will be 
provided by the IXRS based on the subject’s weight.  Data regarding the saline batch number 
and the volume to be injected should be recorded in RAVE. 
7.4.4 
Study drug dose preparation  
Section modified by Amendment 7 (Section 15.6). 
In order to keep the treating physician blinded to the assignment of study medication, the 
unblinded person (e.g., from the hospital pharmacy or Nuclear Medicine department) will be 
responsible for blinding the syringe, and responsible for calculating the required dosage.  
Data regarding activity and volume to be injected should be recorded in the IMP preparation 
log and in the appropriate eCRF, both of which will not be available to the treating physician.  


 
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Copies of the vial label and the syringe serial number are to be attached with each entry in the 
IMP preparation log.  Additional written instructions for study drug administration, for 
blinded and unblinded personnel, will be provided. 
Personnel should use appropriate protective clothing and equipment during syringe filling 
and application to prevent contamination with the radioactive solution (lab coats, medical 
gloves/protective glasses) and to reduce radiation exposure.  Sites should adhere to all 
relevant radiation safety regulations as prescribed by local authorities administering their site 
radiation license, including as low as reasonably achievable principles.  
Filling of the syringe should take place in a safety bench or similar cabinet in the 
Radiopharmacy/Nuclear Medicine department.  The individual responsible for study drug 
preparation will draw the correct volume of study drug into a syringe.  The size of the syringe 
should be chosen according to the applied volume to reach the required dosing accuracy.  In 
some countries/study sites a third party vendor will be used to prepare the injections to be 
used by the study site.  
Radium-223 dichloride should not be diluted or mixed with any solutions.  If the vials have 
been stored in a refrigerator, they should be left at room temperature for 1 hour prior to use, 
since cold material should not be injected in a subject. 
To maintain traceability, each subject will be assigned 1 syringe label set, with a unique serial 
number.  The serial number will link the vial/batch received with the preparation and blinded 
administration of the syringe.  
For subjects in the placebo arm, a syringe with isotonic saline will be prepared in the same 
way as for the active treatment, including the use of unique serial numbers on the syringe.  
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, are to be treated as radioactive waste and should be disposed in 
accordance with hospital procedure for the handling of radioactive material and according to 
local laws.  Written information about radium-223 dichloride and instructions for the 
handling and injection of radioactive material will be provided to study personnel. 
7.4.5 
Dose administration 
Section modified by Amendment 1 (Section 15.1). 
In this subject population, disease progression is expected.  Expected symptoms in this 
population are: bone pain, fatigue, nausea, anorexia, depression, constipation (also secondary 
to opioids), hematological complication as well as additional visceral metastases.  
Chemotherapy is not permitted during treatment with radium-223 dichloride/placebo.  If such 
treatment is necessary then radium-223 dichloride/placebo treatment must be stopped.  
Chemotherapy treatment administered in the follow-up period should not be given before a 
4-week washout period after the last administration of study drug.  
Every effort will be made to administer the full dosing regimen.  Single dose level adjustment 
of radium-223 dichloride/placebo is not permitted.  Treatment delays or discontinuations of 


 
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radium-223 dichloride/placebo may be instituted for the AEs described in Section 7.4.6 and 
dose adjustments, treatment delays, or discontinuations of hormonal treatment may be 
instituted according to the local label and standard of practice. 
7.4.6 
Dose adjustments, delays, and treatment discontinuations 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), and 
Amendment 4 (Section 15.3). 
Radium-223 dichloride/placebo administration may be delayed by no more than 4 weeks 
(maximum 8 weeks between 2 injections) for recovery of AEs.  If administration is delayed 
for >4 weeks (maximum 8 weeks between 2 injections), radium-223 dichloride/placebo 
administration should be discontinued. 
AEs will be reported and graded according to NCI-CTCAE version 4.03. 
Myelosuppression 
Changes in hematology parameters may occur after injection of study drug. 
Neutropenia: In case of NCI-CTCAE Grade 3 to 4 neutropenia, study drug administration 
should be delayed until recovery to Grade 2 (minimum ANC 1.0 x 109/L) or better before the 
next study drug administration.  
Thrombocytopenia: In case of thrombocytopenia NCI-CTCAE Grade 2 to 4, study drug 
administration should be delayed until recovery to CTCAE Grade 1 (minimum subjects with 
a platelet count 75 x 109/L) or better before the next study drug administration.  
Anemia: In case of anemia NCI-CTCAE Grade 3 to 4, study drug administration should be 
delayed until recovery to CTCAE Grade 2 (minimum hemoglobin [Hb] 8.0 g/dL) or better 
before the next study drug administration.  
If a subject experiences CTCAE Grade 3 to 4 anemia, neutropenia, or thrombocytopenia 
lasting >2 weeks in spite of adequate treatment, the subject must be discontinued from 
treatment with radium-223 dichloride/placebo.  
Blood transfusion is acceptable between study drug administrations.  Use of biologic 
response modifiers, such as G-CSF or GM-CSF and erythropoietin, is allowed in the 
management of acute toxicity. 
Gastrointestinal events 
Diarrhea: No prophylactic treatment for diarrhea is recommended.  Anti-diarrheals can be 
used when needed.  A further dose of study medication should not be given before diarrhea 
has recovered to CTCAE Grade ≤1.  
Nausea/Vomiting: No prophylactic treatments for nausea or vomiting are recommended, but 
anti-emetic drugs can be used when needed.  A further dose of study medication should not 
be given before nausea/vomiting has recovered to CTCAE Grade ≤1.  
Constipation: Subjects can continue laxative as concomitant medication, but start of 
prophylactic treatments before study drug injection is not recommended.  Laxative can be 


 
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used when needed.  A further dose of study medication should not be given before 
constipation has recovered to CTCAE Grade ≤1. 
Fatigue 
In cases of NCI-CTCAE Grade 3 to 4 fatigue, study drug administration should be delayed 
until recovery to Grade ≤1 before the next study drug administration. 
Osteonecrosis of jaw 
There is no specific radium-223 dose modification guidance for patients who develop 
osteonecrosis of jaw during radium-223 treatment.  The management plan of individual 
patients who develop osteonecrosis of jaw in the course of the study should be set up in close 
collaboration between the treating physician and a dentist or oral surgeon with expertise in 
osteonecrosis of jaw, and in accordance with the local labeling of denosumab and 
bisphosphonates. 
Non-pathological fractures 
For traumatic fracture in weight bearing bones during treatment phase, the study drug 
administration should be delayed 2 to 4 weeks from the time of fracture.  
If a subject experiences any non-hematological NCI-CTCAE Grade 4 toxicity lasting 
>1 week despite adequate treatment, the subject will have to discontinue radium-223 
dichloride/placebo treatment. 
If radium-223 dichloride or placebo is discontinued prior to an on-study SSE, subjects will 
enter the follow-up period and will be followed up for these events.  During this time, the 
standard of care hormonal treatment background therapy will continue according to the local 
standard of practice.  Hormonal treatment may be changed according to the local standard of 
practice; however, for the purpose of this study, a new hormonal treatment initiated due to 
disease progression will be considered a new anti-cancer therapy. 
If radium-223 dichloride/placebo treatment is still ongoing but standard of care hormonal 
treatment is no longer considered an option, and the subject must start cytotoxic therapy, the 
subject will terminate radium-223 dichloride or placebo treatment.  Subjects will then enter 
the follow-up period and will continue to be followed for SSEs and radiological progression. 
Background standard of care hormonal treatment 
The standard of care treatment with a single hormonal agent will be administered by each 
participating site according to the local label and standard of practice.  Local label directions 
for dose modifications must be applied. 
7.4.7 
Supportive care guidelines 
Section modified by Amendment 2 (Section 15.2). 
Ancillary treatment (guidelines) 
 Persistent neutropenia (neutrophils/granulocytes CTCAE Grade 4 [<0.5 x 109/L]) 
without fever: These subjects may be started on G-CSF 5 g/kg/d subcutaneously 
(SC) until the neutrophil count has reached the local hospital’s reference range.  


 
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 Neutropenia with fever (neutrophils/granulocytes CTCAE Grade 3 to 4 [<1 x 109/L]; 
fever >38.5C): Blood cultures will be obtained and the subject started on empiric 
antibiotics for as long as clinically indicated.  It is highly recommended that the 
subject receive G-CSF 5 g/kg/d SC until the neutrophil count has reached the local 
hospital’s reference range with 2 separate measurements, at least 12 hours apart.  
 Severe thrombocytopenia (CTCAE Grade 4 [<25.0 x 109/L]) or bleeding with 
CTCAE Grade 3 to 4 thrombocytopenia (<50.0 x 109/L): multiple platelet transfusions 
may be required to maintain platelet count ≥75 x 109/L if clinically indicated to 
control bleeding.  Epsilon aminocaproic acid may be given to subjects with mucosal 
bleeding and platelet count CTCAE Grade 3 to 4.  
 Severe anemia (Hb CTCAE Grade 3 [<80 x109g/L; 8.0 g/dL; 4.9 mmol/L]):  Subjects 
will be transfused with packed red cells to maintain an Hb value >80 g/L; 8.0 g/dL; 
4.9 mmol/L if clinically indicated.  Treatment with erythropoietin is allowed between 
study drug administrations for treatment of anemia.  
 During treatment with denosumab or bisphosphonates, subjects should be 
administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily. 
 All label specific instructions for the standard of care hormonal treatment will apply.  
Subjects must be treated according to the local standard of care requirements. 
7.5 
Blinding 
Every effort will be made to keep the study blinded.  Subjects will be randomized to receive 
radium-223 dichloride or placebo in a double-blind fashion.  All subjects will also receive the 
background standard of care hormonal treatment suitable for each subject.  This treatment 
will be locally sourced by the site and will be provided in an open-label format. 
Due to the nature of radium-223 dichloride, there must be at least 2 persons in the study site’s 
Nuclear Medicine department who are unblinded to the treatment arms assigned to subjects.  
One of these unblinded individuals will serve as back-up for the other.  In order to maintain 
the study blind for the hospital personnel who provide treatment to the subject, the unblinded 
person at the study site will be responsible for filling the syringe with the correct amount of 
radium-223 dichloride or placebo (saline) and labeling it.  Both radium-223 dichloride and 
placebo are clear solutions; thus, syringes with radium-223 dichloride and placebo cannot be 
distinguished from each other visually.  The person performing the administration of study 
drug must be blinded to the treatment arm.  The subject will not be told whether they have 
received radium-223 dichloride or placebo.  All treating physicians, clinical staff, subjects, 
and sponsor personnel will be blinded as to the treatment to which a subject is randomized, 
except for named representatives who will perform the verification of the drug accountability 
at the study sites and drug ordering.  
The background standard of practice treatment with a single hormonal agent is not blinded. 
Unblinding: 
In compliance with applicable regulations, in the event of a suspected unexpected serious 
adverse reaction (SUSAR) (see Section 9.6.1.4), the subject’s treatment code will usually be 


 
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unblinded before reporting to the health authorities and ethic committees if the SUSAR was 
related to the blinded treatment.  Investigators may only unblind subjects under emergency 
unblinding rules.  If a subject is unblinded by the Investigator, she must discontinue study 
drug(s). 
Investigators should note that the occurrence of an SAE or PD should not routinely 
precipitate the immediate unblinding of the label.   
If emergency unblinding is necessary for the treatment of a subject for an SAE, the study 
treatment can be unblinded via the IXRS (refer to the IXRS manual for instructions).  The 
participating site has unrestricted and immediate access to break the treatment code in IXRS.  
Should the blind code be broken for a subject, the medical monitor or designee should be 
contacted by the Principal Investigator within one working day of unblinding to discuss the 
rationale for the premature unblinding.  
7.6 
Drug logistics and accountability 
All study drugs will be stored at the investigational study site, in accordance with Good 
Clinical Practice (GCP) and GMP requirements, and the instructions given by the clinical 
supplies department of the sponsor will be inaccessible to unauthorized personnel.  
In some countries/study sites, it will be required to use a third party vendor to prepare the 
injections to be used by the study site.  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 site.  Any labels or mandatory logs provided by the sponsor are to 
be utilized according to instructions.  A copy of study drug documentation will be collected 
for the sponsor file. 
The responsible study site personnel will use the study drug only within the framework of 
this clinical study and in accordance with this protocol.  Instructions for drug handling, 
logistics, and accountability will be reviewed with study staff prior to the initiation of the 
study.  Summaries of these instructions are provided below. 
For radium-223 dichloride:  
Radium-223 dichloride will be shipped to study site upon IXRS shipment request.  Lead 
times differ per country but the shipment will arrive at the study site one day before the 
planned treatment at the latest.  The responsible unblinded study site personnel will confirm 
receipt of sponsor-supplied study drug via IXRS. 
The unblinded person at the study site is responsible for drug accountability.  A dedicated 
unblinded person representing the sponsor will monitor the drug accountability logs.  Receipt, 
distribution, and destruction of the study drug must be properly documented according to the 
sponsor’s agreed and specified procedures.  An unblinded monitor will review overall drug 
accountability and destruction per the study 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 
radium-223 dichloride (received, administered to subjects, and destroyed) must be maintained 


 
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and signed and the appropriate eCRF pages completed by the unblinded person responsible 
for drug handling at each site. 
For locally provided isotonic saline (placebo): 
Isotonic saline (placebo) will be provided by the study site pharmacy.  Drug accountability 
for saline will also be performed.  At a minimum, storage conditions, dispensing, batch 
numbers, and expiry dates will be retained in the study site files.  A log of isotonic saline 
(administered to subjects and destroyed) must be maintained and signed and the appropriate 
eCRF pages completed by the unblinded person responsible for drug handling at each site.  
The used vials must be stored until the drug accountability has been completed by the 
unblinded monitor. 
For locally provided background hormone treatment: 
For background treatment which will be provided to the subjects from the study site's 
commercial supply, it is required at minimum that the assignment, batch numbers, and expiry 
dates are recorded.   
7.7 
Treatment compliance 
Subjects will receive treatment with radium-223 dichloride under supervision of a physician 
licensed in the administration of radioisotopes.  Unblinded study personnel will check the 
administration volume and total radioactivity injected.  The dose activity and the volume 
injected will be recorded in a study drug log and the eCRF pages, neither of which will be 
available to the treating physician or site personnel.  Only the unblinded monitor will review 
overall drug accountability and destruction per the site documentation. 
8. 
Non-study therapy 
8.1 
Prior and concomitant therapy 
At baseline screening, all prior cancer-related treatments are to be recorded. 
All concomitant medications taken by the subject from signing of the ICF to 4 weeks after 
last study drug administration must be recorded in the eCRF.  Thereafter, until the end of the 
active follow-up period, only medications given to treat any grade AEs related to the study 
drug, analgesic medication, and any subsequent anti-cancer treatment medication need to be 
recorded in the eCRF.  
The generic name and trade name of each prior or concomitant medication, its indication, 
dosage, and, when applicable, the start and stop dates will be recorded.  
The sponsor’s representative will encode all therapy and medication according to 
well-recognized dictionaries of medical codes. 
It is not required to report the administration of contrast media or radioactive tracer in 
conjunction with the protocol-specified radiological procedure (CT or bone scan) on the 
concomitant medications eCRF page unless there is an AE related to the administration of the 
contrast agent (e.g., an allergic reaction related to the administration of a contrast agent) or 
the tracer. 


 
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8.1.1 
Prohibited concomitant therapy 
Section modified by Amendment 1 (Section 15.1) and Amendment 4 (Section 15.3). 
Other cancer treatment with established efficacy in breast cancer except hormonal treatments 
or the permissible therapies mentioned in Section 8.1.2 should not be used during the 
treatment period.  If such treatments are considered to be the best standard of care during the 
treatment period, further radium-223 dichloride/placebo administrations must be discontinued 
and the subject should enter the active follow-up period. 
All supportive care for the subject may be provided at the discretion of the Investigator. 
Note that all treatments for breast cancer, including other investigational drugs taken after 
withdrawal from treatment with radium-223 dichloride or placebo, will be recorded in the 
eCRFs until the end of the active follow-up period. 
Concomitant therapy during the treatment phase of the study with any of the following listed 
is prohibited: 
 Chemotherapy 
 Radiopharmaceuticals, such as strontium-89, samarium-153, rhenium-186, or 
rhenium-188 
 Hemibody external radiotherapy  
 Other investigational drugs 
 All medications that are prohibited as per the local label instructions for the 
background hormonal treatment.  It is the site’s responsibility to ensure that hormonal 
background treatment is administered in line with standard practice and local label 
instructions.  The same applies for bisphosphonates and denosumab. 
8.1.2 
Permitted concomitant therapy 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), and Amendment 5 (Section 15.4.1). 
The following supportive care medications are considered permissible during the study: 
 Conventional multivitamins, selenium, and soy supplements 
 All subjects are expected to have been on therapy with either denosumab or 
bisphosphonates for at least 1 month before the start of study treatment and to 
continue on this therapy during the course of the study, with no change to therapy 
expected during the treatment phase of the study, except for toxicity reasons.   
 During treatment with denosumab or bisphosphonates, the subjects should be 
administered an oral calcium supplement of 500 mg and 400 IU vitamin D daily.  
 In pre-menopausal women with ovarian suppression, treatment with LH-RH agonists 
or antagonists must start at least 4 weeks prior to enrollment (signature of informed 


 
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consent) and continue during the treatment period.  Non-hormonal methods of 
contraception should be employed during therapy until menses resume. 
 Subjects of child-bearing potential who are sexually active must agree to utilize, 
during the treatment period and for 6 months after last dose of radium-223 dichloride 
or placebo, 2 reliable and acceptable methods of contraception used simultaneously: a 
barrier method such as a) condoms (male or female) with spermicidal agent or 
b) diaphragm or cervical cap with spermicide, combined with a highly effective 
non-hormonal birth control method such as an intra-uterine device. 
 Standard of care background hormone treatment with any of the following as a single 
agent: 
o SERMs, such as tamoxifen and toremifene  
o NSAIs, such as anastrozole and letrozole  
o Steroidal AIs, such as exemestane 
o ER down-regulators such as fulvestrant  
 Subjects enrolled in the current study must start treatment with the single hormone 
agent either within 15 days prior to randomization or after randomization (either 
before or simultaneously to the first injection of radium-223 dichloride/placebo).  For 
subject’s convenience injections of fulvestrant may be scheduled on the same day of 
the radium-223 dichloride or placebo injection. 
 Hormonal background treatment is to be administered in line with standard practice 
and local label instructions. 
 Following discontinuation of the single agent background hormone treatment, further 
lines of hormone treatment as well as exemestane in combination with everolimus, 
may be administered concomitantly with radium-223 dichloride/placebo, in line with 
the local standard of practice. 
 Blood transfusions and treatment with erythropoietin stimulating agents are allowed 
after randomization (if required to ensure that the treatment range for Hb is met at 
Day 1 of each cycle) but not within 4 weeks prior to randomization.  Platelet 
transfusions are allowed after randomization but not within 4 weeks prior to 
randomization. 
 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.  These drugs are not allowed within 4 weeks prior 
to randomization.  
 Analgesic use will be captured via a subject diary (analgesic consumption diary) and 
the eCRF (24-hour analgesics use page and regular analgesics concomitant 
medication page, see schedule of assessments, Table 9–1).  Subjects will be asked to 
track their analgesic use on an analgesic consumption diary for 24 hours prior to their 
clinic visit.  Any medication taken for pain, whether for palliation of bone pain or 


 
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relief of other type of pain, and any changes should be recorded in the eCRF at each 
visit.  Note that EBRT treatment should be recorded in the eCRFs until end of the 
active follow-up period without clinic visits. 
8.2 
Post-study treatment therapy 
Treatment with radium-223 dichloride or placebo will be halted following completion of the 
full assigned treatment or at early termination.  The background standard of care hormonal 
treatment will be continued according to the local standard of practice (i.e., until the time of 
disease progression).  
Following radium-223 dichloride/placebo treatment discontinuation, subjects will be treated 
and followed as per the institutional standard of care and/or according to the physician’s 
clinical judgment. 
If possible, cytotoxic chemotherapy, other systemic radioisotope, hemibody external 
radiotherapy, or other investigational drug should not be given before a 4-week washout 
period after last administration of radium-223 dichloride/placebo, provided the subject’s bone 
marrow is not compromised. 
Details of post-study anti-cancer treatment will be recorded on the appropriate eCRF page. 
9. 
Procedures and variables 
9.1 
Tabular schedule of evaluations 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), Amendment 5 (Section 15.4), Amendment 6 (Section 15.5), Amendment 7 
(Section 15.6), and Amendment 8 (Sections 15.7.1.1 and 15.7.1.4). 
All laboratory analyses will be conducted by local laboratories. 
Efficacy and safety measurements obtained during the course of the study are summarized in 
the schedule of assessments (Table 9–1).


 
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Table 9–1:  Schedule of assessments 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random. 
 
C1, Day 1 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 wk 
until 
SSE; 
q12 wk 
after 
SSEf 
q4 wk 
until SSE; 
q12 wk 
after 
SSEg 
 
 
Window (days): 
 
 
 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
±7 
±7 
±7 
Informed consenth 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject ID assignment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior SRE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationa 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPI-SFi 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Resource utilization 
questionnaire 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
Xj 
X 
Xj 
AEs, SAEs, new 1° 
malignanciesk 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X l 
Xj,l 
X l 
Xj,l 
Prior and con medsm 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
X 
Xj 
Cancer-related txn 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 
X 
Xj 
Analgesic consumption diaryo 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Record 24 h analgesic useo 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 


 
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Table 9–1:  Schedule of assessments 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random. 
 
C1, Day 1 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 wk 
until 
SSE; 
q12 wk 
after 
SSEf 
q4 wk 
until SSE; 
q12 wk 
after 
SSEg 
 
 
Window (days): 
 
 
 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
±7 
±7 
±7 
Record opiate use 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Vital signsp 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xhh 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Weight (kg) 
X 
 
Xq 
X 
Xq 
X 
Xq 
X 
Xq 
Xq 
Xq 
X 
 
 
 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationr 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Xhh 
 
X 
 
ECOG-PS 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
Hematologys 
Xt 
 
Xu 
X 
Xu 
X 
Xu 
 
Xu 
Xu 
Xu 
X 
Xhh 
 
X 
 
Clinical chemistryv 
Xt 
 
Xw 
X 
Xw 
X 
Xw 
 
Xw 
Xw 
Xw 
X 
Xhh 
 
X 
 
Coagulation panelx 
Xt 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Pregnancy test and estradiol 
assayy 
Xt 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
 
Serum, plasma, and urine 
biomarkersz 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Whole Blood for CTCsii 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
  
 
 
 
Technetium-99m bone scan or 
FDG PET/CT or NaF PET/CT, 
same technique for all 
X 
X 


 
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Table 9–1:  Schedule of assessments 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random. 
 
C1, Day 1 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 wk 
until 
SSE; 
q12 wk 
after 
SSEf 
q4 wk 
until SSE; 
q12 wk 
after 
SSEg 
 
 
Window (days): 
 
 
 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
±7 
±7 
±7 
assessmentsaa,bb 
Chest, abdominal and pelvic 
CT scanaa,cc,dd,ee 
X 
X 
SSEs 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Drug orderff 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
Radium-223 Cl2 or placebo 
injectiongg 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xj 
X 
Xj 
Drug accountability 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
Abbreviations:  AE = adverse event; BPI-SF = Brief Pain Inventory-Short Form; Cl2 = dichloride; con med = concomitant medication; CT = computed tomography; Cx = Cycle x; 
ECG = electrocardiogram; ECOG PS = Eastern Co-operative Oncology Group performance status; eCRF = electronic case report form; EOT = end of treatment; 
ID = identification number; INR = international normalized ratio of prothrombin time; IXRS = interactive voice/web response system, PRD = patient ready dose; PT = prothrombin 
time; PTT = partial thromboplastin time; q = every; SAE = serious adverse event; SRE = skeletal related event; SSE = symptomatic skeletal event; tx = treatment; wk = week; 
W/O = without. 
a. All screening evaluations must be complete and reviewed prior to randomization.  Screening evaluations must be complete within 3 weeks prior to randomization.  If all 
screening data are available and the subject is eligible for the study, randomization may occur at the end of the screening visit. 
b. All assessments at treatment visits should be performed before study drug administration. 
c. Subjects will continue in the treatment period until the occurrence of an SSE (Section 9.4.2.1).  If based on the Investigator assessment the subject continues to receive 
clinical benefit, administration of study drug can be continued.  In case an SSE is not defined as progression, the subject will continue to be followed as per protocol until 
radiological progression.  All subjects will continue to receive background treatment. 
d. Any unscheduled visits are to be conducted in the same manner as visits described for Cycle 1, Day 15. 
e. EOT follow-up visit will be conducted 4 weeks after last dose of study treatment (radium-223 dichloride or placebo) or after discontinuation from study treatment. 


 
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f. For subjects who can travel to the clinic site: every 4 weeks (±7 days) for subjects who have not experienced an SSE during the treatment period until they experience an 
SSE or every 12 weeks (±7 days) for subjects who have experienced an SSE during the treatment or this period.  All subjects will be followed in the active follow-up with 
clinic visits until the subject dies, experiences an SSE and radiological progression, can no longer travel to the clinical site, or the study is terminated.  Subjects who receive 
subsequent 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. 
g. For subjects who cannot travel to the clinic site: Telephone follow-up every 4 weeks (±7 days) for subjects who have not experienced an SSE during the treatment or the 
previous period until they experience an SSE or every 12 weeks (±7 days) for subjects who have experienced an SSE during the treatment, previous period, or this period 
until the subject dies or the study is terminated.  Subjects who receive subsequent 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. 
h. Informed consent is to be collected before the initiation of any study-related procedures. 
i. BPI-SF will be dispensed to the subject at the visit just before Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1; Cycle 6, Day 1; EOT; and 
follow-up clinic visits.  Additionally, PRO Questionnaire Information Sheet is to be completed by clinical staff based on discussion with patient, even if patient does not 
complete the BPI-SF questionnaire. 
j. It is the clinical site’s responsibility to obtain and make available the source documentation for the information collected from the telephone call and to document it in the 
eCRF. 
k. Adverse events will be collected through 30 days post the last administration of study medications.  Investigator should check for occurrences of leukemia, myelodysplastic 
syndrome, aplastic anemia, and any new malignancy.   
l. All treatment-related AEs and SAEs occurring during the active follow-up period are to be documented.  Investigator should check for occurrences of leukemia, 
myelodysplastic syndrome, aplastic anemia, any new malignancy.  All bone fractures and bone associated events (e.g., osteoporosis) need to be reported as either AEs or 
SAEs if the criteria of SAE were met, regardless of the investigator’s causality assessment. 
m. At baseline screening, all prior concomitant medications, including analgesics, are to be recorded.  Thereafter, all concomitant medications should be collected, including 
analgesics, up to 4 weeks post last study drug administration.  Thereafter, until the end of the active follow-up period, only collect concomitant medications used to treat any 
grade adverse drug reaction and analgesics should be collected only up to the end of the active follow-up visits.  Analgesic use has to be recorded via the analgesic 
concomitant medication eCRFs. 
n. Record any cancer-related treatments. 
o. An individual analgesic consumption diary will be dispensed to the subject just the visit before Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1; 
Cycle 6, Day 1; EOT; and follow-up clinic visits.  Subjects will be asked to record analgesic use in 24 hours prior to their clinic visit. 
p. The measurement of vital signs will include:  blood pressure, heart rate, respiratory rate, and temperature. 
q. Subject’s weight should be re-checked prior to each injection to calculate appropriate drug dosing.  At all sites, weight is to be taken only once for each dose and it should be 
measured within 5 days prior to dosing.  For US sites using the central PRD depot only, the subject weight for the dose day must be reported in a timely manner to the 
country PRD depot to allow adequate time for the 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.  
r. A full physical examination must include the evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, gastrointestinal, dermatological, musculoskeletal, and 
neurological systems. 
s. Hematocrit, hemoglobin, platelet counts, red blood cell counts, white blood cell counts, and white blood cell differential.  Subjects with abnormal platelet count or white blood 
cell count at EOT should be followed until resolution. 
t. The screening clinical chemistry and hematology values are recommended to be measured within 1 week prior to randomization and the first injection should be done as 
soon as possible after randomization. 
u. Blood sample for hematology must be taken, analyzed, and evaluated within the 5 days prior to each study drug administration.  
v. Sodium, potassium, chloride, calcium, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, bone alkaline phosphatase (if testing is available and 
can be performed locally), serum creatinine, phosphate, blood urea nitrogen, bilirubin (total), total cholesterol, and albumin.   
w. Blood sample for clinical chemistry must be taken within 5 days prior to each study drug administration, and must be evaluated prior to the administration.   
x. PT, INR, and PTT: Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to participate in the 
study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of INR/PTT will be required until stability is achieved for 
anticoagulants that require their monitoring as per local label. Blood sample for coagulation tests must be taken and evaluated within 5 days prior to each study drug 


 
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administration. 
y. Pre-menopausal women must have a negative serum pregnancy test performed within 7 days prior to randomization, prior to each study drug administration (taken and 
evaluated within 5 days prior to administration), and EOT.  Post-menopausal women (as defined in Section 6.1) are not required to undergo a pregnancy test.  A 
plasma/serum estradiol assay is required within 7 days prior to randomization in pre-menopausal women with radiotherapy ovarian ablation or medical ovarian suppression 
and post-menopausal women age <55 years and one year or more of amenorrhea. 
z. Blood and/or urine sample for exploratory evaluation of biomarkers, prior to radium-223 dichloride or placebo administration.  Serum and plasma samples will be collected 
within 5 days of dosing at Cycle 1, Day 1; Cycle 4, Day 1; and EOT or disease progression, whichever occurs first.  Urine samples will be collected at Cycle 1, Day 1; Cycle 
4, Day 1; and EOT visits (or at the time of disease progression, whichever occurs earlier). 
aa. Radiological tumor evaluation must be performed 8 weeks (±7 days) after the first radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 
(radiological progression) is documented. If radiologic soft tissue or visceral progression in absence of bone progression (according to mRECIST 1.1 criteria) is observed, 
bone imaging and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of bone-specific rPFS until bone progression occurs or start of a 
new anticancer treatment.  This schedule is to be maintained and will not be shifted because of treatment interruptions/delays.  Scans will be read locally.  The time window 
for the scans is ±7 days. 
bb. A historic bone scan is acceptable if taken within 3 weeks of randomization.  If one is not available, it will be required as part of the protocol procedures within the screening 
period.   FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m bone scintigraphy if it is the standard of care at the institution, provided the 
same bone imaging modality is used throughout the study. 
cc. Chest/abdominal/pelvic magnetic resonance imaging will be accepted instead of chest/abdominal/pelvic CT. FDG PET scan, if performed as part of standard of care imaging, 
can be used as an adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the scan can be used for tumor measurements only if 
the site can document that the CT is of identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
dd. To maintain a consistent evaluation of each subject, the same imaging technique and procedure must be used through the assessment periods.  Any unexpected 
abnormality must be reported by the site personnel to the treating physician or the subject’s general practitioner. 
ee. A historic chest/abdominal/pelvic CT is acceptable if taken within 3 weeks of randomization. If not available, a scan is required as part of the protocol within the screening 
period. 
ff. IXRS drug (re-)supply order should be coordinated at each study visit to coincide with delivery prior to the subject’s next scheduled study visit. 
gg. The minimum time window between 2 injections of radium-223 dichloride or placebo must be 4 weeks. 
hh. Performed every 12 weeks 
ii. Details of sampling are described in the Laboratory Manual. Blood samples for analysis of circulating tumor cells will be collected within 5 days of Day 1 of Cycles 1 through 6 
prior to study drug dosing, and within 5 days of the EOT visit or disease progression, whichever occurs first. 
 


 
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9.2 
Visit description 
9.2.1 
Screening period (Visits 0 to 1) 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), and Amendment 5 (Section 15.4). 
The screening period lasts from date of signature of informed consent until the date of subject 
randomization in IXRS.  The screening period duration is 3 weeks. 
Pre-treatment evaluations will only be performed after the subject has agreed to participate 
and has signed and dated the ICF.  No treatment or study-related procedures will be initiated 
before the signed consent has been obtained.   
Standard of care imaging, such as CT/MRI, as well as routine bone scans performed within 
3 weeks prior to randomization will be accepted as baseline imaging if they meet protocol 
requirements (anatomic coverage, image acquisition as per RECIST 1.1 guidelines for 
CT/MRI scans).  Pre-treatment evaluations will be performed according to the eligibility 
criteria.  If the subject is eligible for the study, the parameters at the screening visit showing 
subject health status including blood values will be recorded in the eCRF. 
The following procedures and evaluations will be performed within 3 weeks prior to planned 
randomization unless otherwise specified: 
 Sign informed consent 
 Subject registration and subject number assignment via IXRS 
 Review of inclusion and exclusion criteria and confirm eligibility 
 Demographics 
 Record medical history  
 Record disease history: HER2 status can be determined by evaluating for HER2 over-
expression using IHC and/or HER2 gene amplification using in situ hybridization, 
e.g., FISH or CISH.  For subjects with equivocal HER2 IHC (IHC 2+), it is 
recommended that HER2 status be confirmed using a validated assay for HER2 gene 
amplification. 
 Record prior SRE 
 Record AEs 
 Record concomitant medications/therapy, including analgesics 
 Record breast cancer-related treatment (prior and current)  
 Record vital signs: blood pressure, heart rate, respiratory rate, and temperature  
 12-lead electrocardiograms (ECG).  Electrocardiograms should not be obtained when 
serum potassium is <3.5 mmol/L.  Hypokalemia should be corrected prior to ECG 
collection. 


 
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 Record height (cm) and weight (kg).   
 Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 
gastrointestinal, dermatological, musculoskeletal, and neurological systems. 
 ECOG performance status 
 Radiological tumor assessment 
o A chest/abdominal/pelvic CT or MRI.  This is not needed if standard of care 
chest/abdominal/pelvic CT or MRI images taken within 3 weeks prior to 
randomization are available. 
A bone technetium-99m scan with careful identification of all disease-related 
hotspots.  This is not needed if standard of care bone scan performed within 
3 weeks prior to planned randomization date is available and in line with 
protocol requirements.  Confirmatory scan using single photon emission 
tomography (SPECT)-CT/MRI or CT/MRI (with and without contrast media) 
should be obtained if not performed within 3 weeks prior to randomization.  
The field of acquisition should include all areas where bone lesions are 
present. 
CT/MRI done as part of the standard of practice and standard of care bone 
scans done within 3 weeks prior to randomization are acceptable. 
o FDG PET scan, if performed as part of standard of care imaging, can be used as 
an adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT 
scan, the CT component of the scan can be used for tumor measurements only if 
the site can document that the CT is of identical diagnostic quality to a 
diagnostic CT. (See also Appendix 16.2). 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the institution, 
provided the same bone imaging modality is used throughout the study. 
 
The following procedures and evaluations should be performed within 1 week prior to 
randomization.  Results must be available, reviewed, and signed and dated by the Investigator 
prior to randomization.  
 Blood draw for clinical chemistry: sodium (Na), potassium (K), chloride (Cl), calcium 
(Ca), ALT, AST, lactate dehydrogenase (LDH), bone ALP (if testing is available and 
can be performed locally), serum creatinine, phosphate, blood urea nitrogen (BUN), 
total bilirubin, total cholesterol, and albumin. 
 Blood draw for hematology: hematocrit, Hb, platelet counts, red blood cell (RBC) 
counts, white blood cell (WBC) counts, and WBC differential. 
 A coagulation panel: prothrombin time (PT), PTT, and INR.  Subjects treated with 
warfarin, heparin, enoxaparin, rivaroxaban, dabigatran, apixaban or aspirin (e.g. 


 
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≤100 mg daily) will be allowed to participate in the study if no underlying 
abnormality in coagulation parameters exists per prior history; weekly evaluation of 
INR/PTT will be required until stability is achieved for anticoagulants that require 
their monitoring as per local label. 
 Pregnancy test: pre-menopausal women must have a negative serum pregnancy test 
performed within 7 days prior to randomization.  Post-menopausal women (as defined 
in Section 6.1) are not required to undergo a pregnancy test. 
 Estradiol assay: a plasma/serum estradiol assay is required within 7 days prior to 
randomization in pre-menopausal women with radiotherapy ovarian ablation or 
medical ovarian suppression and post-menopausal women age <55 years and one year 
or more of amenorrhea. 
One week prior to randomization, the subject should be given a subject diary to be used for 
subject questionnaires and the analgesic consumption and should receive training in its use.   
Important Note: If re-screening is indicated, it must be completed with approval from the 
medical monitor of the sponsor.  No more than one re-screening attempt will be allowed for 
each subject.  Please refer to Section 6 for further guidance on cases in which rescreening is 
allowed and the time window for rescreening. 
9.2.2 
Randomization 
Randomization in the IXRS may occur only after the completion of the screening evaluations 
and confirmation of subject eligibility.  Randomization may coincide with the end of a 
screening visit if all evaluations are complete; otherwise, randomization may be performed in 
a separate clinic visit.  
 IXRS must be called for drug supply in preparation for the next study visit.  This 
should be done on the day of randomization (where possible) to provide the maximum 
time in advance of the next scheduled subject visit date and in accordance with 
country-specific order lead times. 
9.2.3 
Treatment period 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), and 
Amendment 4 (Section 15.3). 
The treatment period extends from the day of randomization to 4 weeks post the final 
injection of radium-223 dichloride/placebo.  
The time between randomization and first injection should be as brief as possible in 
accordance with the country-specific drug order lead time.  
 During the treatment period, the subject will visit the study site at regular intervals.  
Radium-223 dichloride or placebo will be injected at 4-week intervals for 6 cycles on 
an outpatient basis (Section 9.1).  The minimum time window between 2 injections of 
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study termination will finish study treatment with radium-223 dichloride or placebo as 
part of the study. 
 All subjects will receive background standard of care hormonal treatment for breast 
cancer.  Subjects enrolled in the current study must start treatment with the single 
hormone agent either within 15 days prior to randomization or after randomization 
(either before or simultaneously to the first injection of radium-223 
dichloride/placebo).  For subject’s convenience, injections of fulvestrant may be 
scheduled on the same day of the radium-223 dichloride/placebo injection. 
 It is the responsibility of the unblinded person to calculate the required volume of 
study drug (i.e., dose of radium-223 dichloride or saline placebo) for the subject based 
on the subject’s body weight within 5 days of administration and the reference date of 
the received study medication (Section 7.4.3). 
For US sites using the central PRD depot ONLY, the subject weight for the dose day must be 
reported to the country PRD depot in a timely manner to allow adequate time for the PRD 
preparation and delivery.  The subject’s weight measurement, order confirmation call to the 
IXRS, and prescription for the central PRD depot are to be performed 5 days prior to 
injection.  All efforts should be made to measure weight at the same visit with the pre-dose 
laboratory assessments in order to avoid 2 pre-dose clinic visits. 
Before administration of radium-223 dichloride/placebo, the subject must be well hydrated; 
thus, the subject should be instructed to drink ad libitum.   
Hematology parameters requirements prior to study drug administration 
The blood samples for clinical chemistry and hematology should be taken within 5 days before 
each study drug administration, and the hematology parameters must be evaluated before each 
study drug administration (within 5 days).  
First radium-223 dichloride/placebo administration 
Before the first administration of radium-223 dichloride/placebo (within 5 days), the ANC 
should be ≥1.5 x 109/L, the platelet count ≥100 x 109/L, and Hb ≥8.0 g/dL. 
Blood transfusions and treatment with erythropoietin stimulating agents are allowed after 
randomization but not within 4 weeks prior to randomization.  Platelet transfusions are allowed 
after randomization but not within 4 weeks prior to randomization.  
Subsequent radium-223 dichloride/placebo between study drug administrations 
The following hematological parameters value should be met prior to each subsequent 
radium-223 dichloride/placebo administration: Hb level ≥8.0 g/dL, ANC ≥1.0 x 109/L, and the 
platelet count ≥75 x 109/L. 
If Hb levels are below 8.0 g/dL, the Hb needs to recover to 8.0 g/dL or higher before next study 
drug administration.   
If ANC is lower than 1.0 x 109/L or platelet count is lower than 75 x 109/L, radium-223 
dichloride/placebo injection should be delayed until recovery to ANC ≥1.0 x 109/L and platelet 
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If there is more than a 4-week delay in the next injection (i.e., more than 8 weeks between 
injections), the study drug should be permanently discontinued and the subject should enter the 
active follow-up period with clinic visits.  Treatment of low Hb is acceptable between study 
drug administrations.  
9.2.3.1 
Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each 
visit) 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), and Amendment 5 (Section 15.4). 
Assessments to be performed PRIOR to radium-223 dichloride or placebo (“study 
drug”) administration: 
 BPI-SF questionnaire will be completed prior to any other study 
assessments/procedures and should be checked for completion at the visit. 
Additionally PRO Questionnaire Information Sheet is to be completed by clinical 
staff based on discussion with patient, even if patient does not complete the BPI-SF 
questionnaire. 
 Resource utilization questionnaire to be completed by site 
 Record AEs, SAEs, and all occurrences of leukemia, MDS, aplastic anemia, or any 
other new primary malignancy.  
Note: Specifically, for this study, relevant symptoms related to SSEs should be 
reported as AEs independent of the timing of occurrence (prior to 30 days after last 
dose of study treatment or after this interval) or relationship with study drug. 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in 
by the subjects for 24 hours prior to the visit.  The analgesic use for 24 hours 
prior to the visit will be recorded by the investigator on the eCRF. 
 Record opiate use 
 Record concomitant medications/therapy 
 Record breast cancer-related treatment  
 Record vital signs: blood pressure, heart rate, respiratory rate, and temperature 
 12-lead ECG (Visit 6 [Cycle 3, Day 1] and Visit 9 [Cycle 5, Day 1]).  
Electrocardiograms should not be obtained when serum potassium is <3.5 mmol/L.  
Hypokalemia should be corrected prior to ECG collection. 
 Record weight (kg), within 5 days prior to dosing 
 Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 


 
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gastrointestinal, dermatological, musculoskeletal, and neurological systems (all 
abnormal findings must be reported in the AE eCRF pages). 
 ECOG performance status 
 Blood draw for hematology evaluation (must be taken and evaluated within 5 days 
before radium-223 dichloride or placebo administration): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC differential.  Results to be assessed and 
documented prior to study drug treatment.  The Hb values need to be confirmed to be 
at least 8 g/dL prior to each dose.  If blood is drawn the day of the administration of 
radium-223 dichloride/placebo, results must be available prior to study drug 
administration. 
 Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP (if 
testing is available and can be performed locally), serum creatinine, phosphate, BUN, 
bilirubin (total), total cholesterol, and albumin (blood sample for clinical chemistry 
must be taken and evaluated within 5 days prior to each study drug administration).  
 A coagulation panel (blood sample to be taken and evaluated within 5 days prior to 
each study drug administration): PT, PTT, and INR. 
 Pregnancy test: pre-menopausal women must have a negative serum pregnancy test 
performed and evaluated within 5 days before radium-223 dichloride or placebo 
administration.  Post-menopausal women (as defined in Section 6.1) are not required 
to undergo a pregnancy test. 
 Blood draw and urine sample for exploratory biomarker analysis: serum, plasma, and 
urine samples will be collected within 5 days of Visit 2 (Cycle 1, Day 1) and within 
5 days of Visit 8 (Cycle 4, Day 1) prior to study drug dosing. 
 Blood draw for analysis of circulating tumor cells (CTCs) collected within 5 days of 
Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6), prior to study drug dosing. 
 Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2. 
 Record SSEs.  The Investigator will assess the subject for the following disease 
events: 
o Use of EBRT to relieve skeletal symptoms 
o New symptomatic pathological bone fractures (vertebral and non-vertebral) 
o Tumor-related orthopedic surgical intervention 
o Spinal cord compression 
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether the subject starts a new anti-cancer therapy (i.e., 
chemotherapy, other). 
 Administer radium-223 dichloride or placebo.  All subjects will receive the 
background standard of care treatment with a single hormonal agent according to the 
local label and standard of care. 


 
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Assessments to be performed AFTER each injection of radium-223 dichloride or 
placebo: 
 Perform drug accountability  
 IXRS must be called for drug re-supply in preparation for the next study visit 
(Cycles 1 through 5 only).  This should be done on the day of the current treatment 
visit (where possible) to provide the maximum time in advance of the next scheduled 
subject visit date and in accordance with country-specific order lead times. 
 For US sites using the central PRD depot ONLY, the subject weight for the dose day 
must be reported to the country PRD depot in a timely manner to allow adequate time 
for the PRD preparation and delivery.  The subject’s weight measurement, order 
confirmation call to the IXRS, and prescription for the central PRD depot are to be 
performed 5 days prior to injection.  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.  
9.2.3.2 
Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), and 
Amendment 5 (Section 15.4). 
Radium-223 dichloride or placebo will not be administered at these visits. 
 Record AEs, SAEs, and all occurrences of leukemia, MDS, aplastic anemia, or any 
other new primary malignancy. 
Note: Specifically for this study, relevant symptoms related to SSEs should be 
reported as AEs independent of the timing of occurrence (prior to 30 days after last 
dose of study treatment or after this interval) or relationship with study drug. 
 Record concomitant medications/therapy, including analgesics  
 Record breast cancer-related treatment  
 Record vital signs: blood pressure, heart rate, respiratory rate, and temperature  
 Record weight  
 Blood draw for hematology evaluation: hematocrit, Hb, platelet counts, RBC counts, 
WBC counts, and WBC differential.  (Performed only at Visit 3 [Cycle 1, Day 15] 
and Visit 5 [Cycle 2, Day 15]) 
 Blood draw for clinical chemistry is only required at Visit 3 (Cycle 1, Day 15) and 
Visit 5 (Cycle 2, Day 15): Na, K, Cl, Ca, ALT, AST, LDH, bone ALP (if testing is 
available and can be performed locally), serum creatinine, phosphate, BUN, bilirubin 
(total), total cholesterol, and albumin.  


 
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9.2.3.3 
End of treatment visit 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), and Amendment 5 (Section 15.4). 
An EOT visit will be performed within 4 weeks ±7 days post discontinuation or completion 
of radium-223 dichloride or placebo treatment.  The following procedures/evaluations should 
be performed at this visit: 
 BPI-SF questionnaire will be completed prior to any other study 
assessments/procedures and should be checked for completion at the visit.  
Additionally PRO Questionnaire Information Sheet is to be completed by clinical staff 
based on discussion with patient, even if patient does not complete the BPI-SF 
questionnaire. 
 Resource utilization questionnaire to be completed by site  
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF 
o Analgesic consumption diary (completion to be checked by site) to be filled in 
by the subjects for 24 hours prior to the visit.  The analgesic use for 24 hours 
prior to the visit will be recorded by the investigator on the eCRF. 
 Record opiate use 
 Record AEs and SAEs for 30 days after the last treatment 
Note: Specifically for this study, relevant symptoms related to SSEs should be reported 
as AEs independent of the timing of occurrence (prior to 30 days after last dose of 
study treatment or after this interval) or relationship with study drug.  
 Record all occurrences of leukemia, MDS, aplastic anemia, or any other new primary 
malignancy 
 Record concomitant medications/therapy 
 Record breast cancer-related treatment  
 Record vital signs: blood pressure, heart rate, respiratory rate, and temperature  
 12-lead ECG.  Electrocardiograms should not be obtained when serum potassium is 
<3.5 mmol/L.  Hypokalemia should be corrected prior to ECG collection. 
 Record weight 
 Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 
gastrointestinal, dermatological, musculoskeletal, and neurological systems. 
 ECOG performance status 
 Blood draws for hematology (within 5 days of the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC differential 


 
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 Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP (if testing is available and can be performed locally), serum 
creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin 
 A coagulation panel (within 5 days of the visit): PT, PTT, and INR. 
 Pregnancy test (within 5 days of the visit): pre-menopausal women must have a 
negative serum pregnancy test.  Post-menopausal women (as defined in Section 6.1) 
are not required to undergo a pregnancy test. 
 Blood draw and urine sample for exploratory biomarker analysis (serum, plasma, and 
urine samples will be collected within 5 days or at the time of disease progression, 
whichever occurs earlier) 
 Record SSEs 
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether the subject starts a new anti-cancer therapy (i.e., 
chemotherapy, other). 
 Blood draw for analysis of CTCs (within 5 days of the visit). 
 Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2. 
If subjects cannot travel to the clinical site due to deterioration of disease, the EOT visit will 
be replaced by a follow-up telephone call from the clinical site.  Adverse events, information 
on all occurrences of leukemia, MDS, aplastic anemia, or any other new primary malignancy, 
as well as any anti-cancer 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. 
9.2.4 
Active follow-up 
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 
clinic visits to active follow-up without clinic visits, the subject will not be allowed to switch 
back.  
If a subject can no longer travel, all scans and clinic visits have to be discontinued.  The 
subject will begin active follow-up without scheduled clinic visits (telephone follow-up). 
All subjects, regardless of reaching a study endpoint (on-study SSE) will enter the follow-up 
period in order to collect the required long-term safety information. 
9.2.4.1 
Active follow-up with clinic visits 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), Amendment 5 (Section 15.4), and Amendment 8 (Section 15.7.1.1). 


 
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Subjects who discontinued or completed radium-223 dichloride/placebo, did not experience 
an SSE and radiological progression during the treatment period, had an EOT visit, and can 
travel to the clinic will enter an active follow-up period with clinic visits.  During this period, 
clinic visits are to occur as follows:  
 For subjects who have not experienced an SSE during the treatment period, visits will 
continue with the same frequency as during treatment (every 4 weeks ±7 days) until 
the subject has an SSE.  After the occurrence of the SSE, the subjects will be switched 
to a frequency of visits every 12 weeks ±7 days at the next scheduled visit.  
 For subjects that experienced an SSE during the treatment period, visits will occur 
every 12 weeks ±7 days.  The subjects will continue to be followed for radiological 
progression and long-term safety. 
 Subjects who miss 2 consecutive follow-up visits will be considered unable to travel 
to the site and will enter the active follow-up without clinic visits. 
The active follow-up period with clinic visits extends from the EOT visit until the subject can 
no longer travel to the clinic, experiences SSE and radiological progression, 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 until study termination. 
The following procedures/evaluations should be performed at these visits. (Note that vital 
signs measurement, full physical examination, blood draws, and radiological tumor 
assessment are only to be performed every 12 weeks ±7 days):  
 BPI-SF questionnaire will be completed prior to any other study 
assessments/procedures and should be checked for completion at the visit. 
Additionally PRO Questionnaire Information Sheet is to be completed by clinical staff 
based on discussion with patient, even if patient does not complete the BPI-SF 
questionnaire 
 Resource utilization questionnaire to be completed by site  
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in 
by the subjects for 24 hours prior to visit.  The analgesic use for 24 hours prior 
to the visit will be recorded by the investigator on the eCRF. 
 Record opiate use 
 All AEs and SAEs occurring during this period must be documented and reported if 
considered to be related to study medication or study-related procedures. Note: 
Specifically for this study, relevant symptoms related to an SSE should be reported as 
AEs independent of the timing of occurrence (prior to 30 days after last dose of study 
treatment or after this interval) or relationship with study drug. 


 
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 All bone fractures and bone associated events (e.g., osteoporosis) should be collected 
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment. 
 All occurrences of leukemia, MDS, aplastic anemia, or any other new primary 
malignancy must be reported as SAEs regardless of the Investigator’s causality 
assessment.  Concomitant medications 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. 
 Record concomitant medications/therapy 
 Record breast cancer-related treatment  
 Record vital signs (every 12 weeks):  blood pressure, heart rate, respiratory rate, and 
temperature  
 Perform full physical examination (every 12 weeks): A full physical examination 
must include the evaluation of head, eyes, ears, nose, throat, cardiovascular, 
respiratory, gastrointestinal, dermatological, musculoskeletal and neurological 
systems. 
 ECOG performance status 
 Blood draws for hematology every 12 weeks (within 5 days of the visit):  hematocrit, 
Hb, platelet counts, RBC counts, WBC counts, and WBC differential  
 Blood draws for clinical chemistry every 12 weeks (within 5 days of the visit):  Na, K, 
Cl, Ca, ALT, AST, LDH, bone ALP (if testing is available and can be performed 
locally), serum creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and 
albumin 
 Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2. 
 Record SSEs 
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether the subject starts a new anti-cancer therapy (i.e., 
chemotherapy, other). 
 Record survival status 
Subjects who receive subsequent cytotoxic chemotherapy will be followed up for the 
development of febrile neutropenia and hemorrhage due to thrombocytopenia during their 
chemotherapy treatment and for up to 6 months at a frequency based on local clinical 
practice. 


 
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9.2.4.2 
Active follow-up without clinic visits 
Section modified by Amendment 1 (Section 15.1), Amendment 7 (Section 15.6), and 
Amendment 8 (Section 15.7.1.1). 
Subjects from the treatment period or the active follow-up period with clinic visits who can 
no longer travel to the clinic site or those who experienced an SSE and radiological 
progression will be followed for survival, treatment-related AEs and SAEs, the initiation of 
other anti-cancer therapies, and SSEs with phone calls as follows: 
The active follow-up period without clinic visits extends from the EOT visit or last visit of 
the active follow-up with clinic visits until the subject 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 until study termination. 
During this follow-up, contact with the subject will take place by telephone call as follows: 
 For subjects that did not experience an SSE during treatment or the previous 
follow-up period, the frequency of the phone calls will be every 4 weeks ±7 days until 
the subject has an SSE.  After the occurrence of the SSE, the subjects will be switched 
to a frequency of phone calls every 12 weeks ±7 days at the next scheduled phone 
call. 
 For subjects who did experience an SSE during treatment or the previous follow-up 
period, the frequency of the phone calls will be every 12 weeks ±7 days. 
The following data should be collected during these calls: 
 All AEs and SAEs occurring during this period must be documented and reported if 
considered to be related to study medication or study-related procedures. Note: 
Specifically for this study, relevant symptoms related to an SSE should be reported as 
AEs independent of the timing of occurrence (prior to 30 days after last dose of study 
treatment or after this interval) or relationship with study drug.  
 All bone fractures and bone associated events (e.g., osteoporosis) should be collected 
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment. 
 All occurrences of leukemia, MDS, aplastic anemia, or any other new primary 
malignancy must be reported as SAEs at any time regardless of the Investigator’s 
causality assessment.  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. 
 Resource utilization questionnaire to be completed by site 
 Record SSEs 
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether the subject starts a new anti-cancer therapy (i.e., 
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 Record concomitant medications/therapy (concomitant medications used to treat any 
grade adverse drug reaction only) 
 Record breast cancer-related treatment 
 Record survival status  
If possible, radiological tumor assessments, as per timepoints and guidelines specified in 
Section 9.2.6 and Appendix 16.2, were to be performed, as applicable. 
Subjects who receive subsequent cytotoxic chemotherapy will be followed 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. 
Note: As this information will be collected over the telephone from the subject, it is the 
clinical site’s responsibility to obtain and make available the source documentation for the 
information collected from the subject and documented in the eCRF. 
Only subjects who withdraw consent from the study will be required to follow the procedures 
outlined in Section 6.3.1.2 (i.e., sign the Declaration of Objection to the Collection of Study 
Data after Withdrawal of Consent for the active assessment follow-up period). 
9.2.4.3 
End of active follow-up 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), Amendment 5 (Section 15.4), and Amendment 8 (Section 15.7.1.1). 
This visit will be performed only once, either at the end of the active follow-up with clinic 
visits or at the end of the active follow-up without clinic visits.  
The procedures for subjects who complete the active follow-up with clinic visits period will 
include: 
 BPI-SF questionnaire will be completed prior to any other study 
assessments/procedures and should be checked for completion at the visit. 
Additionally PRO Questionnaire Information Sheet is to be completed by clinical 
staff based on discussion with patient, even if patient does not complete the BPI-SF 
questionnaire 
 Resource utilization questionnaire to be completed by site 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in 
by the subjects for 24 hours prior to the visit.  The analgesic use for 24 hours 
prior to the visit will be recorded by the investigator on the eCRF. 
 Record opiate use 
 All AEs and SAEs must be documented and reported if considered to be related to 
study medication or study-related procedures. Note: Specifically for this study, 


 
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relevant symptoms related to an SSE should be reported as AEs independent of the 
timing of occurrence (prior to 30 days after last dose of study treatment or after this 
interval) or relationship with study drug. 
 All bone fractures and bone associated events (e.g., osteoporosis) should be collected 
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment. 
 All occurrences of leukemia, MDS, aplastic anemia, or any other new primary 
malignancy must be reported as SAEs regardless of the Investigator’s causality 
assessment.  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. 
 Record concomitant medications/therapy (concomitant medications used to treat any 
grade adverse drug reaction only) 
 Record breast cancer-related treatment 
 Record vital signs: blood pressure, heart rate, respiratory rate, and temperature  
 Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 
gastrointestinal, dermatological, musculoskeletal, and neurological systems. 
 ECOG performance status 
 Blood draws for hematology (within 5 days of the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC differential  
 Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP (if testing is available and can be performed locally), serum 
creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin 
 Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2) 
 Record SSEs 
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether the subject starts a new anti-cancer therapy (i.e., 
chemotherapy, other). 
 Record survival status 
For subjects who die >30 days after the administration of last study treatment, submission of 
the AE complementary pages of the eCRF is not required unless the death is considered 
related to radium-223 dichloride/placebo.  For all deaths, the date of death information will 
be collected in the end-of-follow-up page of the eCRF. 
The end of active follow-up procedures for subjects who are in the active follow-up without 
clinic visits period will include: 
 Resource utilization questionnaire to be completed by site 


 
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 All AEs and SAEs must be documented and reported if considered to be related to 
study medication or study-related procedures. 
 All bone fractures and bone associated events (e.g., osteoporosis) should be collected 
as either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s 
causality assessment. 
 All occurrences of leukemia, MDS, aplastic anemia, or any other new primary 
malignancy must be reported as SAEs regardless of the Investigator’s causality 
assessment.  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. 
 Record concomitant medications/therapy (concomitant medications used to treat any 
grade adverse drug reaction only) 
 Record breast cancer-related treatment (prior and current) 
 Record SSEs 
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether the subject starts a new anti-cancer therapy (i.e., 
chemotherapy, other). 
 Record survival status 
Note: 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 documented in the eCRF. 
9.2.5 
End of Study 
Section modified by Amendment 8 (Section 15.7.1.2). 
All ongoing study subjects who have completed at a minimum the EOT visit or 30 days from 
last study treatment dose, whichever is latest, may be transitioned into a separate long-term 
follow-up study (BAY 88-8223 study 16996 / NCT02312960). 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 primary objective of this study is 
to define the long-term safety profile of radium-223 dichloride.  
All subjects who transition into this separate long-term follow-up study will require a 
separate signed informed consent. 
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., death, consent withdrawn and active 
objection for further data collection, lost to follow-up). Until the transition to the long-term 
follow up study, subjects will continue to follow all the protocols required procedures and 
visits in the current protocol.  


 
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9.2.6 
Radiological assessment: tumor and response evaluation 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), Amendment 5 (Section 15.4), and Amendment 7 (Section 15.6). 
Radiological tumor evaluation, using the mRECIST 1.1 guidelines (See Section 16.2), must 
be performed as follows (see also Figure 9–1): 
 Within 3 weeks prior to randomization, 
 8 weeks (±7 days) after the first radium-223 dichloride/placebo administration  
 Every 12 weeks (± 7 days) thereafter until PD (radiological progression) is 
documented.   
A technetium-99m bone scan and CT or MRI (chest/abdomen/pelvis and any additional sites 
of disease, as applicable) should be performed at all the above mentioned timepoints.  
This schedule is to be maintained and will not be shifted because of treatment 
interruptions/delays.   
Figure 9–1:  Radiological tumor evaluation schedule  
 
If radiologic soft tissue or visceral progression in absence of bone progression (according to 
mRECIST 1.1 criteria) is observed, bone imaging and MRI/CT scan of the chest, abdomen, 
and pelvis should continue to allow assessment of bone-specific rPFS until bone progression 
occurs or start of a new anticancer treatment. 
If radiologic bone progression occurs prior to occurrence of visceral metastases, MRI/CT 
scan of the chest, abdomen, and pelvis should continue until occurrence of visceral metastasis 
or start of a new anticancer treatment after the end of the current study treatment. This will 
allow assessment of time to visceral metastases onset.    
Subjects who discontinue study treatment for reasons other than disease progression will 
continue to undergo tumor response evaluations until PD is documented (radiological 
progression). 
Standard of care CT/MRI done within 3 weeks of randomization and standard of care bone 
scans done within 3 weeks of randomization are acceptable provided they are in line with 


 
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protocol requirements criteria (anatomic coverage chest/abdomen/pelvis and in line with 
RECIST 1.1/mRECIST 1.1 guidelines for image acquisition).  All suspected sites of disease 
should be imaged.  
Note: FDG PET scan, if performed as part of standard of care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can document that 
the CT is of identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
A technetium-99m bone scan with careful identification of all disease-related hotspots should 
be performed for all patients at the above mentioned timepoints. All visible bone lesions must 
also be imaged with conventional anatomical imaging procedures such as CT or MRI scan.  
During the study a new bone lesion or progression of existing bone lesion/s initially identified 
on a technetium-99m bone scan must be confirmed by CT or MRI.  If confirmed by CT/MRI, 
the date of occurrence of the new lesion or of progression of existing bone lesion/s will be the 
date it was initially detected (by technetium-99m bone scan) even if the confirmation by 
CT/MRI was done at a subsequent scan.  (See also Section 16.2).  
Note: FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. The same lesions identified at baseline must 
be evaluated at follow-up assessments using the same technique and preferably by the same 
Investigator/radiologist.  
For details on radiological tumor assessment please also refer to Section 16.2. 
9.3 
Population characteristics 
9.3.1 
Demographic  
The following demographic characteristics will be collected: 
 Date of birth 
 Age at randomization 
 Race and ethnicity (where it is allowed by local regulation) 
9.3.2 
Medical history 
Medical history findings (i.e., previous diagnoses, diseases, or surgeries) meeting all criteria 
listed below will be collected:  
 Not pertaining to the study indication 
 Start before signing of the informed consent  
 Considered relevant to the study 
Detailed instructions on the differentiation between (i) medical history and (ii) AEs can be 
found in Section 9.6.1.1. 


 
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9.3.3 
Other baseline characteristics 
Section modified by Amendment 1 (Section 15.1) and Amendment 5 (Section 15.4). 
The following other baseline characteristics will be collected: 
 Date of breast cancer diagnosis 
 Date of diagnosis of metastatic breast cancer 
 Stage of breast cancer at diagnosis 
 Treatment of breast cancer before enrollment (e.g., surgery, radiation) 
 Weight (kg) 
 Vital signs: blood pressure (mmHg), heart rate (bpm), respiratory rate (rpm), and 
temperature (°C)  
 ECOG performance status 
 Cancer pain assessment 
 Laboratory assessments 
o Hematology: hematocrit, Hb, platelet counts, RBC counts, WBC counts, and 
WBC differential 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol, ALT, AST, LDH, bone 
ALP (if testing is available and can be performed locally), serum creatinine, 
phosphate, BUN, total bilirubin, and albumin 
9.4 
Efficacy 
9.4.1 
Efficacy variables 
Section modified by Amendment 4 (Section 15.3). 
The primary efficacy variable is: 
 SSE-FS 
The secondary efficacy variables are: 
 Overall survival (OS) 
 Time to opiate use for cancer pain 
 Time to pain progression (only in subjects with baseline WPS ≤8) 
 Time to cytotoxic chemotherapy 
 Radiological progression free survival (rPFS) 
 Pain improvement rate 


 
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The study will also include the following exploratory efficacy endpoints: 
 Time to first on-study SSE 
 Time to bone ALP progression 
 Bone ALP response at Week 12 and EOT 
 Bone specific rPFS 
 Time to visceral metastases onset 
9.4.2 
Definition of efficacy variables 
9.4.2.1 
Primary endpoint  
Symptomatic skeletal event-free survival is defined as the time from randomization to the 
occurrence of one of the following: 
(1) An on-study SSE, which is defined as: 
a. the use of EBRT to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone fractures (vertebral or 
non-vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
(2) Death from any cause  
Note: All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) must be 
administered prior to randomization.  
9.4.2.2 
Secondary efficacy endpoints 
Section modified by Amendment 1 (Section 15.1), Amendment 2 (Section 15.2), Amendment 4 
(Section 15.3), Amendment 5 (Section 15.4), and Amendment 6 (Section 15.5). 
Overall survival is defined as the time (days) from the date of randomization to the date of 
death due to any cause.  For subjects who are still alive, their OS will be censored at the last 
known alive date or the database cutoff date, whichever occurs first.  
Time to opiate use for cancer pain is defined as the interval from the date of randomization 
to the date of opiate use.  Subjects who have no opiate use at the time of analysis will be 
censored at the last assessment date of no opiate use.  Subjects with no on-study assessment 
or no baseline assessment will be censored at the date of randomization. 
Time to opiate use will be determined by analgesic use captured via different eCRF pages 
(24 hour analgesic use page, analgesic concomitant medication page and opiate use page, 
respectively, see Table 9–1 Schedule of assessments).  
Time to pain progression is defined as the interval from randomization to the first date 
a subject experiences pain progression based on WPS and analgesics use.  Time to pain 


 
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progression will be evaluated in subjects with baseline WPS ≤ 8.  Pain progression is defined 
as an increase of 2 or more points in the “Worst pain in 24 hours” score from baseline 
observed at 2 consecutive evaluations ≥4 weeks apart  
OR 
an increase in pain management (IPM) with respect to baseline, whichever occurs first.   
Assessments will occur on the day of the visit.  An evaluable pain assessment interval 
requires completion of a minimum of 4 out of 7 questions.  Subjects who have not 
experienced pain progression at the time of analysis will be censored on the last post-baseline 
pain assessment date the subject was known to have not progressed. Subjects with no 
on-study assessment or no baseline assessment will be censored at the date of randomization.   
Pain improvement is defined for subjects evaluable for pain improvement, i.e. subjects with 
baseline WPS ≥ 2, as a 2-point decrease or more in WPS from baseline over 2 consecutive 
measurements conducted at least 4 weeks apart, without an IPM. 
Pain improvement rate is defined as the number of subjects with pain improvement as 
defined above, divided by the total number of subjects evaluable for pain improvement (i.e., 
subjects with baseline WPS ≥2). Pain improvement rate at week 12, EOT and any visit will 
be considered. 
Time to cytotoxic chemotherapy is defined as the time (days) from the date of 
randomization to the date of the first cytotoxic chemotherapy.  
Radiological progression-free survival is defined as the time (days) from the date of 
randomization to the date of confirmed radiological progression in either soft tissue, viscera 
or bone, or death (if death occurs before progression).  Subjects without confirmed 
radiological progression or death at the time of analysis will be censored at their last date of 
radiological tumor assessment (See the statistical analysis plan [SAP] for detailed censoring 
rules).  Bone scans and CT/MRIs will be read locally.  All bone lesions visible on a 
technetium-99m bone scan will need to also be imaged using conventional anatomical 
imaging techniques such as SPECT-CT/MRI or CT/MRI (with or without contrast).  Bone 
progression will be declared according to the mRECIST 1.1 criteria (see Section 16.2).  If a 
new bone lesion or unequivocal increase in size of bone lesions is identified on bone scan, the 
lesion must also be confirmed by CT/MRI.  If a new bone lesion or unequivocal increase in 
size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone 
scan, progression will be declared without further confirmation. 
9.4.2.3 
Exploratory efficacy endpoints 
Section modified by Amendment 5 (Section 15.4) and Amendment 6 (Section 15.5). 
Time to first on-study SSE is defined as the time (days) from the date of randomization to 
the date of the first on-study SSE.  
Time to bone ALP progression is defined as the time (days) from the date of randomization 
to the date of first bone ALP progression.  Bone ALP progression is defined as a 25% 
increase from the baseline value, at least 12 weeks from baseline in subjects with no bone 


 
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ALP decline from baseline; or a 25% increase above the nadir value, which is confirmed by 
a second value obtained 4 or more weeks later in subjects with an initial bone ALP decline 
from baseline. 
Bone ALP response is defined as a ≥30% reduction of the blood level at Week 12 or EOT, 
compared to the baseline value.  Confirmed bone ALP response is defined as a ≥30% 
reduction of the blood level, compared to the baseline value, confirmed by a second bone 
ALP value 4 or more weeks later.  
Radiological progression free survival based on bone imaging (bone-specific rPFS) is 
defined as the time (days) from the date of randomization to the date of confirmed 
radiological progression detected by bone imaging or death (if death occurs before 
progression).  Subjects without confirmed radiological progression or death at the time of 
analysis will be censored at their last date of radiological tumor assessment.  (See the SAP for 
detailed censoring rules).  Bone scans will be read locally.  All bone lesions visible on a 
technitium-99m bone scan will need to also be imaged using conventional anatomical 
imaging techniques such as CT/MRI (with or without contrast).  Bone progression will be 
declared according to the mRECIST 1.1 criteria (see Section 16.2).  If a new bone lesion or 
unequivocal increase in size of bone lesions is identified on bone scan, the lesion must also 
be confirmed by CT/MRI.  If a new bone lesion or unequivocal increase in size of bone 
lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, 
progression will be declared without further confirmation.  
Time to visceral metastases onset is defined as the time (days) from the date of 
randomization to the date of the first scan showing visceral metastatic disease. Subjects with 
visceral metastases at baseline will be censored at the randomization date. 
9.5 
Pharmacokinetics  
No pharmacokinetic (PK) measurements will be performed in this study.  No PK interaction 
is expected between radium-223 dichloride and the co-administered hormone therapy.  
Radium-223 is an isotope and is therefore not metabolized.  There are no hints that radium is 
involved in any transporter process.  The main portion of radioactivity is excreted with the 
feces.  The liver seems not to be involved in the excretion of radium-223 or its decay 
products.  They are directly excreted into the small intestine.  The co-administered products 
are typical small molecules that are metabolized in the liver.  Thus, no direct impact of 
radium-223 on the PK of the co-administered products is expected.  
9.6 
Safety  
Section modified by Amendment 1 (Section 15.1). 
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 9.6.1.  


 
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 Safety variables: Safety variables will include the analysis of acute and long-term 
effects and the appearance of new primary malignancies and hematopoietic reserve 
for tolerability of subsequent chemotherapy.  The complete list of variables to be 
analyzed for this study will be provided in the SAP.  
 Laboratory assessments: The following laboratory assessments with reference ranges, 
including Investigator determinations, will be recorded in the source documentation 
and the eCRF: 
o Hematology: hematocrit, Hb, platelet counts, RBC counts, WBC counts, and 
WBC differential 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol, ALT, AST, LDH, bone 
ALP, serum creatinine, phosphate, BUN, total bilirubin, and albumin 
o A coagulation panel: PT, PTT, and INR 
All subjects who receive at least one dose of study drug will be valid for safety analysis.  All 
AEs will be reported and graded according to NCI-CTCAE v4.03.  Laboratory evaluations, 
vital signs, and changes in physical examination findings will also be assessed. 
9.6.1 
Adverse events 
9.6.1.1 
Definitions 
Adverse event 
In a clinical study, an AE is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom, or disease) in a subject 
or clinical investigation subject after providing written informed consent for participation in 
the study.  Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. 
A surgical procedure that was planned prior to the start of the study by any physician treating 
the subject should not be recorded as an AE (however, the condition for which the surgery is 
required may be an AE). 
Adverse event versus medical history 
In the following differentiation between medical history and AEs, the term “condition” may 
include abnormal physical examination findings, symptoms, diseases, laboratory findings, or 
scans.  
 Conditions that started before signing of informed consent and for which no 
symptoms or treatment are present until signing of informed consent are considered as 
medical history (e.g., seasonal allergy without acute complaints).  
 Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
considered as medical history (e.g., allergic pollinosis).  


 
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 Symptoms that were present prior to signing of informed consent but for which the 
diagnosis was confirmed after signing of informed consent should be documented as 
medical history. 
 Conditions that started or deteriorated after signing of informed consent will be 
documented as adverse events.  
Serious adverse event 
An SAE is classified as any untoward medical occurrence that, at any dose, meets any of the 
following criteria (a – 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 
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 
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 any additional malignancies, including AML or hematological 
conditions, such as MDS, aplastic anemia, or myelofibrosis (regardless of the 
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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). 
9.6.1.2 
Classifications for adverse event assessment 
All AEs will be assessed and documented by the Investigator according to the categories 
detailed below.  
9.6.1.2.1 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in 
Section 9.6.1.1. 
9.6.1.2.2 
Intensity 
The intensity of an AE should be documented using the NCI-CTCAE v4.03, JUN 2010; see 
Section 16.1.  
9.6.1.2.3 
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.  Causal relationship of the background 
hormone treatment and concomitant medication of interest, bisphosphonates or denosumab 
will also be collected. 
Possible answers are “yes” or “no” 
An assessment of “no” would include: 
 The existence of a clear alternative explanation, e.g., mechanical bleeding at surgical 
site, 
or 
 Non-plausibility, e.g., the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; cancer 
developing a few days after the first drug administration. 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is associated 
with the use of the study treatment. 


 
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Important factors to be considered in assessing the relationship of the AE to study treatment 
include: 
 The temporal sequence from drug administration: The event should occur after the 
drug is given.  The length of time from drug exposure to event should be evaluated in 
the clinical context of the event. 
 Recovery on drug discontinuation (de-challenge), recurrence on drug re-introduction 
(re-challenge): Subject’s response after de-challenge or subject’s response after 
re-challenge should be considered in the view of the usual clinical course of the event 
in question. 
 Underlying, concomitant, intercurrent diseases: Each event should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the subject may have. 
 Concomitant medication or treatment: The other drugs the subject is taking or the 
treatment the subject receives should be examined to determine whether any of them 
may be suspected to cause the event in question. 
 The pharmacology and PK of the study treatment: The PK properties (absorption, 
distribution, metabolism, and excretion) of the study treatment, coupled with the 
individual subject’s pharmacodynamics should be considered. 
Causal relationship to protocol-required procedure(s) 
The assessment of a possible causal relationship between the AE and protocol-required 
procedure(s) is based on the question whether there was a “reasonable causal relationship” to 
protocol-required procedure(s).  Possible answers are “yes” or “no”. 
9.6.1.2.4 
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 not changed 
 Not applicable 
 Unknown 
9.6.1.2.5 
Other specific treatment(s) of adverse events 
 None 
 Remedial drug therapy 
 Other 


 
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9.6.1.2.6 
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 
9.6.1.3 
Assessments and documentation of adverse events 
Section modified by Amendment 1 (Section 15.1), Amendment 5 (Section 15.4), Amendment 8 
(Section 15.7.1.1). 
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/placebo must be reported on the appropriate eCRF. 
All SAEs that occur during the treatment period and up to 30 days after the last 
administration of radium-223/placebo must immediately (within 24 hours of the 
Investigator’s awareness) be reported in the appropriate eCRF.  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 dose of study treatment must be 
documented and reported if considered to be related to study medication or to study-related 
procedures.  
Subjects who receive cytotoxic chemotherapy during the follow-up period will be followed 
up for the development of febrile neutropenia and hemorrhage during their chemotherapy 
treatment and for up to 6 months after chemotherapy.  Occurrence of these AEs must be 
documented and reported if considered to be related to the chemotherapy treatment.  
However, all occurrences of additional malignancies, including AML and hematological 
conditions, such as MDS, aplastic anemia, and myelofibrosis, must be reported as SAEs, 
regardless of the Investigator’s assessment. 
Note:  Specifically for this study, relevant symptoms related to SSEs should be captured as 
AEs or SAEs (if appropriate) regardless of the relationship to study drug from the date of first 
dose until the end of active follow-up. 
All bone fractures and bone associated events (e.g., osteoporosis) should be collected as 
either AEs or SAEs if the criteria of SAE were met, regardless of the investigator’s causality 
assessment. 


 
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Adverse events may be reported spontaneously by the subject or elicited through open 
(non-leading) questioning during each visit to the clinic and at the end of the active follow-up 
period without clinic visits.  As far as possible, all AEs must be described by their duration 
(start and stop date), severity (graded according to the CTCAE v4.03), relationship to 
treatment, and according to the need of other specific therapy.  All information will be 
recorded in the source documentation and AE eCRF. 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment, causing apparent clinical manifestations, or 
judged as relevant by the Investigator should be reported as an AE.  Each event should be 
described in detail along with start and stop dates (onset and resolution of event), intensity, 
temporal and causal relationship to investigational product and/or protocol-related 
procedures, 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. 
9.6.1.4 
Reporting of serious adverse events 
Section modified by Amendment 2 (Section 15.2) and Amendment 8 (Section 15.7.1.1). 
The definition of SAEs is given in Section 9.6.1.1.  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 an SAE, 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 “alternative 
explanation”. 
Reporting of additional malignancies 
All occurrences of any additional malignancies, including AML and hematological 
conditions, such as MDS, aplastic anemia, or myelofibrosis, must be reported as SAEs, 
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 9.6.1.3 must 
immediately (within 24 hours of the Investigator’s awareness [or the next working day for 
weekends and public holidays]) be reported to the contact at the contract research 
organization (CRO), as detailed in the study manual.  An SAE form must also be completed 
within 24 hours of the Investigator awareness (or the next working day for weekends and 


 
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public holidays) and forwarded to the designated recipient.  Each SAE must be followed up 
until resolution or stabilization by the submission of updated reports to the designated 
recipient. 
Additionally, all occurrences of a MDS, aplastic anemia, or any other new primary 
malignancy, such as AML, must be reported as SAEs at any time, and regardless of the 
Investigator’s causality assessment (Section 9.6.1.3).   All bone fractures and bone associated 
events (e.g., osteoporosis) should be collected as either AEs or SAEs if the criteria of SAE 
were met, regardless of the investigator’s causality assessment.  Grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as SAEs, specifically 
when they are allowed or not excluded by the protocol inclusion/exclusion criteria.  If an 
Investigator is in doubt about the applicable reporting obligations, he/she should consult with 
the medical monitor.  
For subjects who die 30 days after the administration of the last study treatment, submission 
of the AE page of the eCRF is not required.  However, the SAE Complementary Form should 
be submitted to the applicable Bayer HealthCare Pharmacovigilance department if the death 
is considered related to study treatment.  In addition, this death information will also be 
collected in the end of active follow-up page of the eCRF. 
Serious adverse events occurring after the protocol-defined observation period will be 
processed by the sponsor according to all applicable regulations. 
Notification of the independent ethics committees/institutional review boards  
Notification of the independent ethics committees/institutional review boards (IECs/IRBs) 
about all relevant events (e.g., SAEs, SUSARs) will be performed by the sponsor and/or by 
the Investigator according to all applicable regulations. 
Notification of the authorities 
The processing and reporting of all relevant events (e.g., SAEs, SUSARs) to the authorities 
will be done by the sponsor according to all applicable regulations. 
Sponsor’s notification of the investigational study site 
The sponsor will inform all investigational study sites about reported relevant events (e.g., 
SUSARs) according to all applicable regulations.  The sponsor will send SUSARs to a study 
site once ready to enroll and will stop sending SUSARs once the last subject EOT visit for 
that study site (30 days after last dose) occurs. 
9.6.1.5 
Expected adverse events 
For this study, the applicable reference document is the most current version of the 
IB/summary of product characteristics. 
9.6.2 
Pregnancies 
The Investigator must report to the sponsor any pregnancy occurring in a female study 
subject during her participation in this study.  The outcome of the pregnancy should be 


 
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followed up carefully, and any outcome of the mother and the child at delivery should be 
reported. 
For all reports, the forms provided are to be used.  The Investigator should submit them 
within the same timelines as an SAE. 
9.7 
Other procedures and variables 
Other exploratory variables in this study are resource utilization, assessment of biomarkers, 
and impact of baseline total body weight (TBW) and ideal body weight (IBW) on SSE-FS 
and AEs.  Further details about these exploratory endpoints will be provided in the SAP. 
9.7.1 
Resource utilization 
Information on healthcare resource use that is associated with the management of AEs as well 
as subject monitoring will be collected by questionnaire (Section 16.7). 
9.7.2 
Biomarker assessments 
Section modified by Amendment 5 (Section 15.4). 
Biomarker analyses planned within this study may include predictive, prognostic, and 
pharmacodynamic biomarkers analyzed from serum and urine.  Serum, urine, and biomarker 
analyses will be dependent upon the availability of appropriate biomarker assays and may be 
deferred or not performed, if during or at the end of the study, it becomes clear that the 
analysis will have no scientific value, or there are not enough samples or not enough 
responders to allow for adequate biomarker evaluation.  In the event the study is terminated 
early or does not reach a positive primary endpoint, completion of the biomarker assessments 
will be based on justification and intended utility of the data.  Exploratory biomarker data 
including CTC analysis will be reported in a separated biomarker report. 
9.7.2.1 
Urine, plasma, and serum based biomarker analysis 
Section modified by Amendment 1 (Section 15.1) and Amendment 4 (Section 15.3). 
Blood samples will be obtained from all subjects at the following time points: (1) Cycle 1, 
Day 1 (Visit 2) and Cycle 4, Day 1 (Visit 8) within 5 days of the visit prior to radium-223 
dichloride or placebo administration, and within 5 days of the EOT visit or disease 
progression, whichever occurs first.  At these time points, urine samples will also be 
collected. 
 Urine, serum, and plasma from blood samples (Cycle 1, Day 1; Cycle 4, Day 1; and 
EOT/disease progression) may be evaluated for expression levels of bone-related 
biomarkers.  Elevated levels of bone biomarkers are indicative of more aggressive 
disease and are prognostic of worse long-term clinical outcome.  In this study, levels 
of bone biomarkers (measured before, during, and after treatment) that are indicative 
of bone remodeling (e.g., bone ALP, procollagen type I N-terminal propeptide) and 
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C-terminal telopeptide of type I collagen) may be evaluated and correlated with 
clinical outcomes (including SSEs, survival, and levels of other biomarkers).  
In addition to the biomarkers listed above, other biomarkers deemed relevant to gain further 
knowledge about the pathomechanism of the disease and/or about the drug (i.e., mode of 
action related effect or safety of the drug) may be measured, based on newly emerging data 
from other ongoing studies and/or literature data.  
9.7.2.2 
Collection of circulating tumor cells for biomarker analyses 
Section modified by Amendment 5 (Section 15.4) and Amendment 7 (Section 15.6). 
Circulating Tumor Cells (CTCs) are believed to represent a surrogate for tumor cells and can 
be used as surrogate to demonstrate efficacy of the drug by enumeration of CTCs, but also as 
source of tumor molecular characterization.  
Blood samples will be obtained from all subjects at sites in France, Germany, Israel, Spain, 
and the United Kingdom at the following time points: (1) Cycle 1, Day 1 (Visit 2) and every 
subsequent cycles, Day 1 within 5 days of the visit prior to radium-223 dichloride or placebo 
administration, and within 5 days of the EOT visit or disease progression, whichever occurs 
first.   
9.7.3 
Analysis of the impact of body weight on SSE-FS and AEs 
The impact of baseline TBW and IBW on SSE-FS and AEs will be analyzed in this study.  
Baseline TBW and IBW correspond to the subject’s TBW and IBWs on Cycle 1, Day 1 of the 
study; details will be presented in the SAP.   
9.8 
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. 
10. Statistical methods and determination of sample size 
10.1 General considerations 
Section modified by Amendment 4 (Section 15.3). 
Subjects will be randomized to radium-223 dichloride or placebo in a 1:1 ratio.  
Randomization will be stratified by:  
 Geographical regions (Europe/North America [including Israel] versus Asia) 
 Previous lines of hormone therapy in metastatic setting (1 versus 2 or more): for the 
purpose of counting the number of prior lines of hormone therapy, only a change of 
the hormone agent due to progression is counted as a new line of therapy.  A switch of 
hormone therapy from one agent to another due to toxicity or other reasons (e.g., 
subject’s preference) in absence of PD at the time of switch will be counted as one 
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 Prior SREs (1 versus 2): for the purpose of prior SREs stratification, separate SREs 
are those that occur at least 21 days apart from each other. Any procedure which is 
related to an SRE, such as orthopedic surgery to treat a pathological bone fracture or 
multiple doses of radiation during a course of treatment, should not be counted as a 
separate event. In case of bone pain that occurs in several anatomical locations and 
requires separate EBRT sessions, it should be counted as one event if the EBRT 
sessions are administered within a period of 21 days. 
Statistical analysis will be performed using SAS Institute Inc.® (SAS); the version used will 
be specified in the SAP.   
10.2 Analysis sets 
The following 2 populations will be analyzed: 
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 are randomized. 
Safety: All randomized subjects who received at least one dose of any study drug.  This 
safety population will be used in the analyses of all safety endpoints.  Subjects will be 
included in the analyses according to the treatment they receive. 
10.3 Efficacy variables and planned statistical analyses 
Section modified by Amendment 4 (Section 15.3). 
Definition for each variable is given in Section 9.4. 
The primary efficacy variable is SSE-FS.  
The secondary efficacy variables are specified below:  
 Overall survival (OS) 
 Time to opiate use for cancer pain 
 Time to pain progression (only in subjects with baseline WPS ≤8) 
 Time to cytotoxic chemotherapy 
 Radiological progression free survival (rPFS) 
 Pain improvement rate 
Exploratory efficacy variables are:  
 Time to first on-study SSE 
 Time to bone ALP progression 
 Bone-ALP response at Week 12 and EOT 
 Bone-specific radiological progression free survival 


 
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 Time to visceral metastases onset 
10.3.1 Primary efficacy analysis  
The overall one-sided type I error rate for the analysis of primary efficacy endpoint SSE-FS 
is 0.1. 
The null hypothesis that both treatment groups have the same SSE-FS distribution will be 
tested against the alternative hypothesis that the distribution of SSE-FS time in radium-223 
dichloride is different from the placebo group.  The test statistic is assumed to be 
asymptotically normal distribution.  SSE-FS will be analyzed using a stratified log-rank test 
with the same stratification factors as for randomization.  The hazard ratio (radium-223 
dichloride/placebo) will be computed together with the 2-sided 80% and 95% confidence 
interval (CI) using a Cox regression model stratified by the same factors.  Kaplan-Meier 
estimates and survival curves for SSE-FS will also be presented for each treatment group.  
Additional details for the analyses of the primary efficacy endpoint will be provided in the 
SAP.  
10.3.2 Secondary efficacy analysis  
Secondary efficacy endpoints are specified in Section 9.4.  
The secondary efficacy time-to-event endpoints will be analyzed using a stratified log-rank test, 
with the factors from the randomization used for stratification.  A hazard ratio with 2-sided 80% 
and 95% CI from a stratified Cox proportional hazards model will also be provided.  
Kaplan-Meier estimates and survival curves will also be presented for each treatment group. 
Additional details for the analyses of secondary endpoints will be provided in the SAP. 
10.3.3 Exploratory efficacy analysis  
The exploratory time-to-event efficacy endpoints will be analyzed using a log-rank test, stratified 
by the same factors as the randomization factors.   
Additional details for the analyses of exploratory endpoints will be provided in the SAP. 
10.3.4 Safety analysis  
Safety variables will be analyzed using frequency tables and descriptive statistics.  
10.4 Determination of sample size 
Section modified by Amendment 2 (Section 15.2). 
Sample size is calculated based on the primary endpoint, SSE-FS.  EAST 6.3 was used to 
calculate event number.  Assuming a one-sided alpha of 0.1, power of 90%, with a median 
SSE-FS for the control group of 8.3 months and a randomization ratio of 1:1 between 
treatments, approximately 119 events will be required to detect a 60% increase in SSE-FS for 
a total of 227 subjects in the 2 treatment groups combined.  The dropout rate is assumed to be 


 
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15%.  Dropout was taken into account when calculating the sample size and study duration. 
The targeted improvement of 60% is not based on a bibliographical reference. 
10.5 Planned interim data review  
Section modified by Amendment 7 (Section 15.6). 
An administrative interim data review will be performed when approximately 40 rPFS events 
are reached. The interim data review will be primarily focused on the rPFS, and the results 
will inform on future radium-223 clinical development plans in this indication.  An 
independent unblinded data review committee will be formed.  
No formal statistical testing will be performed for either SSE-FS or rPFS at the time of this 
interim review. Only summary statistics will be produced. There is no plan to stop the trial 
due to superior efficacy; therefore, no alpha adjustment is applied for this interim look at the 
primary endpoint of SSE-FS. The study will remain blinded after the interim data review.  
Details of the interim data review will be provided in the statistical analysis plan.  
11. Data handling and quality assurance 
11.1 Data recording 
It is the expectation of the sponsor that all data entered into the eCRF has source 
documentation available at the study site.  The study site must implement processes to ensure 
this happens.  A source document checklist will be used at the study site to identify the source 
data for all data points collected and the monitor will work with the study 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 a minimum, data to be recorded in the 
eCRF are demographic information (subject number, date of birth/age, sex, race [if 
applicable] 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:  
o Concomitant medication 
o Medical history 
o Other information needed for SAE complementary page 


 
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11.2 Monitoring 
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors 
will contact the study site prior to the start of the study to review with the study 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 study 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. 
11.3 Data processing 
The data collection tool for this study will be a validated electronic system.  Subject data 
necessary for analysis and reporting will be transmitted into a validated database or data 
system (e.g., TOSCA; SAS).  Clinical data management will be performed in accordance 
with applicable sponsor’s standards and data cleaning procedures.  This is applicable for data 
recorded on eCRF as well as for data from other sources (e.g., IXRS, laboratory, adjudication 
committees). 
For data coding (e.g., AEs, medication), internationally recognized and accepted dictionaries 
will be used such as the Medical Dictionary for Regulatory Activities and World Health 
Organization Drug Dictionary. 
11.4 Missing data 
Every effort should be made to retain subjects who discontinue the treatment period for any 
reason.  These subjects are to be encouraged to remain on the study for follow-up of primary, 
secondary, and exploratory endpoints (i.e., continue in the active follow-up period with or 
without clinic visits). 
The method used for imputation of missing data will be described in the SAP. 
11.5 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 prior to a sponsor (or designated CRO) audit 


 
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inspections to ensure all required staff are available during the audit process.  The 
Investigator/institution will be informed of the audit outcome. 
In addition, inspections by regulatory health authority representatives and IEC(s)/IRB(s) are 
possible.  The Investigator should notify the sponsor immediately of any such inspection. 
The Investigator/institution agrees to allow the auditor or inspector direct access to all 
relevant documents and allocate his/her time and the time of his/her staff to the 
auditor/inspector to discuss findings and any issues.  Audits and inspections may occur at any 
time during or after completion of the study. 
11.6 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 must notify 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 
site. 
12. Premature termination of the study 
The sponsor has the right to close this study (or, if applicable, individual segments thereof 
[e.g., treatment arms; dose steps; sites]) at any time, which may be due, but not limited, to the 
following reasons:  
 If the risk-benefit ratio becomes unacceptable owing to, for example, 
o Results of parallel clinical studies 
o Results of parallel animal studies (e.g., toxicity, teratogenicity, 
carcinogenicity, or reproduction toxicity). 
 If the study conduct (e.g., recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the study within a reasonable 
time frame. 
The Investigator has the right to close his/her site 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. 


 
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 All affected institutions (e.g., IEC(s)/IRB(s); competent authority(ies); study site; 
head of study site) must be informed as applicable according to local law. 
 All study materials (except documentation that has to remain stored at study site) 
must be returned to the sponsor or (for radium-223 dichloride samples) be destroyed 
at the study site in accordance with the local radioprotection regulations.  The 
Investigator will retain all other documents until notification given by the sponsor for 
destruction. 
 In case of a partial study closure, ongoing subjects, including those in post study 
follow-up, must be taken care of in an ethical manner. 
 All ongoing subjects at the time of study termination will finish study treatment with 
radium-223 dichloride or placebo as part of the study. 
Details for individual subject's withdrawal can be found in Section 6.3.1. 
13. Ethical and legal aspects 
13.1 Investigators and other study personnel 
All other study personnel not included in this section are identified in a separate personnel list 
(not part of this clinical study protocol) as appropriate.  This list will be updated as needed; 
an abbreviated version with personnel relevant for the sites will be available in each site’s 
investigator site file. 
Whenever the term “Investigator” is noted in the protocol text, it may refer to either the 
Principal Investigator at the study site or an appropriately qualified, trained, and delegated 
individual of the investigational study site. 
The Principal Investigator of each site must sign the protocol signature sheet before subject 
recruitment may start at the respective site.  Likewise, all protocol amendments/integrated 
protocols must be signed and dated by the Principal Investigator before coming into effect at 
the respective site. 
In addition to signing the protocol signature sheet, all ethical and legal aspects (Section 13) 
should be in place prior to any subject recruitment. 
A complete list of all participating sites and their Investigators, as well as all required 
signature documents, will be maintained in the sponsor study file. 
The global sponsor of this study is identified on the title page of this protocol.  If required by 
local law, local co-sponsors will be nominated; they will be identified on the respective 
country-specific signature page. 
13.1.1 Independent data monitoring committee  
Not applicable 


 
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13.1.2 Independent radiological review  
Section modified by Amendment 7 (Section 15.6). 
This study will have no central review.  
13.1.3 Independent Data Review Committee (IDRC)  
Section modified by Amendment 7 (Section 15.6). 
An independent unblinded data review committee will be established. 
The IDRC will conduct a one-time unblinded review of the data. IDRC review will be 
supported by an independent unblinded statistical analysis center, as further described in the 
IDRC operational plan. 
13.2 Funding and financial disclosure 
Funding 
This study will be funded by its sponsor. 
Financial disclosure  
Each Investigator (including principal and/or any sub-investigators) who is directly involved 
in the treatment or evaluation of research subjects has to provide a financial disclosure 
according to all applicable legal requirements.  All relevant documentation will be filed in the 
trial master file. 
13.3 Ethical and legal conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and Investigator abide by 
GCP guidelines and under the guiding principles detailed in the Declaration of Helsinki.  The 
study will also be carried out in keeping with applicable local law(s) and regulation(s). 
Documented approval from appropriate IEC(s)/IRBs will be obtained for all participating 
sites/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 site/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 study subjects without prior IEC/IRB/sponsor approval/favorable opinion.  


 
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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 12. 
13.4 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 site.  A sample subject information and 
ICF is provided as a document separate to this protocol. 
Based on this subject information sheet, the Investigator or designee will explain all relevant 
aspects of the study to each subject or legal representative or proxy consenter (if the subject is 
under legal protection), prior to her 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 inform the subject that written approval of the IRB/IEC has been 
obtained. 
Each subject or legal representative or proxy consenter will have ample time and opportunity 
to ask questions and will be informed about the right to withdraw from the study at any time 
without any disadvantage and without having to provide reasons for this decision. 
Only if the subject or legal representative or proxy consenter voluntarily agrees to sign the 
ICF and has done so, may she enter the study.  Additionally, the Investigator and other 
information provider (if any) will personally sign and date the form.  The subject or legal 
representative or proxy consenter will receive a copy of the signed and dated form. 
The signed informed consent statement is to remain in the investigator site file or, if locally 
required, in the subject’s note/file of the medical institution. 
A summary of the consenting process, participation in the study, and date of informed 
consent given by the subject should be documented appropriately in the source 
documentation. 
In the event that informed consent is obtained on the date that baseline study procedures are 
performed, the study record or subject´s clinical record must clearly show that informed 
consent was obtained prior to these procedures. 
If the subject is not capable of providing a signature, a verbal statement of consent can also 
be given in the presence of an impartial witness (independent of the sponsor and the 
Investigator).  This is to be documented by a signature from the informing physician as well 
as by a signature from the witness. 
For adults under legal protection, consent shall be given by the legal guardian(s).  The 
consent of an adult under legal protection shall also be requested where such a person is able 
to express her own will.  Her refusal or the withdrawal of her consent may not be 
disregarded. 


 
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The ICF and any other written information provided to subjects or legal representatives or 
proxy consenters will be revised whenever important new information becomes available that 
may be relevant to the subject’s consent, or there is an amendment to the protocol that 
necessitates a change to the content of the subject information and/or the written ICF.  The 
Investigator will inform the subject or legal representative or proxy consenter of changes in a 
timely manner and will ask the subject to confirm her participation in the study by signing the 
revised ICF.  Any revised written ICF and written information must receive the IEC/IRB`s 
approval or favorable opinion in advance of use. 
A summary of any revised written ICF signed by the subject or a legal representative or a 
proxy should be appropriately documented by the study site within the source documents. 
If at any time during the study the subject would like to withdraw consent, the Investigator 
must discuss with the subject the active follow-up period without the clinic visits part of the 
study.  If the subject continues to object to having any study data collected the subject must 
sign the “Declaration of Objection to the Collection of Study Data after Withdrawal of 
Consent” form. 
13.5 Publication policy and use of data 
The sponsor has made the information regarding the study protocol publicly available on the 
internet at www.clinicaltrials.gov.  
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other Investigators. 
Regarding public disclosure of study results, the sponsor will fulfill its obligations according 
to all applicable laws and regulations.  The sponsor is interested in the publication of the 
results of every study it performs.  
The sponsor recognizes the right of the Investigator to publish the results upon completion of 
the study.  However, the Investigator, whilst free to utilize study data derived from his/her 
center for scientific purposes, must obtain written consent of the sponsor on the intended 
publication manuscript before its submission.  To this end, the Investigator must send a draft 
of the publication manuscript to the sponsor within a time period specified in the contract.  
The sponsor will review the manuscript promptly and will discuss its content with the 
Investigator to reach a mutually agreeable final manuscript. 
13.6 Compensation for health damage of subjects/insurance 
The sponsor maintains clinical study insurance coverage for this study in accordance with the 
laws and regulations of the country in which the study is performed. 
13.7 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. 


 
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Subject names will not be supplied to the sponsor.  Only the subject number will be recorded 
in the CRF.  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. 


 
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14. Reference list 
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16 Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, et al. 
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22 Plunkett TA, Smith P, Rubens RD. Risk of complications from bone metastases in breast 
cancer: implications for management. Eur J Cancer, 2000;36:476-82. 
23 Coleman R, Gnant M, Paterson A, Powles T, von Minckwitz G, Pritchard K, et al. Effects 
of bisphosphonate treatment on recurrence and cause-specific mortality in women with 
early breast cancer: A meta-analysis of individual patient data from randomised trials. 
Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San 
Antonio, TX. Abstract S4-07. 


 
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24 Perez JE, Machiavelli M, Leone BA, Romera A, Rabinovich MG, Vallejo CT, et al. 
Bone-only versus visceral-only metastatic pattern in breast cancer: analysis of 
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1990;13:294-8. 
25 Coleman RE, Smith P, Rubens RD. Clinical course and prognostic factors following bone 
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26 Quattrocchio CC, Piicucchi S, Sammarra M, Santini D, Vincenzi B, Tonini G, et al. Bone 
metastases in breast cancer: higher prevalence of osteoblastic lesions. Radiol Med. 
2007;112:1049-59. 
27 Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Long-term 
efficacy and safety of zoledronic acid compared with pamidronate disodium in the 
treatment of skeletal complications in patients with advanced multiple myeloma or breast 
carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 
2003;98:1735-44. 
28 Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, et al. Efficacy of 
pamidronate in reducing skeletal complications in patients with breast cancer and lytic 
bone metastases: protocol 19 Aredia Breast Cancer Study Group. N Engl J Med. 
1996;335:1785-91. 
29 Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, et al. Zoledronic acid 
versus pamidronate in the treatment of skeletal metastases in patients with breast cancer 
or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. 
Cancer J. 2001;7:377-87. 
30 Theriault RL, Lipton A, Hortobagyi GN, Leff R, Glück S, Stewart JF, et al. Pamidronate 
reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: 
a randomized, placebo-controlled trial-Protocol 18 Aredia Breast Cancer Study Group. J 
Clin Oncol. 1999;17:846-54. 
31 Stopeck A, Lipton A, Body JJ, Steger GG, Tonkin KS, de Boer R, et al. Denosumab 
compared with zoledronic acid for the treatment of bone metastases in patients with 
advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132-9. 
32 Martin M, Bell R, Bourgeois H, Brufsky A, Diel I, Eniu A, et al. Bone-related 
complications and quality of life in advanced breast cancer: results from a randomized 
phase III trial of denosumab versus zoledronic acid. Clin Cancer Res. 2012;18:4841-9. 
33 Wong MHF, Stockler MR, Pavlakis N. Bisphosphonates and other bone agents for breast 
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34 Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE, Biermann JS, et al. 
American Society of Clinical Oncology executive summary of the clinical practice 
guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin 
Oncol. 2011;29(9):1221-7. 


 
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35 Tu SM, Millikan RE, Mengistu B, Delpassand ES, Amato RJ, Pagliaro LC, et al. 
Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a 
randomised phase II trial. Lancet. 2001;357(9253):336-41. Epub 2001/02/24, 
http://dx.doi.org/10.1016/ S0140-6736(00)03639-4). 
36 Morris MJ, Pandit-Taskar N, Carrasquillo J, Divgi CR, Slovin S, Kelly WK, et al. Phase I 
study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic 
prostate cancer. J Clin Oncol. 2009;27(15):2436-42. Epub 2009/04/15, 
http://dx.doi.org/10.1200/ JCO.2008.20.4164. 
37 Nilsson S, Franzen L, Parker C, Tyrrell C, Blom R, Tennvall J, et al. Bone-targeted 
radium-223 in symptomatic, hormone-refractory prostate cancer: a randomized, 
multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587-94. 
38 Henriksen G, Breistol K, Bruland OS, Fodstad O, Larsen RH. Significant antitumor effect 
from bone-seeking, alpha-particle-emitting (223)Ra demonstrated in an experimental 
skeletal metastases model. Cancer Res. 2002;62:3120-5. 
39 Parker C, et al. Updated analysis of the phase III, double-blind, randomized, multinational 
study of radium-223 chloride in castration-resistant prostate cancer (CRPC) patients with 
bone metastases (ALSYMPCA). J Clin Oncol 2012;30(suppl). Abstract LBA4512. 
40 Coleman R, Aksnes A-K, Naume1 B, Garcia C, Jerusalem G, Piccart M, et al. A 
phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer 
patients with bone-dominant disease. Breast Cancer Res Treat. 2014(2);411-8. doi: 
10.1007/s10549-014-2939-1. Epub 2014 Apr 13. 
41 Barrios C, Forbes JF, Jonat W, Conte P, Gradishar W, Buzdar A, et al. The sequential use 
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42 Nabholtz JM, Bonneterre J, Buzdar A, et al. Anastrozole (Arimidex) versus tamoxifen as 
first-line therapy for advanced breast cancer in postmenopausal women: survival analysis 
and updated safety results. Eur J Cancer. 2003;39:1684-9. 
43 Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Phase 
III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in 
postmenopausal women: analysis of survival and update of efficacy from the 
International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21:2101-9. 
44 Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, et al. Phase III study 
comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic 
breast cancer in postmenopausal women: the European Organisation for Research and 
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45 Costa L, Badia X, Chow E, Lipton A, Wardley A. Impact of skeletal complications on 
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46 Weinfurt KP, Castel LD, Li Y, Timbie JW, Glendenning GA, Schulman KA. 
Health-related quality of life among patients with breast cancer receiving zoledronic acid 
orpamidronate disodium for metastatic bone lesions. Med Care. 2004;42:164-75. 
47 Wardley A, Davidson N, Barrett-Lee P, Hong A, Mansi J, Dodwell D, et al. Zoledronic 
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administration. Br J Cancer. 2005;92:1869-76. 
48 Body JJ, Diel IJ, Bell R, Pecherstorfer M, Lichinitser MR, Lazarev AF, et al. Oral 
ibandronate improves bone pain and preserves quality of life in patients with skeletal 
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49 Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane 
Database Syst Rev. 2005 Jul 20;(3):CD003474. 
50 Harris K, Chow E, Zhang L, Velikova G, Bezjak A, Wu J, et al. Patients' and health care 
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Cancer. 2009;45:2510–8. 
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response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45:228-47. 
52 Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation 
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15. Protocol amendments 
In the sections on changes to the protocol text, all protocol sections affected by the respective 
amendment are detailed; the sequence of the sections follows the structure of the most recent 
previous protocol version.  As applicable, changes to the protocol text are highlighted as 
follows: 
 Addition of a whole new portion Brief identification of the new portion 
 Removal of a whole portion Complete display of the removed portion, formatted as 
crossed out 
 Editing of an existing portion Comparative presentation of “Old text” versus “New 
text,” with “Old text” referring to the most recent previous protocol version. Deletions 
are crossed out in the “Old text.”  Additions are underlined in the “New text.” 
 Tables / figures  The term “amended” is added to the caption. 
 Terminological changes  Brief specification of the terminological change 
Correction of typos or omissions and formatting changes are not highlighted. 
Starting with Amendment 8, changes to the protocol text are provided in a separate tracked 
changes document. 
15.1 Amendment 1 
Amendment 1 (dated 16 DEC 2014) is an amendment to the original protocol dated 
13 MAY 2014.  Changes to the protocol include: 
 Clarified the inclusion criterion of menopausal status 
 Changed the requirement for baseline scans to be within 3 weeks prior to 
randomization, not within 6 weeks of randomization 
 Clarified that all prior SRE-related procedures must be administered prior to 
randomization 
 Clarified that subjects who are considered by the treating Investigator to be 
appropriate candidates for treatment with everolimus as current treatment for their 
metastatic breast cancer would be excluded from the study 
 Clarified that SSEs should be recorded until the end of active follow-up regardless of 
whether subjects start new anti-cancer therapies 
 Clarified that permanent discontinuation of study treatment is not required for 
subjects who experience bone or non-bone disease progression unless chemotherapy 
is required 
 Clarified that study treatment is radium-223 dichloride/placebo 
 Changed resolution of gastrointestinal symptoms from Grade 2 to Grade 1, and 
added fatigue as a toxicity requiring resolution prior to administration of the next dose 


 
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 Added plasma collection to biomarker analysis 
 Clarified that the timing of the on-treatment radiological assessments is Cycle 3, Day 
1, Cycle 6, Day 1, and every 12 weeks thereafter until PD (radiological progression) 
is documented 
 Added phosphate to the list of clinical chemistry tests to be evaluated 
 Clarified the timing of blood and urine sample collection for biomarker analysis  
 Corrected the calculation of the BPI-SF items from sums to means 
 Added a requirement that all relevant symptoms related to SSEs be recorded as AEs  
 Replaced the GFR formula with a link to the specific GFR calculator using the 
MDRD study equation 
 Added an exclusion criterion for breastfeeding women 
 Replaced bullets with numbering for the lists of inclusion and exclusion criteria  
 Changed duration of screening period from 2 to 3 weeks to allow more time for 
baseline imaging. 
 Changed the required duration of bisphosphonate treatment from at least 3 months 
prior to start of study treatment to at least 1 month prior to start of study treatment 
 Clarified description of standard of care hormonal treatment background therapy 
 Updated exclusion criteria to exclude only subjects with confirmed visceral 
metastases 
 
15.1.1 Overview of changes to the study 
Modification 1 
Clarified the inclusion criterion of menopausal status based on feedback received from the 
sites. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria 
 
Modification 2 
Changed the requirement for baseline scans to be within 3 weeks prior to randomization not 
within 6 weeks of randomization to ensure the time interval between baseline disease 
assessment and start of treatment is in line with RECIST 1.1 guidelines. 


 
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Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria 
 Table 9-1: Schedule of assessments 
 9.2.1 Screening period (Visits 0 to 1) 
 9.2.6 Radiological assessment: tumor and response evaluation 
 
Modification 3 
Added text that all prior SRE-related procedures must be administered prior to randomization 
for clarification purposes. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria 
 
Modification 4 
Clarified that subjects who are considered by the treating Investigator to be appropriate 
candidates for treatment with everolimus as current treatment for their metastatic breast 
cancer would be excluded from the study based on feedback from the sites. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.2 Exclusion criteria 
 
Modification 5 
Added text that SSEs should be recorded until the end of active follow-up regardless of 
whether subjects start new anti-cancer therapies for clarification purposes. 
Sections affected include: 
 Synopsis: Methods 
 5.1.1 Study periods and duration 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.2 Active follow-up without clinic visits 
 9.2.4.3 End of active follow-up 


 
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Modification 6 
Clarified that permanent discontinuation of study treatment is not required for subjects who 
experience bone or non-bone disease progression unless chemotherapy is required.  This 
change was made at the request of the FDA because subjects may derive clinical benefit from 
continuation of radium-223 treatment. 
Sections affected include: 
 6.3.1.1 Withdrawal from treatment period (collection of follow-up data) 
 
Modification 7 
Clarified that study treatment is radium-223 dichloride/placebo. 
Sections affected include: 
 7.4.5 Dose administration 
 7.4.6 Dose adjustments, delays, and treatment discontinuations 
 9.2.3 Treatment period 
 
Modification 8 
Reduced the maximum CTCAE grade required prior to re-dosing with radium-223 
dichloride/placebo after recovery from diarrhea, nausea, vomiting, and constipation from 
Grade 2 to Grade 1.  Fatigue was also added as a toxicity, which required recovery to 
Grade 1 prior to the next study drug administration.  These changes were made at the 
request of the FDA. 
Sections affected include: 
 7.4.6 Dose adjustments, delays, and treatment discontinuations 
 
Modification 9 
Add plasma to the serum and urine biomarker collection since biomarkers will be assessed 
from plasma in this study. 
Sections affected include: 
 Table 9-1: Schedule of assessments 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.7.2.1 Urine, plasma, and serum based biomarker analysis 


 
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Modification 10 
Clarified that the timing of the on-treatment radiological assessments is Cycle 3, Day 1, 
Cycle 6, Day 1, and every 12 weeks thereafter until PD (radiological progression) is 
documented to ensure consistency. 
Sections affected include: 
 Table 9-1: Schedule of assessments 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 
Modification 11 
Added phosphate to the list of clinical chemistry tests to be evaluated during this study to 
allow a more complete evaluation of Ca2+/Phosphate metabolism as all subjects will receive 
concomitant bisphosphonates or denosumab based on comments received from Italian 
regulatory authorities. 
Sections affected include: 
 Table 9-1: Schedule of assessments 
 9.2.1 Screening period (Visits 0 to 1) 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.2 Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 9.3.3 Other baseline characteristics 
 9.6 Safety 
 
Modification 12 
Clarified for consistency that blood and urine samples will be collected for biomarker 
analysis at Cycle 1, Day 1; Cycle 4, Day 1; and EOT or disease progression, whichever 
occurs first. 
Sections affected include: 
 Table 9-1: Schedule of assessments 
 


 
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Modification 13 
Corrected the calculation of the BPI-SF items from sums to means. 
Sections affected include: 
 9.4.2.2 Secondary efficacy endpoints 
 
Modification 14 
Added a requirement that all relevant symptoms related to SSEs be recorded as AEs.  SSEs 
refer to symptomatic skeletal events and the respective CRF (SSE form) requires the 
investigator to report the symptoms using a dynamic search list.  To be able to select the 
symptoms in the SSEs form, the investigator must have completed an AE form that reports 
the relevant symptom(s).   
Sections affected include: 
 9.6.1.3 Assessments and documentation of adverse events 
 
Modification 15 
Replaced the GFR formula with a link to the specific GFR calculator using the MDRD study 
equation.  The MDRD formula to be used for the calculation of GFR varies depending on the 
method used for serum creatinine assessment (standardized/traceable to isotope dilution mass 
spectrometry method versus non-standardized/non-traceable to isotope dilution mass 
spectrometry method). 
Sections affected include: 
 16.3 Calculation for glomerular filtration rate 
 
Modification 16 
Replaced bullets with numbering for the lists of inclusion and exclusion criteria for 
consistency with the eCRF. 
Sections affected include: 
 Synopsis 
 6.1 Inclusion criteria 
 6.2 Exclusion criteria 
 
Modification 17 
Added an exclusion criterion for breastfeeding women. 


 
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Sections affected include: 
 Synopsis 
 6.2 Exclusion criteria 
 
Modification 18 
Changed duration of screening period from 2 to 3 weeks to allow more time for baseline 
imaging. 
Sections affected include: 
 Synopsis: Methodology 
 5.1.1 Study Periods and Durations 
 6. Study Population 
 Table 9-1 Schedule of Assessments 
 9.2.1 Screening. (Visits 0 to 1) 
 
Modification 19 
Changed the required duration of bisphosphonate treatment from at least 3 months prior to 
start of study treatment to at least 1 month prior to start of study treatment because 1 month is 
sufficient to allow these treatments to have full effect on the bone function. 
Sections affected include: 
 Synopsis 
 6.1 Inclusion Criteria 
 7.1 Treatments to be administered 
 8.1.2 Permitted concomitant therapy 
 
Modification 20 
Clarified description of standard of care hormonal treatment background therapy per 
investigator feedback to allow subject to switch to local standard of treatment, which may 
include exemestane in combination with everolimus or 2 hormonal agents in combination 
(such as aromatase inhibitor and goserelin). 
Sections affected include: 
 Synopsis 
 5.1.1 Study periods and duration 
 8.1.1 Prohibited concomitant therapy 


 
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Modification 21 
Updated exclusion criteria to exclude only subjects with confirmed visceral metastases per 
investigator feedback to clarify that subjects with small nodules not yet characterized and that 
are not considered to have confirmed visceral disease are not excluded 
Sections affected include: 
 Synopsis 
 6.2 Exclusion criteria 
 
Modification 22 
Updated criteria for when estradiol assay must be conducted for consistency within the 
protocol. 
Sections affected include: 
 9.1 Tabular schedule of evaluations  
 9.2.1 Screening period (Visits 0 to 1) 
 
15.1.2 Changes to the protocol text 
Changes to the protocol text are highlighted as specified at the beginning of Section 15. 
 
Synopsis: Diagnosis and main criteria for inclusion and exclusion  
This section was changed as a result of Modifications 1 and 2. Note that for all inclusion 
criteria listed in the synopsis, the bulleted list has been replaced with numbering as a result of 
Modification 16. 
Old text: 
 Tumors (from either primary or metastatic sites) must be ER+ defined as ≥10% 
positive tumor nuclei in the analyzed sample.  ER+/ progesterone positive (PR+), 
ER+/ progesterone receptor negative (PR-) subjects are eligible whereas estrogen 
receptor negative (ER-)/PR+ and ER-/PR- disease will not be eligible. 
 Documentation of menopausal status: post-menopausal or pre-menopausal subjects 
are eligible. 
 
Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone 
(LH-RH) agonist/antagonist is permitted for induction of ovarian suppression. 
o Pre-menopausal subjects as well as subjects with ovarian radiation or 
concomitant treatment with an LH-RH agonist/antagonist must have a 


 
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negative pregnancy test and agree to use an adequate method of 
contraception as recommended by their treating physicians 
 Measurable or non-measurable disease (but radiologically evaluable) according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.  All disease 
burden must be assessed at baseline by CT or MRI of chest, pelvis, and abdomen and 
any additional fields as needed.  A bone scan should also be done at baseline for all 
subjects. 
 
CT/MRI done as part of the standard of practice within 6 weeks of randomization and 
standard of care bone scans done within 6 weeks of randomization are acceptable. 
 
18F-sodium fluoride positron emission tomography/CT scan is acceptable as an 
alternative to technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout the study. 
New text: 
2. Tumors (from either primary or metastatic sites) must be ER+ defined as ≥10% 
positive tumor nuclei in the analyzed sample.  ER+/ progesterone receptor positive 
(PR+), ER+/ progesterone receptor negative (PR-) subjects are eligible whereas 
estrogen receptor negative (ER-)/PR+ and ER-/PR- disease will not be eligible. 
5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects are 
eligible. 
 
Note: In premenopausal subjects, ovarian radiation or treatment with a luteinizing 
hormone-releasing hormone (LH-RH) agonist/antagonist is permitted for induction of 
ovarian suppression.  Baseline estradiol assay must be <20 pg/mL at screening.  
6. Pre-menopausal subjects with or without ovarian radiation or concomitant treatment 
with an LH-RH agonist/antagonist must have a negative pregnancy test at screening 
and agree to use an adequate method of contraception as recommended by their 
treating physicians 
7. Measurable or non-measurable disease (but radiologically evaluable) according to 
Response Evaluation Criteria in Solid Tumors v1.1 criteria.  All disease burden must 
be assessed at baseline by CT or MRI of chest, pelvis and abdomen and any additional 
fields as needed.  A bone scan should also be done at baseline for all subjects.  
18F-sodium fluoride positron emission tomography/CT scan is acceptable as an 
alternative to technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout the study. 


 
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Synopsis: Diagnosis and main criteria for inclusion and exclusion 
This section was changed as a result of Modifications 3 and 19. 
Old text: 
 Subjects must have experienced no more than 2 skeletal-related events (SREs) prior to 
study entry defined as: external beam radiotherapy (EBRT) for bone pain, 
pathological bone fracture (excluding major trauma), spinal cord compression, and/or 
orthopedic surgical procedure.  Subjects with no prior SREs are not permitted.  
 
Note: For the purpose of counting prior SREs, any procedure which is related to an 
SRE, such as orthopedic surgery to treat a pathological bone fracture should not be 
counted as a separate event. 
 Subjects must be on therapy with bisphosphonate or denosumab and are required to 
have been on such therapy for at least 3 months before the start of study treatment. 
New text: 
10. Subjects must have experienced no more than 2 skeletal-related events (SREs) prior to 
study entry defined as: external beam radiotherapy (EBRT) for bone pain, pathological 
bone fracture (excluding major trauma), spinal cord compression, and/or orthopedic 
surgical procedure.  Subjects with no prior SREs are not permitted.  
 
Note: For the purpose of counting prior SREs, any procedure which is related to an SRE, 
such as orthopedic surgery to treat a pathological bone fracture, should not be counted 
as a separate event.  All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) 
must be administered prior to randomization. 
11. Subjects must be on therapy with bisphosphonate or denosumab and are required to have 
been on such therapy for at least 1 month before the start of study treatment. 
 
Synopsis: Diagnosis and main criteria for inclusion and exclusion 
This section was changed as a result of Modifications 4, 17, and 21.  Note that for all 
exclusion criteria, the bulleted list has been replaced with numbering as a result of 
Modification 16. 
Old text: 
 Subjects eligible for treatment with everolimus 
 History and/or presence of visceral metastases 
 
New text: 
2. Subjects considered by the treating physician to be appropriate candidates for treatment 
with everolimus as current treatment for their metastatic breast cancer 


 
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4. History and/or presence of confirmed visceral metastases 
19. Breastfeeding women 
 
Synopsis: Methodology 
This section was changed as a result of Modification 18. 
Old text: 
Screening period:  
All trial related procedures and evaluations will only be performed after the subject has 
agreed to participate and has signed the informed consent form.  The screening period will 
consist of multiple evaluations that will take place within 2 weeks prior to randomization to 
ensure that all eligibility criteria are met. 
New text: 
Screening period:  
All trial related procedures and evaluations will only be performed after the subject has 
agreed to participate and has signed the informed consent form.  The screening period will 
consist of multiple evaluations that will take place within 3 weeks prior to randomization to 
ensure that all eligibility criteria are met. 
 
Synopsis: Methodology 
This section was changed as a result of Modifications 5 and 20. 
Old text: 
All subjects will continue to receive standard of care hormonal treatment background 
therapy.  Hormonal treatment may also be changed according to the local standard of practice 
however, only single agent hormonal treatment will be allowed.  For the purpose of this 
study, only a new hormonal treatment initiated due to disease progression will be considered 
a new anti-cancer therapy. 
If radium-223 dichloride/placebo treatment is still ongoing but the hormonal treatment is no 
longer considered a treatment option and the subject must start cytotoxic treatment or 
treatment with everolimus, the subject will terminate radium-223 dichloride/placebo 
treatment.  Subjects will continue to be followed up for SSEs and radiological progression.   
New text: 
All subjects will continue to receive standard of care hormonal treatment background 
therapy.  Hormonal treatment may also be changed according to the local standard of 
practice, including exemestane in combination with everolimus.  For the purpose of this 
study, only a new hormonal treatment initiated due to disease progression will be considered 
a new anti-cancer therapy. 


 
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If radium-223 dichloride/placebo treatment is still ongoing but the hormonal treatment is no 
longer considered a treatment option and the subject must start cytotoxic treatment, the 
subject will terminate radium-223 dichloride/placebo treatment.  Subjects will continue to be 
followed up for SSEs and radiological progression.  Symptomatic skeletal events should be 
recorded until end of active follow-up, independent of whether patient starts a new anticancer 
therapy (i.e. chemotherapy, other). 
Added text: 
 Subjects who miss 2 consecutive follow-up visits will be considered unable to travel 
to the site and will enter the active follow-up without clinic visits. Symptomatic 
skeletal events should be recorded until end of active follow-up, independent of 
whether patient starts a new anticancer therapy (i.e. chemotherapy, other). 
Added text: 
 For subjects who experienced an SSE during treatment or the previous follow-up 
period, the frequency of the phone calls will be every 12 weeks ±7 days.  
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether patient starts a new anticancer therapy (i.e. chemotherapy, 
other). 
 
Section 5.1.1 Study periods and duration 
This section was changed as a result of Modifications 5, 18, and 20. 
Added text (in 3 locations): 
Symptomatic skeletal events should be recorded until end of active follow-up, independent of 
whether the subject starts a new anti-cancer therapy (i.e., chemotherapy, other). 
Old text: 
All trial related procedures and evaluations will only be performed after the subject has 
agreed to participate and has signed the informed consent form (ICF).  The screening period 
will consist of multiple evaluations that will take place within 2 weeks prior to randomization 
to ensure that all eligibility criteria are met (Section 6). 
New text: 
All trial related procedures and evaluations will only be performed after the subject has 
agreed to participate and has signed the informed consent form (ICF).  The screening period 
will consist of multiple evaluations that will take place within 3 weeks prior to randomization 
to ensure that all eligibility criteria are met (Section 6). 
Old text: 
All subjects will continue to receive standard of care hormonal treatment background 
therapy.  Hormonal treatment may also be changed according to the local standard of practice 
however, only single agent hormonal treatment will be allowed.  For the purpose of this 


 
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study, only a new hormonal treatment initiated due to disease progression will be considered 
a new anti-cancer therapy. 
Radium-223 dichloride/placebo administration should be discontinued as per the withdrawal 
criteria described in Section 6.3.1 (e.g., subject experiences unacceptable toxicities, delays in 
radium-223 dichloride/placebo >4 weeks, subject enters the active follow-up without clinic 
visits as she can no longer travel to the clinical site, and if in the Investigator’s opinion, 
continuation of the study treatment would be harmful to the subject’s well-being). 
If radium-223 dichloride/placebo treatment is still ongoing but the hormonal treatment is no 
longer considered a treatment option and the subject must start cytotoxic treatment or 
treatment with everolimus, the subject will terminate radium-223 dichloride/placebo 
treatment.  Subjects will continue to be followed up for SSEs and radiological progression. 
New text: 
All subjects will continue to receive standard of care hormonal treatment background 
therapy.  Hormonal treatment may also be changed according to the local standard of 
practice, including exemestane in combination with everolimus.  For the purpose of this 
study, only a new hormonal treatment initiated due to disease progression will be considered 
a new anti-cancer therapy. 
Radium-223 dichloride/placebo administration should be discontinued as per the withdrawal 
criteria described in Section 6.3.1 (e.g., subject experiences unacceptable toxicities, delays in 
radium-223 dichloride/placebo >4 weeks, subject enters the active follow-up without clinic 
visits as she can no longer travel to the clinical site, and if in the Investigator’s opinion, 
continuation of the study treatment would be harmful to the subject’s well-being). 
If radium-223 dichloride/placebo treatment is still ongoing but the hormonal treatment is no 
longer considered a treatment option and the subject must start cytotoxic treatment, the 
subject will terminate radium-223 dichloride/placebo treatment.  Subjects will continue to be 
followed up for SSEs and radiological progression.  
 
Section 6. Population Study 
This section was changed as a result of Modification 18. 
Old text: 
o Subjects who underwent screening procedures (i.e., scans and laboratory work) that 
expired (are outside of the 14-day window) may need the screening procedures to be 
repeated in order to be within the window required prior to randomization. 
New text: 
o Subjects who underwent screening procedures (i.e., scans and laboratory work) that 
expired (are outside of the 21-day window) may need the screening procedures to be 
repeated in order to be within the window required prior to randomization 
 


 
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Section 6.1 Inclusion criteria 
This section was changed as a result of Modifications 1, 2, 3, and 19.  Note that for all 
inclusion criteria listed in Section 6.1, the bulleted list has been replaced with numbering as a 
result of Modification 16. 
Old text: 
o Documentation of menopausal status: post-menopausal or pre-menopausal subjects are 
eligible. 
 
Note: Ovarian radiation or treatment with an LH-RH agonist/antagonist is permitted for 
induction of ovarian suppression. 
o Pre-menopausal subjects as well as subjects with ovarian radiation or 
concomitant treatment with an LH-RH agonist/antagonist must have a 
negative pregnancy test and agree to use an adequate method of 
contraception as recommended by their treating physicians 
o Measurable or non-measurable disease (but radiologically evaluable) according to 
Response Evaluation Criteria in Solid Tumors v1.1 criteria.  All disease burden must be 
assessed at baseline by CT or MRI of chest, pelvis, and abdomen and any additional 
fields as needed.  A bone scan should also be done at baseline for all subjects. 
CT/MRI done as part of the standard of practice within 6 weeks of randomization and 
standard of care bone scans done within 6 weeks of randomization are acceptable. 
18F-sodium fluoride positron emission tomography/CT scan is acceptable as an alternative 
to technetium-99m bone scintigraphy if it is the standard of care at the institution, 
provided the same bone imaging modality is used throughout the study. 
o Subjects must have experienced no more than 2 SSEs prior to study entry defined as: 
EBRT for bone pain, pathological bone fracture (excluding major trauma), spinal cord 
compression, and/or orthopedic surgical procedure.  Subjects with no prior SREs are not 
permitted.  
Note: For the purpose of counting prior SREs any procedure which is related to an SRE, 
such as orthopedic surgery to treat a pathological bone fracture should not be counted as 
a separate event. 
o Subjects must be on therapy with bisphosphonate or denosumab and are required to have 
been on such therapy for at least 3 months before the start of study treatment. 
New text: 
5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects are 
eligible. 
 
Note: In premenopausal subjects, ovarian radiation or treatment with an LH-RH 
agonist/antagonist is permitted for induction of ovarian suppression.  Baseline estradiol 
assay must be <20 pg/mL at screening.  


 
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6. Pre-menopausal subjects with or without ovarian radiation or concomitant treatment with 
an LH-RH agonist/antagonist must have a negative pregnancy test at screening and agree 
to use an adequate method of contraception as recommended by their treating physicians 
(please refer to Section 8.1.2) 
7. Measurable or non-measurable disease (but radiologically evaluable) according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.  All disease burden 
must be assessed at baseline by CT or MRI of chest, pelvis and abdomen and any 
additional fields as needed.  A bone scan should also be done at baseline for all subjects. 
CT/MRI done as part of the standard of practice within 3 weeks prior to randomization and 
standard of care bone scans done within 3 weeks prior to randomization are acceptable.  
18F-sodium fluoride positron emission tomography (PET)/CT scan is acceptable as an 
alternative to technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout the study. 
10. Subjects must have experienced no more than 2 SREs prior to study entry defined as: 
EBRT for bone pain, pathological bone fracture (excluding major trauma), spinal cord 
compression, and/or orthopedic surgical procedure.  Subjects with no prior SREs are not 
permitted.  
Note: For the purpose of counting prior SREs, any procedure which is related to an SRE, 
such as orthopedic surgery to treat a pathological bone fracture, should not be counted 
as a separate event.  All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) 
must be administered prior to randomization. 
11. Subjects must be on therapy with bisphosphonate or denosumab and are required to have 
been on such therapy for at least 1 month before the start of study treatment. 
 
Section 6.2 Exclusion criteria 
This section was changed as a result of Modifications 4 and 21.  Note that for all exclusion 
criteria listed in Section 6.2 the bulleted list has been replaced with numbering as a result of 
Modification 16. 
Old text: 
Subjects eligible for treatment with everolimus 
History and/or presence of visceral metastases 
New text: 
2. Subjects considered by the treating physician to be appropriate candidates for treatment 
with everolimus as current treatment for their metastatic breast cancer 
4. History and/or presence of confirmed visceral metastases 
 


 
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Section 6.3.1.1 Withdrawal from treatment period (collection of follow-up data) 
This section was changed as a result of Modification 6. 
Added text: 
Subjects who experience disease progression (bone or non-bone) may continue to receive 
radium-223 dichloride (or placebo) until completion if the Investigator feels the subject will 
receive clinical benefit.  These subjects may continue to receive additional hormonal 
treatments according to the local standard of care.  If, however, chemotherapy is required as 
the next line of treatment, study treatment will be permanently discontinued, as concurrent 
chemotherapy administration is an exclusion criterion. 
 
Section 7.1 Treatments to be administered 
This section was changed as a result of Modification 19. 
Old text: 
• Bone-targeted agents: bisphosphonates or denosumab: Eligible subjects are required to be 
on therapy with bisphosphonates or denosumab at time of study entry (for at least 3 
months prior to the start of investigational study treatment, radium-223 
dichloride/placebo).  
New text: 
• Bone-targeted agents: bisphosphonates or denosumab: Eligible subjects are required to be 
on therapy with bisphosphonates or denosumab at time of study entry (for at least 1 month 
prior to the start of investigational study treatment, radium-223 dichloride/placebo). 
 
Section 7.4.5 Dose administration 
This section was changed as a result of Modification 7. 
Old text: 
Every effort will be made to administer the full dosing regimen.  Single dose level adjustment 
of radium-223 dichloride is not permitted.  Treatment delays or discontinuations of radium-
223 dichloride may be instituted for the AEs described in Section 7.4.6 and dose adjustments, 
treatment delays, or discontinuations of hormonal treatment may be instituted according to 
the local label and standard of practice. 
New text: 
Every effort will be made to administer the full dosing regimen.  Single dose level adjustment 
of radium-223 dichloride/placebo is not permitted.  Treatment delays or discontinuations of 
radium-223 dichloride/placebo may be instituted for the AEs described in Section 7.4.6 and 
dose adjustments, treatment delays, or discontinuations of hormonal treatment may be 
instituted according to the local label and standard of practice. 
 


 
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Section 7.4.6 Dose adjustments, delays, and treatment discontinuations 
This section was changed as a result of Modifications 7 and 8. 
Old text: 
If a subject experiences CTCAE Grade 3 to 4 anemia, neutropenia, or thrombocytopenia 
lasting >2 weeks in spite of adequate treatment, the subject must be discontinued from 
treatment with radium-223 dichloride. 
 
Diarrhea: No prophylactic treatment for diarrhea is recommended.  Anti-diarrheals can be 
used when needed.  A further dose of study medication should not be given before diarrhea 
has recovered to CTCAE Grade ≤2. 
Nausea/Vomiting: No prophylactic treatments for nausea or vomiting are recommended, but 
anti-emetic drugs can be used when needed.  A further dose of study medication should not 
be given before nausea/vomiting has recovered to CTCAE Grade ≤2. 
Constipation: Subjects can continue laxative as concomitant medication, but start of 
prophylactic treatments before study drug injection are not recommended.  Laxative can be 
used when needed.  A further dose of study medication should not be given before 
constipation has recovered to CTCAE Grade ≤2. 
 
If radium-223 dichloride treatment is still ongoing but standard of care hormonal treatment is 
no longer considered an option, and the subject must start cytotoxic therapy, the subject will 
terminate radium-223 dichloride or placebo treatment.  Subjects will then enter the follow-up 
period and will continue to be followed for SSEs and radiological progression. 
New text: 
If a subject experiences CTCAE Grade 3 to 4 anemia, neutropenia, or thrombocytopenia 
lasting >2 weeks in spite of adequate treatment, the subject must be discontinued from 
treatment with radium-223 dichloride/placebo. 
 
Diarrhea: No prophylactic treatment for diarrhea is recommended.  Anti-diarrheals can be 
used when needed.  A further dose of study medication should not be given before diarrhea 
has recovered to CTCAE Grade ≤1. 
Nausea/Vomiting: No prophylactic treatments for nausea or vomiting are recommended, but 
anti-emetic drugs can be used when needed.  A further dose of study medication should not 
be given before nausea/vomiting has recovered to CTCAE Grade ≤1. 
Constipation: Subjects can continue laxative as concomitant medication, but start of 
prophylactic treatments before study drug injection is not recommended.  Laxative can be 
used when needed.  A further dose of study medication should not be given before 
constipation has recovered to CTCAE Grade ≤1. 


 
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Fatigue 
In cases of NCI-CTCAE Grade 3 to 4 fatigue, study drug administration should be delayed 
until recovery to Grade ≤1 before the next study drug administration. 
 
If radium-223 dichloride/placebo treatment is still ongoing but standard of care hormonal 
treatment is no longer considered an option, and the subject must start cytotoxic therapy, the 
subject will terminate radium-223 dichloride or placebo treatment.  Subjects will then enter 
the follow-up period and will continue to be followed for SSEs and radiological progression. 
 
Section 8.1.1 Prohibited concomitant therapy 
This section was changed as a result of Modification 20. 
Old text: 
Concomitant therapy during the treatment phase of the study with any of the following listed 
is prohibited: 
 Chemotherapy 
 Radiopharmaceuticals, such as strontium-89, samarium-153, rhenium-186, or 
rhenium-188 
 Everolimus 
 Hemibody external radiotherapy  
 Other investigational drugs 
 Combination hormonal treatment 
 All medications that are prohibited as per the local label instructions for the 
background hormonal treatment.  It is the site’s responsibility to ensure that hormonal 
background treatment is administered in line with standard practice and local label 
instructions.  The same applies for bisphosphonates and denosumab. 
New text: 
Concomitant therapy during the treatment phase of the study with any of the following listed 
is prohibited: 
 Chemotherapy 
 Radiopharmaceuticals, such as strontium-89, samarium-153, rhenium-186, or 
rhenium-188 
 Hemibody external radiotherapy  
 Other investigational drugs 
 All medications that are prohibited as per the local label instructions for the 
background hormonal treatment.  It is the site’s responsibility to ensure that hormonal 


 
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background treatment is administered in line with standard practice and local label 
instructions.  The same applies for bisphosphonates and denosumab. 
 
Section 8.1.2 Permitted concomitant therapy 
This section was changed as a result of Modification 19. 
Old text: 
• All subjects are expected to have been on therapy with either denosumab or 
bisphosphonates for at least 3 months before the start of study treatment and to continue on 
this therapy during the course of the study, with no change to therapy expected during the 
treatment phase of the study, except for toxicity reasons. 
New text: 
• All subjects are expected to have been on therapy with either denosumab or 
bisphosphonates for at least 1 month before the start of study treatment and to continue on 
this therapy during the course of the study, with no change to therapy expected during the 
treatment phase of the study, except for toxicity reasons. 
 
 


 
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Table 9-1:  Schedule of assessments 
This section was changed as a result of Modifications 2, 9, 10, and 18. 
Old text: 
Table 9-1:  Schedule of assessments (continued) 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
2 wk pre-
random. 
1 to 3 wk 
pre-Dose 1 
C1, Day 1 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 wk 
until 
SSE; 
q12 wk 
after 
SSEf 
q4 wk 
until SSE; 
q12 wk 
after 
SSEg 
 
 
Window (days): 
 
 
±7 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
±7 
±7 
±7 
Serum and urine biomarkersz 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Technetium-99m bone scanaa 
 
 
 
 
 
 
Xaa 
 
 
 
 
 
 
 
 
 
Chest, abdominal and pelvic 
CT scanaa,cc,d 
 
 
 
 
 
 
Xaa 
 
 
 
 
 
 
 
 
 
Progression 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
SSEs  
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Drug orderff 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
Radium-223 Cl2 or placebo 
injectiongg 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xj 
X 
Xj 
Drug accountability 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 


 
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New text: 
Table 9-1:  Schedule of assessments (continued) 
Study Period 
Screeninga 
Randomization 
Treatmentb, c 
 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random. 
1 to 3 wk 
pre-Dose 1 
C1, Day 1 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 wk 
until 
SSE; 
q12 wk 
after 
SSEf 
q4 wk 
until SSE; 
q12 wk 
after 
SSEg 
 
 
Window (days): 
 
 
±7 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
±7 
±7 
±7 
Serum, plasma, and urine 
biomarkersz 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
Technetium-99m bone scanaa 
Xbb 
 
 
 
 
 
 
Xaa 
 
 
Xaa 
Xaa 
Xaa 
 
Xaa 
 
Chest, abdominal and pelvic 
CT scanaa, cc, dd 
X 
 
 
 
 
 
 
 
Xaa 
 
Xaa 
Xaa 
Xaa 
 
Xaa 
 
Progression 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
SSEs  
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Drug orderee 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
Radium-223 Cl2 or placebo 
injectionff 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Xj 
X 
Xj 
Drug accountability 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
 


 
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Table 9-1:  Schedule of assessments 
This section was changed as a result of Modifications 2, 9 to 12, and 22. 
Old text: 
a. 
All screening evaluations must be complete and reviewed prior to randomization.  Screening evaluations 
must be complete within 2 weeks prior to randomization.  If all screening data are available and the subject 
is eligible for the study, randomization may occur at the end of the screening visit.   
v. Sodium, potassium, chloride, calcium, aspartate aminotransferase, alanine aminotransferase, lactate 
dehydrogenase, bone alkaline phosphatase, serum creatinine, blood urea nitrogen, bilirubin (total), total 
cholesterol, and albumin.   
y. Pre-menopausal women must have a negative serum pregnancy test performed within 7 days prior to 
randomization, prior to each study drug administration, and EOT.  Post-menopausal women (as defined in 
Section 6.1) are not required to undergo a pregnancy test.  An estradiol assay is required within 7 days prior 
to randomization in pre-menopausal women with radiotherapy ovarian ablation or medical ovarian 
suppression and post-menopausal women age <55 years and one year or more of amenorrhea and no 
ovarian suppression. 
z. 
Blood and/or urine sample for exploratory evaluation of biomarkers, prior to radium-223 dichloride or 
placebo administration.  Serum samples will be collected at Cycle 1, Day 1; Cycle 4, Day 1; and EOT.  
Urine samples will be collected at Cycle, Day 1; Cycle 4, Day 1; and EOT visits (or at the time of disease 
progression, whichever occurs earlier). 
aa. Scans to be scheduled for Cycle 3, Day 1; EOT; and then every 12 weeks during the active follow-up 
periods.  Scans will be read locally.  The time window for the scans is ±7 days. 
bb. A historic bone scan is acceptable if taken within 6 weeks of randomization.  If one is not available, it will 
be required as part of the protocol procedures within the screening period.  18F-sodium fluoride positron 
emission tomography/CT scan is acceptable as an alternative to technetium-99m bone scintigraphy if it is 
the standard of care at the institution, provided the same bone imaging modality is used throughout the 
study. 
ee. A historic chest/abdominal/pelvic CT is acceptable if taken within 6 weeks of randomization.  If not 
available, a scan is required as part of the protocol within the screening period. 
 
New text: 
a. 
 All screening evaluations must be complete and reviewed prior to randomization.  Screening evaluations 
must be complete within 3 weeks prior to randomization.  If all screening data are available and the subject 
is eligible for the study, randomization may occur at the end of the screening visit.   
v. Sodium, potassium, chloride, calcium, aspartate aminotransferase, alanine aminotransferase, lactate 
dehydrogenase, bone alkaline phosphatase, serum creatinine, phosphate, blood urea nitrogen, bilirubin 
(total), total cholesterol, and albumin.  
y. Pre-menopausal women must have a negative serum pregnancy test performed within 7 days prior to 
randomization, prior to each study drug administration, and EOT.  Post-menopausal women (as defined in 
Section 6.1) are not required to undergo a pregnancy test.  An estradiol assay is required within 7 days prior 
to randomization in pre-menopausal women with radiotherapy ovarian ablation or medical ovarian 
suppression and post-menopausal women age <55 years and one year or more of amenorrhea. 
z. Blood and/or urine sample for exploratory evaluation of biomarkers, prior to radium-223 dichloride or 
placebo administration.  Serum and plasma samples will be collected at Cycle 1, Day 1; Cycle 4, Day 1; and 
EOT or disease progression, whichever occurs first.  Urine samples will be collected at Cycle 1, Day 1; 
Cycle 4, Day 1; and EOT visits (or at the time of disease progression, whichever occurs earlier). 


 
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aa. Radiological tumor evaluation must be performed 8 weeks (±7 days) after the first radium-223 
dichloride/placebo administration and every 12 weeks thereafter until PD (radiological progression) is 
documented. If radiologic soft tissue or visceral progression in absence of bone progression (according to 
mRECIST 1.1 criteria) is observed, bone imaging and MRI/CT scan of the chest, abdomen, and pelvis 
should continue to allow assessment of bone-specific rPFS.  This schedule is to be maintained and will not 
be shifted because of treatment interruptions/delays.  Scans will be read locally. The time window for the 
scans is ±7 days. 
bb. A historic bone scan is acceptable if taken within 3 weeks of randomization.  If one is not available, it will 
be required as part of the protocol procedures within the screening period.   18F-sodium fluoride positron 
emission tomography/CT scan is acceptable as an alternative to technetium-99m bone scintigraphy if it is the 
standard of care at the institution, provided the same bone imaging modality is used throughout the study. 
ee. A historic chest/abdominal/pelvic CT is acceptable if taken within 3 weeks of randomization.  If not 
available, a scan is required as part of the protocol within the screening period. 
 
Section 9.2.1 Screening period (Visits 0 to 1) 
This section was changed as a result of Modifications 2, 11, 18, and 22. 
Old text: 
The screening period lasts from date of signature of informed consent until the date of subject 
randomization in IXRS.  The screening period duration is 2 weeks. 
 
Standard of care imaging, such as CT/MRI, as well as routine bone scans performed within 
6 weeks prior to randomization will be accepted as baseline imaging if they meet protocol 
requirements (anatomic coverage, image acquisition as per RECIST 1.1 guidelines for 
CT/MRI scans).  Pre-treatment evaluations will be performed according to the eligibility 
criteria.  If the subject is eligible for the study, the parameters at the screening visit showing 
subject health status including blood values will be recorded in the eCRF. 
The following procedures and evaluations will be performed within 2 weeks prior to planned 
randomization unless otherwise specified: 
 Radiological tumor assessment 
o A chest/abdominal/pelvic CT or MRI.  This is not needed if standard of care 
chest/abdominal/pelvic CT or MRI images taken within 6 weeks prior to 
randomization are available. 
o A bone technetium-99m scan with careful identification of all disease-related hotspots.  
This is not needed if standard of care bone scan performed within 6 weeks prior to 
planned randomization date is available and in line with protocol requirements.  
Confirmatory scan using single photon emission tomography (SPECT)-CT/MRI or 
CT/MRI (with and without contrast media) should be obtained if not performed within 
6 weeks of randomization.  The field of acquisition should include all areas where 
bone lesions are present. 
 
18F-sodium fluoride PET/CT scan is acceptable as an alternative to technetium-99m 


 
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bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
 
CT/MRI done as part of the standard of practice and standard of care bone scans done 
within 6 weeks of randomization are acceptable. 
The following procedures and evaluations should be performed within 1 week prior to 
randomization.  Results must be available, reviewed, and signed and dated by the Investigator 
prior to randomization. 
o Blood draw for clinical chemistry: sodium (Na), potassium (K), chloride (Cl), calcium 
(Ca), ALT, AST, lactate dehydrogenase (LDH), bone ALP, serum creatinine, blood urea 
nitrogen (BUN), total bilirubin, total cholesterol, and albumin. 
o Estradiol assay: an estradiol assay is required within 7 days prior to randomization in pre-
menopausal women with radiotherapy ovarian ablation or medical ovarian suppression 
and post-menopausal women age <55 years and one year or more of amenorrhea and no 
ovarian suppression. 
 
New text: 
The screening period lasts from date of signature of informed consent until the date of subject 
randomization in IXRS.  The screening period duration is 3 weeks. 
Standard of care imaging, such as CT/MRI, as well as routine bone scans performed within 
3 weeks prior to randomization will be accepted as baseline imaging if they meet protocol 
requirements (anatomic coverage, image acquisition as per RECIST 1.1 guidelines for 
CT/MRI scans).  Pre-treatment evaluations will be performed according to the eligibility 
criteria.  If the subject is eligible for the study, the parameters at the screening visit showing 
subject health status including blood values will be recorded in the eCRF. 
The following procedures and evaluations will be performed within 3 weeks prior to planned 
randomization unless otherwise specified: 
o Radiological tumor assessment 
o A chest/abdominal/pelvic CT or MRI.  This is not needed if standard of care 
chest/abdominal/pelvic CT or MRI images taken within 3 weeks prior to 
randomization are available. 
o A bone technetium-99m scan with careful identification of all disease-
related hotspots.  This is not needed if standard of care bone scan 
performed within 3 weeks prior to planned randomization date is available 
and in line with protocol requirements.  Confirmatory scan using single 
photon emission tomography (SPECT)-CT/MRI or CT/MRI (with and 
without contrast media) should be obtained if not performed within 3 
weeks prior to randomization.  The field of acquisition should include all 
areas where bone lesions are present. 
 


 
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18F-sodium fluoride PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
 
CT/MRI done as part of the standard of practice and standard of care bone scans done 
within 3 weeks prior to randomization are acceptable 
The following procedures and evaluations should be performed within 1 week prior to 
randomization.  Results must be available, reviewed, and signed and dated by the Investigator 
prior to randomization. 
o Blood draw for clinical chemistry: sodium (Na), potassium (K), chloride (Cl), calcium 
(Ca), ALT, AST, lactate dehydrogenase (LDH), bone ALP, serum creatinine, phosphate, 
blood urea nitrogen (BUN), total bilirubin, total cholesterol, and albumin. 
o Estradiol assay: an estradiol assay is required within 7 days prior to randomization in pre-
menopausal women with radiotherapy ovarian ablation or medical ovarian suppression 
and post-menopausal women age <55 years and one year or more of amenorrhea. 
 
Section 9.2.3 Treatment period 
This section was changed as a result of Modification 7. 
Old text: 
Before administration of radium-223 dichloride, the subject must be well hydrated; thus, the 
subject should be instructed to drink ad libitum. 
Before the first administration of radium-223 dichloride (within 3 days), the ANC should be 
≥1.5 x 109/L, the platelet count ≥100 x 109/L, and Hb ≥9 g/dL. 
New text: 
Before administration of radium-223 dichloride/placebo, the subject must be well hydrated; 
thus, the subject should be instructed to drink ad libitum. 
Before the first administration of radium-223 dichloride/placebo (within 3 days), the ANC 
should be ≥1.5 x 109/L, the platelet count ≥100 x 109/L, and Hb ≥9 g/dL. 
 
Section 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each 
visit) 
This section was changed as a result of Modifications 9 to 11. 
Old text: 
o Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, serum 
creatinine, BUN, bilirubin (total), total cholesterol, and albumin (blood sample for 
clinical chemistry must be taken within 72 hours prior to each study drug administration).  


 
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o Blood draw and urine sample for exploratory biomarker analysis: Serum and urine 
samples will be collected at Visit 2 (Cycle 1, Day 1) and Visit 8 (Cycle 4, Day 1). 
o 
At Visit 6 (Cycle 3, Day 1) only: 
 
New text: 
o Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, serum 
creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin (blood sample 
for clinical chemistry must be taken within 72 hours prior to each study drug 
administration).   
 
o Blood draw and urine sample for exploratory biomarker analysis: Serum, plasma, and 
urine samples will be collected at Visit 2 (Cycle 1, Day 1) and Visit 8 (Cycle 4, Day 1). 
o 
At Visit 6 and Visit 10 (Cycle 3, Day 1 and Cycle 6, Day 1) only (see also 
Section 9.2.6): 
 
Added text: 
o Spinal cord compression 
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether the subject starts a new anti-cancer therapy (i.e., 
chemotherapy, other). 
 
Section 9.2.3.2 Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
This section was changed as a result of Modification 11. 
Old text: 
o Blood draw for clinical chemistry is only required at Visit 3 (Cycle 1, Day 15) and Visit 5 
(Cycle 2, Day 15): Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, serum creatinine, BUN, 
bilirubin (total), total cholesterol, and albumin. 
New text: 
o Blood draw for clinical chemistry is only required at Visit 3 (Cycle 1, Day 15) and Visit 5 
(Cycle 2, Day 15): Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, serum creatinine, 
phosphate, BUN, bilirubin (total), total cholesterol, and albumin. 
 


 
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Section 9.2.3.3 End of treatment visit, Section 9.2.4.1 Active follow-up with clinic visits, 
Section 9.2.4.3 End of active follow-up 
This section was changed as a result of Modification 11. 
Old text: 
o Blood draws for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, serum 
creatinine, BUN, bilirubin (total), total cholesterol, and albumin. 
New text: 
o Blood draws for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, serum 
creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin. 
 
Section 9.2.3.3 End of treatment visit 
This section was changed as a result of Modification 9. 
Old text: 
o Blood draw and urine sample for exploratory biomarker analysis (serum and urine 
samples will be collected at the EOT or at the time of disease progression, whichever 
occurs earlier) 
New text: 
o Blood draw and urine sample for exploratory biomarker analysis (serum, plasma, and 
urine samples will be collected at the EOT or at the time of disease progression, 
whichever occurs earlier) 
 
Section 9.2.3.3 End of treatment visit, Section 9.2.4.1 Active follow-up with clinic visits, 
Section 9.2.4.2 Active follow-up without clinic visits, Section 9.2.4.3 End of active 
follow-up 
This section was changed as a result of Modification 5. 
Added text: 
o Record SSEs 
Symptomatic skeletal events should be recorded until end of active follow-up, 
independent of whether the subject starts a new anti-cancer therapy (i.e., chemotherapy, 
other). 
 
o All AEs and SAEs occurring during this period must be documented and reported if 
considered to be related to study medication or study-related procedures. Note: 
Specifically for this study, relevant symptoms related to an SSE should be reported as 
AEs independent of the timing of occurrence (prior to 30 days after last dose of study 
treatment or after this interval) or relationship with study drug. 
 


 
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Section 9.2.6 Radiological assessment: tumor and response evaluation 
This section was changed as a result of Modification 2. 
Old text: 
Radiological tumor evaluation, using the mRECIST 1.1 guidelines (See Section 16.2), must 
be performed at baseline and every 12 weeks (±7 days) after the first radium-223 
dichloride/placebo administration, until PD (radiological progression) is documented.  If 
radiologic soft tissue or visceral progression in absence of bone progression (according to 
mRECIST 1.1 criteria) is observed, bone imaging and MRI/CT scan of the chest, abdomen, 
and pelvis should continue to allow assessment of bone-specific rPFS. 
 
Standard of care CT/MRI and standard of care bone scans done within 6 weeks prior to 
randomization are acceptable provided they are in line with protocol requirements criteria 
(anatomic coverage chest/abdomen/pelvis and in line with RECIST 1.1/mRECIST 1.1 
guidelines for image acquisition).  All suspected sites of disease should be imaged. 
New text: 
Radiological tumor evaluation, using the mRECIST 1.1 guidelines (See Section 16.2), must 
be performed at baseline (within 3 weeks prior to randomization), 8 weeks (±7 days) after the 
first radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 
(radiological progression) is documented.  If radiologic soft tissue or visceral progression in 
absence of bone progression (according to mRECIST 1.1 criteria) is observed, bone imaging 
and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS. 
 
Standard of care CT/MRI and standard of care bone scans done within 3 weeks prior to 
randomization are acceptable provided they are in line with protocol requirements criteria 
(anatomic coverage chest/abdomen/pelvis and in line with RECIST 1.1/mRECIST 1.1 
guidelines for image acquisition).  All suspected sites of disease should be imaged. 
 
Section 9.3.3 Other baseline characteristics 
This section was changed as a result of Modification 11. 
Old text: 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol, ALT, AST, LDH, bone ALP, serum 
creatinine, BUN, total bilirubin, and albumin 
New text: 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol, ALT, AST, LDH, bone ALP, serum 
creatinine, phosphate, BUN, total bilirubin, and albumin 
 


 
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Section 9.4.2.2 Secondary efficacy endpoints 
This section was changed as a result of Modification 13. 
Old text: 
The items are aggregated into 2 dimensions: (1) Pain severity index, using the sum of the 
4 items on the pain intensity, and (2) Function interference index, using the sum of the seven 
pain interference items.  All 4 severity items must be completed for aggregating the pain 
severity index.  The function interference index is scored as the mean of the item scores 
multiplied by 7, given that more than 50% or 4 of 7 of the items have been completed. 
New text: 
The items are aggregated into 2 dimensions: (1) Pain severity index, using the mean of the 
4 items on the pain intensity, and (2) Function interference index, using the mean of the 
7 pain interference items.  All 4 severity items must be completed for aggregating the pain 
severity index.  The function interference index is scored as the mean of the item scores 
multiplied by 7, given that more than 50% or 4 of 7 of the items have been completed. 
 
Section 9.6 Safety 
This section was changed as a result of Modification 11. 
Old text: 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol, ALT, AST, LDH, bone ALP, serum 
creatinine, BUN, total bilirubin, and albumin 
New text: 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol, ALT, AST, LDH, bone ALP, serum 
creatinine, phosphate, BUN, total bilirubin, and albumin 
 
Section 9.6.1.3 Assessments and documentation of adverse events 
This section was changed as a result of Modification 14. 
Added text: 
Note:  Specifically for this study, relevant symptoms related to SSEs should be captured as 
AEs or SAEs (if appropriate) regardless of the relationship to study drug from the date of first 
dose until the end of active follow-up. 
 
Section 9.7.2.1 Urine, plasma, and serum based biomarker analysis 
This section was changed as a result of Modification 9. 
Old text: 
9.7.2.1 Urine and serum based biomarker analysis 


 
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o Urine and serum from blood samples (Cycle 1, Day 1; Cycle 4, Day 1; and EOT/disease 
progression) may be evaluated for expression levels of bone related biomarkers.  Elevated 
levels of bone biomarkers are indicative of more aggressive disease and are prognostic of 
worse long-term clinical outcome.  In this study, levels of bone biomarkers (measured 
before, during, and after treatment) that are indicative of bone remodeling (e.g., bone 
ALP, procollagen type I N-terminal propeptide) and bone resorption (e.g., urine N-
terminal telopeptide and I collagen telopeptide /serum C-terminal telopeptide of type I 
collagen) may be evaluated and correlated with clinical outcomes (including SSEs, 
survival, and levels of other biomarkers). 
New text: 
9.7.2.1 Urine, plasma, and serum based biomarker analysis 
o Urine, serum, and plasma from blood samples (Cycle 1, Day 1; Cycle 4, Day 1; and 
EOT/disease progression) may be evaluated for expression levels of bone related 
biomarkers.  Elevated levels of bone biomarkers are indicative of more aggressive disease 
and are prognostic of worse long-term clinical outcome.  In this study, levels of bone 
biomarkers (measured before, during, and after treatment) that are indicative of bone 
remodeling (e.g., bone ALP, procollagen type I N-terminal propeptide) and bone 
resorption (e.g., urine N-terminal telopeptide and I collagen telopeptide /serum 
C-terminal telopeptide of type I collagen) may be evaluated and correlated with clinical 
outcomes (including SSEs, survival, and levels of other biomarkers). 
 
Section 16.3 Calculation for glomerular filtration rate 
This section was changed as a result of Modification 15. 
Old text: 
The formula is as follows: 
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), GFR indicates glomerular filtration rate, and serum 
creatinine is measured in mg/dL. 
New text: 
The formula can be found at the following web site: 
http://www.kidney.org/professionals/kdoqi/gfr_calculator 
 
15.2 Amendment 2 
Amendment 2 (dated 29 APR 2015) is an amendment to the Version 2.0 of the protocol, 
dated 16 DEC 2014.  Changes to the protocol include: 
 Clarified software used to calculate sample size and clarified calculation of dropout 
rate per request of the French Ethics Committee 


 
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 Updated the inclusion criteria to specify that new anticoagulants may or may not 
require INR/PTT monitoring are allowed 
 Added exclusion for hypersensitivity for active substance or any excipients for patient 
safety 
 Added exclusion criteria for known presence of osteonecrosis of jaw 
 Revised exclusion criteria regarding platelet transfusions to be within 4 weeks prior to 
randomization for patient safety 
 Revised exclusion criterion regarding use of biologic response modifiers to be within 
4 weeks of randomization for clarification 
 Clarified definition of soft tissue lesions 
 Updated guidance for management of thrombocytopenia for recovery to Grade 1 or 
less before restarting radium-223 treatment to ensure enough bone marrow reserve for 
subsequent lines of chemotherapy 
 Clarified that anti-cancer treatment must be continued with radium-223 and subject 
can continue radium-223 dichloride/placebo until completion or until any withdrawal 
criteria are met.  Clarified that administration of radium-223 monotherapy is not 
allowed 
 Clarified documentation of menopausal status based on feedback from the sites 
 Provided updated information on dosing used in study BC1-09 
 Added FDG PET scan as an adjunct to CT/MRI in line with RECIST 1.1 guidelines 
based on feedback from participating sites and regulatory authorities.  Guidance was 
provided to ensure that this additional imaging modality is used for confirmation of 
new disease only, in compliance with the RECIST 1.1 criteria 
 Updated inclusion criteria to include bone lesions asymptomatic 
 Updated inclusion criteria requirements for duration of laboratory assessments prior to 
randomization 
 Updated all relevant sections of text for consistency with timing of BPI-SF 
questionnaire 
 Specified methods for determining HER2 status in description of screening period to 
be consistent with the rest of the protocol 
 Clarified window between administrations of study drug must be 4 weeks 
 Updated requirement for hemoglobin to be ≥8 g/dL instead of 9 g/dL as per 
investigator input 
 Added a requirement that all relevant symptoms related to SSEs be recorded as AEs 
for consistency within the document 


 
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 Specified timing for coagulation panel to allow required interval prior to treatment to 
ensure timing is within proper safety parameters 
 Changed timing of the CT/MRI confirmatory scan from 8 weeks to 6 to 8 weeks 
 Clarified timing of radiological tumor assessment during active follow-up period with 
clinic visits 
 As per PI input further treatment with exemestane and everolimus must be allowed if 
it is the best treatment option for the subject according to the local standard of 
practice 
 Updated timing for obtaining samples of hematology, clinical chemistry, coagulation 
panel, and pregnancy test to be within 72 hours 
 Clarified description of standard of care hormonal treatment background therapy per 
investigator feedback 
 Updated all relevant protocol sections for consistency with screening procedures 
15.2.1 Overview of changes to the study 
Modification 1 
Clarified software used to calculate sample size and clarified calculation of dropout rate per 
request of the French Ethics Committee. 
Section affected includes: 
 10.4 Determination of sample size 
 
Modification 2 
Updated the inclusion criteria to specify that new anticoagulants may or may not require 
INR/PTT monitoring are allowed. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion  
 6.1 Inclusion criteria 
 Table 9-1: Schedule of assessments 
 9.2.1 Screening Period (Visits 0 to 1) 
 
Modification 3 
Added exclusion for hypersensitivity for active substance or any excipients for patient safety. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion  


 
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 6.2 Exclusion Criteria 
 
Modification 4 
Added exclusion criteria for known presence of osteonecrosis of jaw. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion  
 6.2 Exclusion Criteria 
 7.4.6 Dose adjustments, delays, and treatment discontinuations 
 
Modification 5 
Revised exclusion criteria regarding platelet transfusions to be within 4 weeks prior to 
randomization for patient safety. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion  
 6.2 Exclusion criteria 
 8.1.2 Permitted concomitant therapy 
 9.2.3 Treatment period 
 
Modification 6 
Revised exclusion criterion regarding use of biologic response modifiers to be within 4 weeks 
of randomization for clarification. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion  
 6.2 Exclusion criteria 
 8.1.2 Permitted concomitant therapy 
 
Modification 7 
Clarified definition of soft tissue lesions. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion  
 6.1 Inclusion criteria 


 
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 16.2 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
 
Modification 8 
Updated guidance for management of thrombocytopenia for recovery to Grade 1 or less 
before restarting radium-223 treatment to ensure enough bone marrow reserve for subsequent 
lines of chemotherapy.  
Sections affected include: 
 7.4.6 Dose adjustments, delays, and treatment discontinuations 
 7.4.7 Supportive care guidelines 
 9.2.3 Treatment period 
 
Modification 9 
Clarified that anti-cancer treatment must be continued with radium-223 and subject can 
continue radium-223 dichloride/placebo until completion or until any withdrawal criteria are 
met.  Clarified that administration of radium-223 monotherapy is not allowed. 
Sections affected include: 
 Synopsis: Methodology 
 5.1.1 Study periods and duration 
 6.3.1.1 Withdrawal from treatment period (collection of follow-up data) 
 
Modification 10 
Clarified documentation of menopausal status based on feedback from the sites. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion  
 6.1 Inclusion criteria 
 Table 9-1: Schedule of assessments 
 9.2.1 Screening period (Visits 0 to 1) 
 
Modification 11 
Provided updated information on dosing used in study BC1-09. 
Section affected includes: 
 3.4.1.3 Dosing rationale 


 
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Modification 12 
Added FDG PET scan as an adjunct to CT/MRI in line with RECIST 1.1 guidelines based on 
feedback from participating sites and regulatory authorities.  Guidance was provided to 
ensure that this additional imaging modality is used for confirmation of new disease only, in 
compliance with the RECIST 1.1 criteria.  
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria  
 Table 9-1: Schedule of assessments 
 9.2.1 Screening period (Visit 0 to 1) 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit  
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 9.2.6 Radiological assessment: tumor and response evaluation  
 16.2 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
 
Modification 13 
Updated inclusion criteria to include bone lesions asymptomatic. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria  
 
Modification 14 
Updated inclusion criteria requirements for duration of laboratory assessments prior to 
randomization.  
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion  
 6.1 Inclusion criteria  
 


 
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Modification 15 
Updated for consistency with timing of BPI-SF questionnaire. 
Sections affected include: 
 8.1.2 Permitted concomitant therapy 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 9.4.2.2 Secondary efficacy endpoints 
 
Modification 16 
Specified methods for determining HER2 status in description of screening period to be 
consistent with the rest of the protocol. 
Section affected includes: 
 9.2.1 Screening period (Visits 0 to 1) 
 
Modification 17 
Clarified window between administrations of study drug must be 4 weeks. 
Section affected includes: 
 9.2.3 Treatment period 
 
Modification 18 
Updated requirement for hemoglobin to be ≥8 g/dL instead of 9 g/dL as per investigator 
input. 
Section affected includes: 
 9.2.3 Treatment period 
 
Modification 19 
Added a requirement that all relevant symptoms related to SSEs be recorded as AEs for 
consistency within the document. 
Sections affected include:  
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 


 
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 9.2.3.2 Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
 
Modification 20 
Specified timing for coagulation panel to allow required interval prior to treatment to ensure 
timing is within proper safety parameters. 
Section affected includes: 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 
Modification 21 
Changed timing of the CT/MRI confirmatory scan from 8 weeks to 6 to 8 weeks. 
Sections affected include: 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 16.2 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
 
Modification 22 
Clarified timing of radiological tumor assessment during active follow-up period with clinic 
visits. 
Sections affected include: 
 Synopsis: Methodology 
 5.1.1 Study periods and duration 
 
Modification 23 
As per PI input further treatment with exemestane and everolimus must be allowed if it is the 
best treatment option for the subject according to the local standard of practice. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 Synopsis: Methodology 
 5.1.1 Study periods and duration 
 6.1 Inclusion criteria 
 7.1 Treatments to be administered 


 
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 8.1.2 Permitted concomitant therapy 
 9.2.3 Treatment period 
 
Modification 24 
Updated timing for obtaining samples of hematology, clinical chemistry, coagulation panel, 
and pregnancy test to be within 72 hours. 
Sections affected include: 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 
Modification 25 
Clarified description of standard of care hormonal treatment background therapy per 
investigator feedback 
Section affected includes: 
 8.1.2 Permitted concomitant therapy 
 
Modification 26 
Updated all relevant protocol sections for consistency with screening procedures 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria 
 6.2 Exclusion criteria 
15.2.2 Changes to the protocol text 
Synopsis: Diagnosis and main criteria for inclusion and exclusion, and Section 6.1 
Inclusion criteria 
These sections were changed as a result of Modifications 2, 7, 10, 12, 13, 14, 23, and 26. 
Old text: 
2. Documentation of histological or cytological confirmation of estrogen receptor positive 
(ER+) and HER2 negative adenocarcinoma of the breast must be available.  HER2 status 
should be determined by an accredited/Ministry of Health approved laboratory by 
immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or chromogenic 
in situ hybridization (CISH). 


 
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5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects are 
eligible. 
 
Note: In premenopausal subjects, ovarian radiation or treatment with a luteinizing 
hormone-releasing hormone (LH-RH) agonist/antagonist is permitted for induction of 
ovarian suppression.  Baseline estradiol assay must be <20 pg/mL at screening. 
 
 age <55 years and one year or more of amenorrhea with an estradiol assay <20 
pg/mL 
 bilateral oophorectomy  
6. Subjects with bone dominant disease (with or without metastases in soft tissue 
including lymph nodes) with at least 2 skeletal metastases identified at baseline by 
bone scintigraphy and confirmed by computed tomography (CT)/magnetic resonance 
imaging (MRI). 
 
18F-sodium fluoride positron emission/CT scan is acceptable as an alternative to technetium-
99m bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
 
Subjects enrolled in the current study will start treatment with the single hormone agent after 
randomization either before or simultaneously to the first injection of radium-223 
dichloride/placebo.  Subjects already receiving the single agent hormone treatment prior to 
study entry are not eligible.  Combination hormonal treatment is not allowed. 
 
12. Asymptomatic or mildly symptomatic breast cancer.  A worst pain score (WPS) of 0 
to 1 on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 (worst pain in the 
last 24 hours) will be considered asymptomatic, and a WPS of 2 to 3 will be 
considered mildly symptomatic.  This is to be assessed once during the screening 
period. 
 
15. Laboratory requirements: 
o Platelet count 100 x 109/L without platelet transfusion within 3 weeks 
prior to randomization 
o Hemoglobin 9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or 
erythropoietin within 6 weeks prior to randomization 
 


 
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o International normalized ratio of prothrombin time (INR) and partial 
thromboplastin time (PTT) or activated PTT ≤1.5 x ULN.  Subjects treated 
with warfarin or heparin will be allowed to participate in the study if no 
underlying abnormality in coagulation parameters exists per prior history; 
weekly evaluation of INR/PTT will be required until stability is achieved 
(as defined by local standard of care and based on prestudy INR/PTT 
values) 
New text: 
2. Documentation of histological or cytological confirmation of ER+ and HER2 negative 
adenocarcinoma of the breast must be available.  HER2 status should be determined 
by an accredited/Ministry of Health approved laboratory by immunohistochemistry 
(IHC), fluorescence in situ hybridization (FISH), chromogenic in situ hybridization 
(CISH) or other validated in situ hybridization (ISH) assay for detection of HER2 
gene expression. 
5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects 
are eligible. 
Note: In premenopausal subjects, ovarian radiation or treatment with a luteinizing 
hormone-releasing hormone (LH-RH) agonist/antagonist is permitted for induction of 
ovarian suppression if the plasma/serum estradiol assay is <20 pg/mL at screening 
within 7 days of randomization. 
 
 age <55 years and one year or more of amenorrhea with a plasma/serum 
estradiol assay <20 pg/mL, within 7 days of randomization 
 bilateral ovariectomy  
6. Subjects with bone dominant disease with at least 2 skeletal metastases identified at 
baseline by bone scintigraphy and confirmed by computed tomography 
(CT)/magnetic resonance imaging (MRI). Presence of metastases in soft tissue (skin, 
subcutaneous, muscle, fat, lymph nodes) is allowed. 
 
F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scan, if 
performed as part of standard of care imaging, can be used as an adjunct to CT/MRI 
in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the 
scan can be used for tumor measurements only if the site can document that the CT is 
of identical diagnostic quality to a diagnostic CT (See also Appendix 16.2). 
 
FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
 


 
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Subjects enrolled in the current study will start treatment with the single hormone 
agent after randomization either before or simultaneously to the first injection of 
radium-223 dichloride/placebo.  Subjects already receiving the single agent hormone 
treatment prior to study entry are not eligible. 
 
12. Bone lesions related asymptomatic or mildly symptomatic breast cancer.  A worst 
pain score (WPS) of 0 to 1 on the Brief Pain Inventory-Short Form (BPI-SF) Question 
#3 (worst pain in the last 24 hours) will be considered asymptomatic, and a WPS of 2 
to 3 will be considered mildly symptomatic.  This is to be assessed once during the 
screening period 
 
15. Laboratory requirements:  
o Platelet count 100 x 109/L without platelet transfusion within 4 weeks 
prior to randomization 
o Hemoglobin 9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or 
erythropoietin within 4 weeks prior to randomization 
 
o International normalized ratio of prothrombin time (INR) and partial 
thromboplastin time (PTT) or activated PTT ≤1.5 x ULN at study entry.  
Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, 
dabigatran, apixaban or aspirin (e.g. ≤100 mg daily) will be allowed to 
participate in the study if no underlying abnormality in coagulation 
parameters exists per prior history; weekly evaluation of INR/PTT will be 
required until stability is achieved for anticoagulants that require their 
monitoring as per local label 
 
Synopsis: Diagnosis and main criteria for inclusion and exclusion, Exclusion criteria 
and Section 6.2 Exclusion criteria 
These sections were changed as a result of Modifications 3, 4, 5, 6, and 26. 
Old text: 
1. HER2-positive breast cancer (IHC=3+, positive FISH/or positive CISH); equivocal or 
unknown HER2 status 
Note: Subjects with 3+ by IHC cannot be chosen regardless of their FISH/CISH 
status and those with positive FISH/CISH (≥2 amplifications) cannot be chosen 
either, regardless of the IHC findings.  Subjects with 2+ by IHC will not be eligible if 
no negative FISH/CISH is available. 
 


 
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13. Blood transfusions or use of erythropoietin within 6 weeks prior to randomization.  
Platelet transfusions are not allowed within 3 weeks prior to randomization. 
14. Use of biologic response modifiers, such as granulocyte macrophage-colony-
stimulating factor (GM-CSF) or granulocyte-colony-stimulating factor (G-CSF), 
within 6 weeks prior to randomization 
New text: 
1. HER2-positive breast cancer (IHC=3+, positive FISH/CISH/other ISH validated 
assay); equivocal or unknown HER2 status 
Note: Subjects with 3+ by IHC cannot be chosen regardless of their FISH/CISH/other 
ISH validated assay status and those with positive FISH/CISH/other ISH validated 
assay cannot be chosen either, regardless of the IHC findings.  Subjects with 2+ by 
IHC will not be eligible if no negative FISH/CISH/other ISH validated assay for 
detection of HER2 gene expression is available. 
 
13. Blood transfusions, platelet transfusions or use of erythropoietin within 4 weeks prior 
to randomization.   
14. 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 randomization 
Added text: 
20. Known hypersensitivity to the active substance or to any of the excipients of 
radium-223 dichloride 
21. Known presence of osteonecrosis of the jaw 
 
Synopsis: Methodology, Section 5.1.1 Study periods and duration 
These sections were changed as a result of Modifications 9, 22, and 23. 
Old text: 
All subjects will receive hormonal treatment with a single agent and supportive care as 
background treatment according to the local standard of practice.  Combination hormonal 
treatment is not allowed.  Subjects enrolled in the current study will start treatment with the 
single hormone agent after randomization either before or simultaneously to the first injection 
of radium-223 dichloride or placebo.  For subject’s convenience injections of fulvestrant may 
be scheduled on the same day of the radium-223 dichloride or placebo injection.  Subjects 
already receiving hormone treatment prior to study entry are not eligible. 
New text: 
All subjects will receive hormonal treatment with a single agent and supportive care as 
background treatment according to the local standard of practice.  Subjects enrolled in the 
current study will start treatment with the single hormone agent after randomization either 


 
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before or simultaneously to the first injection of radium-223 dichloride or placebo.  For 
subject’s convenience injections of fulvestrant may be scheduled on the same day of the 
radium-223 dichloride or placebo injection.  Subjects already receiving hormone treatment 
prior to study entry are not eligible. 
Added text: 
If radium-223 dichloride/placebo treatment is still ongoing but the background treatment is 
no longer considered a treatment option and the subject must start another hormonal 
treatment, the subject can continue radium-223 dichloride/placebo until completion or until 
any withdrawal criteria are met. 
If however, the background hormonal treatment or further standard of care hormonal 
anticancer therapy are discontinued, radium-223 dichloride/placebo must also be 
discontinued. 
 
Subjects who experience an SSE during radium-223 dichloride/placebo treatment may 
continue treatment until completion or until any withdrawal criteria are met, if in the opinion 
of the Investigator the subject continues to derive benefit.  In case an SSE is not defined as 
progression, the subject will continue to be followed as per protocol until radiological 
progression. 
 
Radiological tumor assessment will be performed every 12 weeks, independently of the 
frequency of the visits, until radiological disease progression is documented. 
 
Section 3.4.1.3 Dosing rationale 
This section was changed as result of Modification 11. 
Added text: 
The same dose was used in a phase II breast cancer study BC1-09 which provided 
preliminary evidence of the effects of radium-223 on bone markers, BPI score, and tumor 
metabolism assessed by serial F-18 fluorodeoxyglucose (FDG) positron emission 
tomography (PET) imaging and supports further investigations to confirm effectiveness of 
radium-223 in treating bone metastases in patients with breast cancer and bone-dominant 
disease.  Data were communicated at the San Antonio Breast Cancer Symposium 2011 and 
published in 2014. (40)  The study results are presented in detail in Section 3.4.1.1. 
 
Section 6.3.1.1 Withdrawal from treatment period (collection of follow-up data) 
This section was changed as a result of Modification 9. 
Added text: 


 
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 If background hormonal treatment or further standard of care protocol permitted 
concomitant systemic anti-cancer therapy are discontinued, radium-223 
dichloride/placebo must also be discontinued.  
 
Subjects who experience an SSE during study treatment may continue to receive radium-223 
dichloride (or placebo) until completion or until any of the above withdrawal criteria are met, 
if the Investigator feels the subject will receive clinical benefit. 
 
Old text: 
Subjects who experience disease progression (bone or non-bone) may continue to receive 
radium-223 dichloride (or placebo) until completion if the Investigator feels the subject will 
receive clinical benefit.  These subjects may continue to receive additional hormonal 
treatments according to the local standard of care.  If, however, chemotherapy is required as 
the next line of treatment, study treatment will be permanently discontinued, as concurrent 
chemotherapy administration is an exclusion criterion. 
New text: 
Subjects who experience disease progression (bone or non-bone) may continue to receive 
radium-223 dichloride (or placebo) until completion or until any of the above withdrawal 
criteria are met, if the Investigator feels the subject will receive clinical benefit.  These 
subjects must continue to receive additional hormonal or other protocol permitted 
concomitant systemic anticancer treatments according to the local standard of care.  If 
however, chemotherapy is required as the next line of treatment, study treatment will be 
permanently discontinued, as concurrent chemotherapy administration is an exclusion 
criterion. 
 
Section 7.1 Treatments to be administered 
This section as changed as a result of Modification 23 
Old text: 
Subjects enrolled in the current study will start treatment with the single hormone agent after 
randomization either before or simultaneously to the first injection of radium-223 dichloride 
or placebo.  For subject’s convenience, injections of fulvestrant may be scheduled on the 
same day of the radium-223 dichloride/placebo injection.  Subjects already receiving 
treatment with single hormone agent prior to study entry cannot be enrolled.  Combination 
hormonal treatment is not allowed. 
New text: 
Subjects enrolled in the current study will start treatment with the single hormone agent after 
randomization either before or simultaneously to the first injection of radium-223 dichloride 
or placebo.  For subject’s convenience, injections of fulvestrant may be scheduled on the 


 
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same day of the radium-223 dichloride/placebo injection.  Subjects already receiving 
treatment with single hormone agent prior to study entry cannot be enrolled.   
 
Section 7.4.6 Dose adjustments, delays, and treatment discontinuations 
This section was changed as a result of Modifications 4 and 8. 
Deleted text: 
If hormonal treatment must be delayed by more than 4 weeks for recovery of AEs, the subject 
should discontinue radium-223 dichloride/placebo and should enter the follow-up period. 
Old text: 
Thrombocytopenia: In case of thrombocytopenia NCI-CTCAE Grade 3 to 4, study drug 
administration should be delayed until recovery to CTCAE Grade 2 (minimum subjects with 
a platelet count 50 x 109/L) or better before the next study drug administration.  
New text: 
Thrombocytopenia: In case of thrombocytopenia NCI-CTCAE Grade 3 to 4, study drug 
administration should be delayed until recovery to CTCAE Grade 1 (minimum subjects with 
a platelet count 75 x 109/L) or better before the next study drug administration.  
Added text: 
Osteonecrosis of jaw 
There is no specific radium-223 dose modification guidance for patients who develop 
osteonecrosis of jaw during radium-223 treatment.  The management plan of individual 
patients who develop osteonecrosis of jaw in the course of the study should be set up in close 
collaboration between the treating physician and a dentist or oral surgeon with expertise in 
osteonecrosis of jaw, and in accordance with the local labeling of denosumab and 
bisphosphonates. 
 
Section 7.4.7 Supportive care guidelines 
This section was changed as a result of Modification 8. 
Old text: 
 Severe thrombocytopenia (CTCAE Grade 4 [<25.0 x 109/L]) or bleeding with 
CTCAE Grade 3 to 4 thrombocytopenia (<50.0 x 109/L): multiple platelet transfusions 
may be required to maintain platelet count >50 x 109/L or higher if clinically indicated 
to control bleeding.  Epsilon aminocaproic acid may be given to subjects with 
mucosal bleeding and platelet count CTCAE Grade 3 to 4.  
New text: 
 Severe thrombocytopenia (CTCAE Grade 4 [<25.0 x 109/L]) or bleeding with 
CTCAE Grade 3 to 4 thrombocytopenia (<50.0 x 109/L): multiple platelet transfusions 


 
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may be required to maintain platelet count ≥75 x 109/L if clinically indicated to 
control bleeding.  Epsilon aminocaproic acid may be given to subjects with mucosal 
bleeding and platelet count CTCAE Grade 3 to 4.  
 
Section 8.1.2 Permitted concomitant therapy 
This section was changed as a result of Modifications 5, 6, 15, 23, and 25. 
Old text: 
 Subjects enrolled in the current study will start treatment with the single hormone 
agent after randomization either before or simultaneously to the first injection of 
radium-223 dichloride/placebo.  For subject’s convenience injections of fulvestrant 
may be scheduled on the same day of the radium-223 dichloride or placebo injection.  
Subjects already receiving treatment with a single hormone agent prior to study entry 
cannot be enrolled.  Combination hormonal treatment is not allowed. 
New text: 
 Subjects enrolled in the current study will start treatment with the single hormone 
agent after randomization either before or simultaneously to the first injection of 
radium-223 dichloride/placebo.  For subject’s convenience injections of fulvestrant 
may be scheduled on the same day of the radium-223 dichloride or placebo injection.  
Subjects already receiving treatment with a single hormone agent prior to study entry 
cannot be enrolled.  
Added text: 
 Following discontinuation of the single agent background hormone treatment, further 
lines of hormone treatment as well as exemestane in combination with everolimus, 
may be administered concomitantly with radium-223 dichloride/placebo, in line with 
the local standard of practice. 
Old text: 
 Blood transfusions and treatment with erythropoietin stimulating agents are allowed 
after randomization (if required to ensure that the treatment range for Hb is met at 
Day 1 of each cycle) but not within 6 weeks prior to randomization.  Platelet 
transfusions are allowed after randomization but not within 3 weeks prior to 
randomization. 
 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.  These drugs are not allowed within 6 weeks prior 
to randomization.  
 Analgesic use will be captured via a subject diary and the eCRF (analgesic 
consumption diary and recorded analgesics, respectively, see schedule of assessments, 
Table 9-1).  Subjects will be asked to track their analgesic use on an analgesic 
consumption diary for 1 week prior to their clinic visit.  Each day the pain question is 


 
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asked of the subject, the subject should be asked to record any pain medication she 
took that day.  Any medication taken for pain, whether for palliation of bone pain or 
relief of other type of pain, and any changes should be recorded in the eCRF at each 
visit.  Note that EBRT treatment should be recorded in the eCRFs until end of the 
active follow-up period without clinic visits. 
New text: 
 Blood transfusions and treatment with erythropoietin stimulating agents are allowed 
after randomization (if required to ensure that the treatment range for Hb is met at 
Day 1 of each cycle) but not within 4 weeks prior to randomization.  Platelet 
transfusions are allowed after randomization but not within 4 weeks prior to 
randomization. 
 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.  These drugs are not allowed within 4 weeks prior 
to randomization.  
 Analgesic use will be captured via a subject diary and the eCRF (analgesic 
consumption diary and recorded analgesics, respectively, see schedule of assessments, 
Table 9-1).  Subjects will be asked to track their analgesic use on an analgesic 
consumption diary for 1 week prior to their clinic visit.  Any medication taken for 
pain, whether for palliation of bone pain or relief of other type of pain, and any 
changes should be recorded in the eCRF at each visit.  Note that EBRT treatment 
should be recorded in the eCRFs until end of the active follow-up period without 
clinic visits. 
 
Table-9.1 Schedule of Assessments 
This section was changed as a result of Modifications 2, 10, and 12. 
Old text: 
k. Adverse events will be collected through 4 weeks post the last administration of study 
medications.  Investigator should check for occurrences of leukemia, myelodysplastic 
syndrome, aplastic anemia, and any new malignancy.   
 
t. The screening clinical chemistry and hematology values are recommended to be 
measured within 1 week prior to randomization if feasible (a 2 week maximum is 
permitted) and the first injection should be done as soon as possible after 
randomization. 
 
x. PT, INR, and PTT: Subjects treated with warfarin or heparin will be allowed to 
participate in the study if no underlying abnormality in coagulation parameters exists 
per prior history; weekly evaluation of INR/PTT will be required until stability is 


 
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achieved (as defined by local standard of care and based on pre-study INR/PTT 
values). 
y. Pre-menopausal women must have a negative serum pregnancy test performed within 
7 days prior to randomization, prior to each study drug administration, and EOT.  
Post-menopausal women (as defined in Section 6.1) are not required to undergo a 
pregnancy test.  An estradiol assay is required within 7 days prior to randomization in 
pre-menopausal women with radiotherapy ovarian ablation or medical ovarian 
suppression and post-menopausal women age <55 years and one year or more of 
amenorrhea. 
 
bb. A historic bone scan is acceptable if taken within 3 weeks of randomization.  If one is 
not available, it will be required as part of the protocol procedures within the 
screening period.  18F-sodium fluoride positron emission tomography/CT scan is 
acceptable as an alternative to technetium-99m bone scintigraphy if it is the standard 
of care at the institution, provided the same bone imaging modality is used throughout 
the study. 
cc. Chest/abdominal/pelvic magnetic resonance imaging will be accepted instead of 
chest/abdominal/pelvic CT.   
New text: 
k. Adverse events will be collected through 30 days post the last administration of study 
medications.  Investigator should check for occurrences of leukemia, myelodysplastic 
syndrome, aplastic anemia, and any new malignancy.   
 
t. The screening clinical chemistry and hematology values are recommended to be 
measured within 1 week prior to randomization and the first injection should be done 
as soon as possible after randomization. 
 
x. PT, INR, and PTT: Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, 
dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to participate in 
the study if no underlying abnormality in coagulation parameters exists per prior 
history; weekly evaluation of INR/PTT will be required until stability is achieved for 
anticoagulants that require their monitoring as per local label.  
y. Pre-menopausal women must have a negative serum pregnancy test performed within 7 
days prior to randomization, prior to each study drug administration, and EOT.  
Post-menopausal women (as defined in Section 6.1) are not required to undergo a 
pregnancy test.  A plasma/serum estradiol assay is required within 7 days prior to 
randomization in pre-menopausal women with radiotherapy ovarian ablation or 
medical ovarian suppression and post-menopausal women age <55 years and one year 
or more of amenorrhea. 
 


 
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bb. A historic bone scan is acceptable if taken within 3 weeks of randomization.  If one is 
not available, it will be required as part of the protocol procedures within the 
screening period.  FDG PET/CT or NaF PET /CT scan is acceptable as an alternative 
to technetium-99m bone scintigraphy if it is the standard of care at the institution, 
provided the same bone imaging modality is used throughout the study. 
cc. Chest/abdominal/pelvic magnetic resonance imaging will be accepted instead of 
chest/abdominal/pelvic CT.  FDG PET scan, if performed as part of standard of care 
imaging, can be used as an adjunct to CT/MRI in line with RECIST 1.1 guidelines. If 
FDG PET/CT scan, the CT component of the scan can be used for tumor 
measurements only if the site can document that the CT is of identical diagnostic 
quality to a diagnostic CT. (See also Appendix 16.2). 
 
Section 9.2.1 Screening period (Visits 0 to 1)  
This section was changed as a result of Modifications 2, 10, 12, and 16. 
Added text: 
 Record disease history: HER2 status can be determined by evaluating for HER2 over-
expression using IHC and/or HER2 gene amplification using in situ hybridization, 
e.g., FISH or CISH.  For subjects with equivocal HER2 IHC (IHC 2+), it is 
recommended that HER2 status be confirmed using a validated assay for HER2 gene 
amplification. 
Added text: 
o FDG PET scan, if performed as part of standard of care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See also 
Appendix 16.2). 
Old text: 
o 
18F-sodium fluoride PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
New text: 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
Old text 
 A coagulation panel: prothrombin time (PT), PTT, and INR.  Subjects treated with 
warfarin or heparin will be allowed to participate in the study if no underlying 
abnormality in coagulation parameters exists per prior history; weekly evaluation of 


 
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INR/PTT will be required until stability is achieved (as defined by local standard of 
care and based on pre-study INR/PTT values). 
New text: 
 A coagulation panel: prothrombin time (PT), PTT, and INR.  Subjects treated with 
warfarin, heparin, enoxaparin, rivaroxaban, dabigatran, apixaban or aspirin (e.g. ≤100 
mg daily) will be allowed to participate in the study if no underlying abnormality in 
coagulation parameters exists per prior history; weekly evaluation of INR/PTT will be 
required until stability is achieved for anticoagulants that require their monitoring as 
per local label. 
Old text 
 Estradiol assay: an estradiol assay is required within 7 days prior to randomization in 
pre-menopausal women with radiotherapy ovarian ablation or medical ovarian 
suppression and post-menopausal women age <55 years and one year or more of 
amenorrhea. 
New text 
 Estradiol assay: a plasma/serum estradiol assay is required within 7 days prior to 
randomization in pre-menopausal women with radiotherapy ovarian ablation or 
medical ovarian suppression and post-menopausal women age <55 years and one year 
or more of amenorrhea. 
 
Section 9.2.3 Treatment period 
This section was changed as a result of Modifications 5, 8, 17, 18, and 23. 
Added text: 
 During the treatment period, the subject will visit the study site at regular intervals.  
Radium-223 dichloride or placebo will be injected at 4-week intervals for 6 cycles on 
an outpatient basis (Section 9.1).  The minimum time window between 2 injections of 
radium-223 dichloride/placebo must be 4 weeks.  All ongoing subjects at the time of 
study termination will finish study treatment with radium-223 dichloride or placebo as 
part of the study. 
Old text: 
 All subjects will receive background standard of care hormonal treatment for breast 
cancer.  Subjects enrolled in the current study will start treatment with the single 
hormone agent after randomization either before or simultaneously to the first 
injection of radium-223 dichloride/placebo.  For subject’s convenience, injections of 
fulvestrant may be scheduled on the same day of the radium-223 dichloride/placebo 
injection.  Subjects already receiving treatment with a single hormone agent prior to 
study entry cannot be enrolled.  Combination hormonal treatment is not allowed.  
 


 
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Before the first administration of radium-223 dichloride/placebo (within 3 days), the ANC 
should be ≥1.5 x 109/L, the platelet count ≥100 x 109/L, and Hb ≥9 g/dL. 
Blood transfusions and treatment with erythropoietin stimulating agents are allowed after 
randomization but not within 6 weeks prior randomization.  Platelet transfusions are allowed 
after randomization but not within 3 weeks prior to randomization. 
The following hematological parameters value should be met prior to each subsequent 
radium-223 dichloride/placebo administration: Hb level ≥8.0 g/dL, ANC ≥1.0 x 109/L, and 
the platelet count ≥50 x 109/L. 
 
If ANC is lower than 1.0 x 109/L or platelet count is lower than 50 x 109/L, radium-223 
dichloride/placebo injection should be delayed until recovery to ANC ≥1.0 x 109/L and 
platelet count ≥50 x 109/L. 
New text: 
 All subjects will receive background standard of care hormonal treatment for breast 
cancer.  Subjects enrolled in the current study will start treatment with the single 
hormone agent after randomization either before or simultaneously to the first 
injection of radium-223 dichloride/placebo.  For subject’s convenience, injections of 
fulvestrant may be scheduled on the same day of the radium-223 dichloride/placebo 
injection.  Subjects already receiving treatment with a single hormone agent prior to 
study entry cannot be enrolled.  
 
Before the first administration of radium-223 dichloride/placebo (within 3 days), the ANC 
should be ≥1.5 x 109/L, the platelet count ≥100 x 109/L, and Hb ≥8.0 g/dL. 
Blood transfusions and treatment with erythropoietin stimulating agents are allowed after 
randomization but not within 4 weeks prior randomization.  Platelet transfusions are allowed 
after randomization but not within 4 weeks prior to randomization. 
The following hematological parameters value should be met prior to each subsequent 
radium-223 dichloride/placebo administration: Hb level ≥8.0 g/dL, ANC ≥1.0 x 109/L, and 
the platelet count ≥75 x 109/L. 
 
If ANC is lower than 1.0 x 109/L or platelet count is lower than 75 x 109/L, radium-223 
dichloride/placebo injection should be delayed until recovery to ANC ≥1.0 x 109/L and 
platelet count ≥75 x 109/L. 
Section 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each 
visit) 
This section was changed as a result of Modifications 12, 15, 19, 20, and 21. 


 
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Old text: 
 BPI-SF questionnaire will be completed for1 week (6 days plus the day of the visit) 
prior to the visit and should be checked for completion at the visit. 
New text: 
 BPI-SF questionnaire will be completed prior to any other study 
assessments/procedures and should be checked for completion at the visit. 
Added text: 
Note: Specifically for this study, relevant symptoms related to SSEs should be reported as 
AEs independent of the timing of occurrence (prior to 30 days after last dose of study 
treatment or after this interval) or relationship with study drug 
Old text: 
A coagulation panel (within 72 hours prior before radium-223 dichloride or placebo 
administration) PT, PTT, and INR. 
New text: 
A coagulation panel (blood sample to be taken within 72 hours prior to each study drug 
administration: PT, PTT, and INR. 
 
Old text: 
o Bone technetium-99m scan with careful identification of all disease-related hotspots.  
All visible bone lesions must also be imaged with conventional anatomical imaging 
procedures, such as SPECT-CT/MRI or CT or MRI scan (with or without contrast 
media).  All new bone lesions or progression of existing bone lesion(s) identified on a 
technetium-99m bone scan will need confirmatory CT or MRI imaging.  In case of a 
new lesion or of progression of existing bone lesion(s) observed on a bone scan that is 
not confirmed by CT/MRI, progression will not be declared until the CT/MRI 
confirmation of progression occurs.  A CT/MRI confirmatory scan must take place 
8 weeks after the new lesion or progression of existing lesion(s) was observed on 
bone scan.  Modified RECIST version 1.1 (mRECIST 1.1) criteria will be applied to 
declare a PFS event. 
New text: 
o Bone technetium-99m scan with careful identification of all disease-related hotspots.  
All visible bone lesions must also be imaged with conventional anatomical imaging 
procedures, such as SPECT-CT/MRI or CT or MRI scan (with or without contrast 
media).  All new bone lesions or progression of existing bone lesion(s) identified on a 
technetium-99m bone scan will need confirmatory CT or MRI imaging.  In case of a 
new lesion or of progression of existing bone lesion(s) observed on a bone scan that is 
not confirmed by CT/MRI, progression will not be declared until the CT/MRI 
confirmation of progression occurs.  A CT/MRI confirmatory scan must take place 6 
to 8 weeks after the new lesion or progression of existing lesion(s) was observed on 


 
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bone scan.  Modified RECIST version 1.1 (mRECIST 1.1) criteria will be applied to 
declare a PFS event. 
Added text: 
FDG PET scan, if performed as part of standard of care imaging, can be used as an adjunct to 
CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the 
scan can be used for tumor measurements only if the site can document that the CT is of 
identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
Old text: 
o 
18F-sodium fluoride PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
New text: 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
 
Section 9.2.3.2 Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
This section was changed as a result of Modification 19. 
Added text: 
Note: Specifically for this study, relevant symptoms related to SSEs should be reported as 
AEs independent of the timing of occurrence (prior to 30 days after last dose of study 
treatment or after this interval) or relationship with study drug. 
 
Section 9.2.3.3 End of treatment visit 
This section was changed was changed as a result of Modifications 12, 15, 21, and 24. 
Old text: 
 BPI-SF questionnaire will be completed for 1 week (6 days plus the day of the visit) 
prior to the visit and should be checked for completion at the visit 
New text: 
 BPI-SF questionnaire will be completed prior to any other study 
assessments/procedures and should be checked for completion at the visit 
Added text: 


 
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 Blood draws for hematology (within 72 hours of the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC differential 
 Blood draws for clinical chemistry (within 72 hours of the visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin  
 A coagulation panel (within 72 hours of the visit): PT, PTT, and INR. 
 Pregnancy test (within 72 hours of the visit): pre-menopausal women must have a 
negative serum pregnancy test.  Post-menopausal women (as defined in Section 6.1) 
are not required to undergo a pregnancy test. 
 
o Bone technetium-99m scan with careful identification of all disease-related 
hotspots.  All visible bone lesions must also be imaged with conventional 
anatomical imaging procedures such as SPECT-CT/MRI or CT or MRI 
scan (with or without contrast media).  All new bone lesions or progression 
of existing bone lesion(s) identified on a technetium-99m bone scan will 
need confirmatory CT or MRI imaging.  In case of a new lesion or of 
progression of existing bone lesion(s) observed on a bone scan that is not 
confirmed by CT/MRI, progression will not be declared until the CT/MRI 
confirmation of progression occurs.  A CT/MRI confirmatory scan must 
take place 6 to 8 weeks after the new lesion or progression of existing 
lesion(s) was observed on bone scan. 
Added text: 
FDG PET scan, if performed as part of standard of care imaging, can be used as an adjunct to 
CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the 
scan can be used for tumor measurements only if the site can document that the CT is of 
identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
Old text: 
o 
18F-sodium fluoride PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
New text: 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
 


 
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Section 9.2.4.1 Active follow-up with clinic visits 
This section was changed as a result of Modifications 12, 15, and 24. 
Old text: 
 BPI-SF questionnaire will be completed for 1 week (6 days plus the day of the visit) 
prior to the visit and should be checked for completion at the visit 
New text: 
 BPI-SF questionnaire will be completed prior to any other study 
assessments/procedures and should be checked for completion at the visit 
Old text: 
 Record concomitant medications/therapy (concomitant medications used to treat any 
grade adverse drug reaction only) 
New text: 
 Record concomitant medications/therapy 
Added text: 
 Blood draws for hematology (within 72 hours of the visit):  hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC differential  
 Blood draws for clinical chemistry (within 72 hours of the visit):  Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin1 
Added text: 
FDG PET scan, if performed as part of standard of care imaging, can be used as an adjunct to 
CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the 
scan can be used for tumor measurements only if the site can document that the CT is of 
identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
Old text: 
o 
18F-sodim fluoride PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
New text: 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
 


 
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Section 9.2.4.3 End of active follow-up  
This section was changed as a result of Modifications 12, 15, and 24. 
Old text: 
 BPI-SF questionnaire will be completed for 1 week (6 days plus the day of the visit) 
prior to the visit and should be checked for completion at the visit 
New text: 
 BPI-SF questionnaire will be completed prior to any other study 
assessments/procedures and should be checked for completion at the visit 
Added text: 
 Blood draws for hematology (within 72 hours of the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC differential  
 Blood draws for clinical chemistry (within 72 hours of the visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin 
Added text: 
FDG PET scan, if performed as part of standard of care imaging, can be used as an adjunct to 
CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the 
scan can be used for tumor measurements only if the site can document that the CT is of 
identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
Old text: 
o 
18F-sodium fluoride PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
New text: 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to 
technetium-99m bone scintigraphy if it is the standard of care at the 
institution, provided the same bone imaging modality is used throughout 
the study. 
 
Section 9.2.6 Radiological assessment: tumor and response evaluation 
This section was changed as a result of Modification 12. 
Old text: 
Radiological tumor evaluation, using the mRECIST 1.1 guidelines (See Section 16.2), must 
be performed at baseline (within 3 weeks prior to randomization), 8 weeks (±7 days) after the 
first radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 


 
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(radiological progression) is documented.  If radiologic soft tissue or visceral progression in 
absence of bone progression (according to mRECIST 1.1 criteria) is observed, bone imaging 
and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS. 
New text: 
Radiological tumor evaluation, using the mRECIST 1.1 guidelines (See Section 16.2), must 
be performed within 3 weeks prior to randomization, at 8 weeks (±7 days) after the first 
radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 
(radiological progression) is documented.  If radiologic soft tissue or visceral progression in 
absence of bone progression (according to mRECIST 1.1 criteria) is observed, bone imaging 
and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS. 
Old text: 
Standard of care CT/MRI and standard of care bone scans done within 3 weeks prior to 
randomization are acceptable provided they are in line with protocol requirements criteria 
(anatomic coverage chest/abdomen/pelvis and in line with RECIST 1.1/mRECIST 1.1 
guidelines for image acquisition).  All suspected sites of disease should be imaged. 
New text: 
Standard of care CT/MRI done within 3 weeks of randomization and standard of care bone 
scans done within 3 weeks of randomization are acceptable provided they are in line with 
protocol requirements criteria (anatomic coverage chest/abdomen/pelvis and in line with 
RECIST 1.1/mRECIST 1.1 guidelines for image acquisition).  All suspected sites of disease 
should be imaged. 
Added text: 
FDG PET scan, if performed as part of standard of care imaging, can be used as an adjunct to 
CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the 
scan can be used for tumor measurements only if the site can document that the CT is of 
identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m bone 
scintigraphy if it is the standard of care at the institution, provided the same bone imaging 
modality is used throughout the study. The same lesions identified at baseline must be 
evaluated at follow-up assessments using the same technique and preferably by the same 
Investigator/radiologist. 
 
Section 9.4.2.2 Secondary efficacy endpoints 
This section was changed as a result of Modification 15. 
Old text: 
Time to pain progression is defined as the interval from randomization to the first date 
a subject experiences pain progression based on WPS.  Pain progression is defined as an 


 
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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  
New text: 
Time to pain progression is defined as the interval from randomization to the first date 
a subject experiences pain progression based on WPS.  Pain progression is defined as an 
increase of 2 or more points in the “Worst pain in 24 hours” score from baseline observed at 
2 consecutive evaluations ≥4 weeks apart 
Old text: 
Assessments will occur daily for one week (including the visit date). An evaluable pain 
assessment interval requires completion of a minimum of 4 out of 7 daily questions. 
New text: 
Assessments will occur on the day of the visit.  An evaluable pain assessment interval 
requires completion of a minimum of 4 out of 7 questions. 
 
Section 9.6.1.4 Reporting of serious adverse events 
This section was changed as a result of consistency. 
Old text: 
For subjects who die 4 weeks after the administration of the last study treatment, submission 
of the AE page of the eCRF is not required.  
New text: 
For subjects who die 30 days after the administration of the last study treatment, submission 
of the AE page of the eCRF is not required.  
 
Section 10.4 Determination of sample size 
This section was changed as a result of Modification 1. 
Old text: 
Sample size is calculated based on the primary endpoint, SSE-FS.  Assuming a one-sided 
alpha of 0.1, power of 90%, with a median SSE-FS for the control group of 7 months and a 
randomization ratio of 1:1 between treatments, approximately 119 events will be required to 
detect a 60% increase in SSE-FS for a total of 227 subjects in the 2 treatment groups 
combined.  The targeted improvement of 60% is not based on a bibliographical reference. 
New text: 
Sample size is calculated based on the primary endpoint, SSE-FS.  EAST 6.3 was used to 
calculate event number.  Assuming a one-sided alpha of 0.1, power of 90%, with a median 
SSE-FS for the control group of 8.3 months and a randomization ratio of 1:1 between 
treatments, approximately 119 events will be required to detect a 60% increase in SSE-FS for 


 
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a total of 227 subjects in the 2 treatment groups combined.  The dropout rate is assumed to be 
15%.  Dropout was taken into account when calculating the sample size and study duration. 
The targeted improvement of 60% is not based on a bibliographical reference. 
 
Section 16.2 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
This section was changed as a result of Modifications 7, 12, and 21. 
Old text: 
Soft tissue lesions: Malignant finding in soft tissue (skin, subcutaneous, and muscle), 
including lymph nodes. 
New text: 
Soft tissue lesions: Malignant finding in soft tissue (skin, subcutaneous, muscle, fat, lymph 
nodes). 
Added text: 
If FDG PET/CT or FDG PET scan is performed as part of the standard of practice imaging, 
the results of the FDG PET scan can be used as a complement to CT scanning in the 
assessment of disease progression – based on occurrence of new lesions – as per the RECIST 
1.1 algorithm (See section on New lesions and FDG PET imaging in this appendix). 
FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m bone 
scintigraphy if it is the standard of care at the institution, provided the same bone imaging 
modality is used throughout the study. 
Added text: 
 A new bone lesion or progression of existing bone lesion/s initially identified on a 
technetium-99m bone scan must be confirmed by CT or MRI.  If confirmed by 
CT/MRI, the date of occurrence of the new lesion or of progression of existing bone 
lesion/s will be the date it was initially detected (by technetium-99m bone scan) even 
if the confirmation by CT/MRI was done at a subsequent scan.  A CT/MRI 
confirmatory scan must take place 6 to 8 weeks after the new lesion or progression of 
existing lesion/s was observed on bone scan 
Added text: 
New lesions and FDG PET imaging 
New lesions on the basis of FDG PET imaging can be identified according to the following 
algorithm: 
 (-) FDG PET at baseline and (+) FDG PET at follow-up = PD based on a new lesion 
 No FDG PET at baseline and (+) FDG PET at follow-up = PD if the new lesion is 
confirmed on CT. If a subsequent CT confirms the new lesion, the date of PD is the 
date of the initial FDG PET scan. 


 
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 No FDG PET at baseline and (+) FDG PET at follow-up corresponding to a pre-
existing lesion on CT that is not progressing is not PD 
Note: A ‘positive’ FDG PET scan lesion means one with uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image 
 
15.3 Amendment 4 
Amendment 4 (dated 29 JUL 2015) is an amendment to the Version 3.0 of the protocol, dated 
29 APR 2015.  Changes to the protocol include: 
 Added pain improvement as a secondary endpoint as patients can now be evaluated 
for pain improvement based on revision of exclusion criteria. 
 Updated text to allow background hormonal treatment to be started as soon as 
possible after progression. 
 Updated the quantification of radium-223 radioactivity in Xofigo® based on the 
revised primary standardization performed by the US NIST. 
 Added text related to counting of SREs for clarification. 
 Removed inclusion criteria 12 per objection from participating sites that majority of 
subjects with advanced breast cancer and bone disease would not be asymptomatic or 
mildly symptomatic. 
 Changed estimated glomerular filtration rate from 60 to 30 to align with denosumab 
and bisphosphonates labeling and exclude only patients with severe renal impairment. 
 Changed thrombocytopenia from grade 3 to grade 2 to for consistency. 
 Removed completion of BPI-SF at screening based on revision of inclusion criteria. 
 Changed body weight to be taken within 5 days to allow more time to receive results. 
 Changed blood samples to be taken within 5 days to allow more time to receive 
results. 
 Added collection time period for biomarkers to be within 5 days to allow more 
flexibility. 
 Added text for the collection of scans that will be reviewed for retrospective analysis. 
 Added new appendix to provide detailed guidance for the administration of the BPI-
SF questionnaire. 
 Added 12-week time interval for performance of assessments during active follow-up. 
 Changed pregnancy test to be taken within 5 days to allow more time to receive 
results. 
 Removed requirement for first dose of study treatment to occur 1 to 3 weeks after 
randomization. 


 
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 Removed requirement that bisphosphonates or denosumab to be administered at least 
2 hours before study treatment. 
 Modified text for clarification. 
 The list of abbreviations was updated to reflect the usage of abbreviations in the 
amended protocol. 
15.3.1 Overview of changes to the study 
Modification 1 
Added pain improvement as a secondary endpoint as patients can now be evaluated for pain 
improvement based on revision of inclusion criteria. 
Sections affected include: 
 Synopsis: Study objectives 
 4. Study objectives 
 5.1.2 Study endpoints 
 9.4.1 Efficacy variables 
 9.4.2.2 Secondary efficacy endpoints 
 10.3 Efficacy variables and planned statistical analyses 
 
Modification 2 
Updated text to allow background hormonal treatment to be started as soon as possible after 
progression.  Subjects who initiated a new line of background hormone treatment within 15 
days of randomization can be considered for the study, provided the other eligibility criteria 
are met.  The change was discussed and agreed with the study statistician. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 Synopsis: Methodology 
 5.1.1 Study periods and duration 
 6.1  Inclusion criteria 
 7.1 Treatments to be administered 
 8.1.2 Permitted concomitant therapy 
 9.2.3 Treatment period 
 


 
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Modification 3 
The quantification of radium-223 radioactivity in Xofigo® is based on the primary 
standardization performed by the US National Institute of Standards and Technology (NIST).  
The NIST Standard Reference Material is used to calibrate the instruments in production and 
quality control of both the drug substance and drug product.  Additionally, the calibrated 
instruments in production at the Institute for Energy Technology (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 (52) and current measurements was confirmed and a 
revised NIST primary reference standard has been issued (53).  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 [53]) 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 CTAs 
have been initiated.   The current standard (NIST 2010 [52]), dial setting and dose will 
remain in effect until a unique implementation date in Q2 2016 as agreed with FDA and 
EMA.  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 
[52]) 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 
the patient dose will be changed to 55kBq/kg body weight (NIST update [53]). 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 [52]) 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 [52]) 
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, 


 
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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 
[53]), 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 [52]); 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 [53]) only), though 
the volume of radium-223 dichloride given to each subject will remain the same.   
 
Sections affected include: 
 Synopsis: Dose 
 Synopsis: Methodology 
 List of Abbreviations 
 3.4.1.3 Dosing rationale 
 5.1.1 Study periods and duration 
 7.1 Treatments to be administered 
 7.2.1.1 Radium-223 dichloride 
 7.4.1 Dose calibration 
 7.4.3 Radium-223 dose calculation 
 14. Reference list 


 
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Modification 4 
Added text related to counting of SREs for clarification. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 5.1 Design overview 
 6.1 Inclusion criteria 
 10.1 General considerations 
 
Modification 5 
Removed inclusion criteria 12 per objection from participating sites that majority of subjects 
with advanced breast cancer and bone disease would not be asymptomatic or mildly 
symptomatic. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria 
 
Modification 6 
Changed estimated glomerular filtration rate from 60 to 30 to align with denosumab and 
bisphosphonates labeling and exclude only patients with severe renal impairment. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria 
 
Modification 7 
Changed thrombocytopenia from grade 3 to grade 2 to for consistency. 
Sections affected include: 
 7.4.6 Dose adjustments, delays, and treatment discontinuations 
 
Modification 8 
Removed completion of BPI-SF at screening based on revision of inclusion criteria. 
Sections affected include: 


 
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 9.1 Tabular schedule of evaluations 
 9.2.1 Screening period (Visit 0 to 1) 
 
Modification 9 
Changed body weight to be taken within 5 days to allow more time to receive results. 
Sections affected include: 
 7.4.3 Radium-223 dose calculation 
 9.1 Tabular schedule of evaluations 
 9.2.3 Treatment period 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 
Modification 10 
Changed blood samples to be taken within 5 days to allow more time to receive results. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 9.2.3 Treatment period 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
Modification 11 
Added collection time period for biomarkers to be within 5 days to allow more flexibility. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.7.2.1 Urine, plasma, and serum based biomarker analysis 
 
Modification 12 
Added text for the collection of scans that will be reviewed for retrospective analysis. 
Sections affected include: 


 
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 9.2.6 Radiological assessment: tumor and response evaluation 
 
Modification 13 
Added new appendix to provide detailed guidance for the administration of the BPI-SF 
questionnaire. 
Sections affected include: 
 Appendix 16.6 BPI-SF 
 14. Reference list 
 
Modification 14 
Added 12-week time interval for performance of assessments during active follow-up. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 9.2.4.1 Active follow-up with clinic visits 
 
Modification 15 
Changed pregnancy test to be taken within 5 days to allow more time to receive results. 
Sections affected include: 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 
Modification 16 
Removed requirement for first dose of study treatment to occur 1 to 3 weeks after 
randomization as some countries will not be able to meet this requirement.  It is not expected 
that the change will affect the safety of the subjects on study because they will undergo safety 
laboratory tests and will be assessed for AEs before first administration of Ra-223 dichloride 
to ensure they continue to meet the protocol requirements. 
Sections affected include: 
 6. Study population 
 9.1 Tabular schedule of evaluations 
 


 
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Modification 17 
Removed requirement that bisphosphonates or denosumab to be administered at least 2 hours 
before study treatment based on feedback from Clinical Pharmacology that any potential risk 
for interaction could be excluded. The change is being implemented across the Ra-223 
clinical program. 
Sections affected include: 
 7.1 Treatments to be administered 
 8.1.2 Permitted concomitant therapy 
 
Modification 18 
Modified text for clarification. 
Sections affected include: 
 8.1.1 Prohibited concomitant therapy 
 9.1 Tabular schedule of evaluations 
 9.2.4.3 End of active follow-up 
 
Modification 19 
The list of abbreviations was updated to reflect the usage of abbreviations in the amended 
protocol. 
Sections affected include: 
 List of abbreviations 
 
15.3.2 Changes to the protocol text 
Changes to the protocol text are highlighted as specified at the beginning of Section 15. 
Global Change 
This was changed as a result of modification 3. 
Old text: 
50 kBq/kg 
New text: 
50 kBq/kg (55 kBq/kg after implementation of NIST update) 
 


 
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Section List of abbreviations 
This section was changed as a result of modification 3 and 19. 
Added text: 
FDG 
Fluorodeoxyglucose 
 
NIST 
National Institute of Standards and Technology 
 
NTX 
N-terminal telopeptide 
 
SC 
Subcutaneously  
Deleted text: 
SERM 
Selective estrogen receptors modulator 
Added text: 
W/O 
Without  
 
Synopsis: Study objectives 
This section was changed as a result of modification 1.  
Old text: 
4. 
Time to pain progression  
New text:  
4. 
Time to pain progression (only in subjects with baseline worst pain score  ≤8) 
Added text: 
7. 
Pain improvement rate 
 
Synopsis: Diagnosis and main criteria for inclusion and exclusion, Section 6 Inclusion 
criteria 
These sections were changed as a result of modifications 2, 4, 5, and 6.  
Old text: 
9. Subjects who are eligible for further standard of care endocrine treatment with any of the 
following administered as in second line or greater of hormone therapy in metastatic 
setting:  


 
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o Selective estrogen receptors modulators such as tamoxifen and toremifene  
o Non-steroidal aromatase inhibitors such as anastrozole and letrozole  
o Steroidal aromatase inhibitors such as exemestane 
o Estrogen receptor down-regulators such as fulvestrant  
Subjects enrolled in the current study will start treatment with the single hormone agent after 
randomization either before or simultaneously to the first injection of radium-223 
dichloride/placebo. Subjects already receiving the single agent hormone treatment prior to 
study entry are not eligible. 
10. Subjects must have experienced no more than 2 skeletal-related events (SREs) prior to 
study entry defined as: external beam radiotherapy (EBRT) for bone pain, pathological 
bone fracture (excluding major trauma), spinal cord compression and/or orthopedic 
surgical procedure.  Subjects with no prior SREs are not permitted.  
Note: For the purpose of counting prior SREs any procedure which is related to an SRE, 
such as orthopedic surgery to treat a pathological bone fracture should not be counted 
as a separate event.  All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) 
must be administered prior to randomization. 
New text: 
9. Subjects who are eligible for further standard of care endocrine treatment with any of 
the following administered as in second line or greater of hormone therapy in 
metastatic setting:  
o Selective estrogen receptors modulators such as tamoxifen and toremifene  
o Non-steroidal aromatase inhibitors such as anastrozole and letrozole  
o Steroidal aromatase inhibitors such as exemestane 
o Estrogen receptor down-regulators such as fulvestrant  
Subjects enrolled in the current study must start treatment with the single hormone agent 
either within 15 days prior to randomization or after randomization (before or simultaneously 
to the first injection of radium-223 dichloride/placebo).  
 
10. Subjects must have experienced no more than 2 skeletal-related events (SREs) prior to 
study entry defined as: external beam radiotherapy (EBRT) for bone pain, pathological 
bone fracture (excluding major trauma), spinal cord compression and/or orthopedic 
surgical procedure.  Subjects with no prior SREs are not permitted.  
Note: All prior SRE-related procedures (i.e., orthopedic surgery, EBRT) must be 
administered prior to randomization. Separate SRE events are the ones that occur at 
least 21 days apart from each other to ensure that linked events (e.g., surgery to repair a 
fracture or multiple doses of radiation during a course of treatment) are not counted as 
separate events. In case of bone pain that occurs in several anatomical locations and 
requires separate EBRT sessions, it should be counted as one event if the EBRT sessions 
are administered within a period of 21 days. 


 
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Deleted Text: 
12. Bone lesions related asymptomatic or mildly symptomatic breast cancer.  A worst pain 
score (WPS) of 0 to 1 on the Brief Pain Inventory-Short Form (BPI-SF) Question #3 
(worst pain in the last 24 hours) will be considered asymptomatic, and a WPS of 2 to 3 
will be considered mildly symptomatic.  This is to be assessed once during the screening 
period. 
Old text: 
14. 60 mL/min/1.73m2 according to the Modification of Diet in Renal Disease abbreviated 
formula. 
New text: 
14. 30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease abbreviated 
formula. (Note: please refer to local labelling for administration of full dose of 
bisphosphonates) 
 
Synopsis: Study Design, Section 5.1 Design overview 
This section was changed as a result of modification 4 
Old text: 
 Prior SREs (1 versus 2): for the purpose of prior SREs stratification, any procedure 
which is related to an SRE, such as orthopedic surgery to treat a pathological bone 
fracture, should not be counted as a separate event. 
New text: 
 Prior SREs (1 versus 2): for the purpose of prior SREs stratification, separate SREs 
are those that occur at least 21 days apart from each other. Any procedure which is 
related to an SRE, such as orthopedic surgery to treat a pathological bone fracture or 
multiple doses of radiation during a course of treatment, should not be counted as a 
separate event. In case of bone pain that occurs in several anatomical locations and 
requires separate EBRT sessions, it should be counted as one event if the EBRT 
sessions are administered within a period of 21 days. 
 
Synopsis: Methodology, Section 5.1.1 Study periods and duration 
This section was changed as a result of modification 2. 
Old text: 
All subjects will receive hormonal treatment with a single agent and supportive care as 
background treatment according to the local standard of practice. Subjects enrolled in the 
current study will start treatment with the single hormone agent after randomization either 
before or simultaneously to the first injection of radium-223 dichloride or placebo.  For 
subject’s convenience, injections of fulvestrant may be scheduled on the same day of the 


 
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radium-223 dichloride or placebo injection. Subjects already receiving treatment with 
hormone treatment prior to study entry are not eligible. 
New text: 
All subjects will receive hormonal treatment with a single agent and supportive care as 
background treatment according to the local standard of practice. Subjects enrolled in the 
current study must start treatment with the single hormone agent either within 15 days prior 
to randomization or after randomization (either before or simultaneously to the first injection 
of radium-223 dichloride or placebo).  For subject’s convenience, injections of fulvestrant 
may be scheduled on the same day of the radium-223 dichloride or placebo injection. 
 
Section 4. Study objectives, Section 5.1.2 Study endpoints, Section 9.4.1 Efficacy 
variables, and Section 10.3 Efficacy variables and planned statistical analyses 
This section was changed as a result of modification 1. 
Old text: 
 Time to pain progression 
New text: 
 Time to pain progression (only in subjects with baseline WPS ≤8) 
Added text: 
 Pain improvement rate 
 
Section 6. Study Population 
This section was changed as a result of modification 16. 
Old text: 
Eligibility is confirmed at the end of the screening period.  At that time the subject is 
randomized and enters the treatment period.  Administration of the first radium-223 
dichloride/placebo dose may occur 1 to 3 weeks after randomization.  This time is required 
for dose ordering and shipment.  Laboratory values will be verified prior to first study drug 
administration as per protocol.  Hematological support will be provided as needed according 
to the protocol guidance during the treatment period. 
New text: 
Eligibility is confirmed at the end of the screening period.  At that time the subject is 
randomized and enters the treatment period.  Laboratory values will be verified prior to first 
study drug administration as per protocol.  Hematological support will be provided as needed 
according to the protocol guidance during the treatment period.  
 


 
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Section 7.1 Treatments to be administered 
This section was changed as a result of modification 2 and 17. 
Old text: 
Subjects enrolled in the current study will start treatment with the single hormone agent after 
randomization either before or simultaneously to the first injection of radium-223 dichloride 
or placebo.  For subject’s convenience, injections of fulvestrant may be scheduled on the 
same day of the radium-223 dichloride/placebo injection. Subjects already receiving 
treatment with single hormone agent prior to study entry cannot be enrolled. 
New text: 
Subjects enrolled in the current study must start treatment with the single hormone agent 
either within 15 days prior to randomization or after randomization (either before or 
simultaneously to the first injection of radium-223 dichloride or placebo).  For subject’s 
convenience, injections of fulvestrant may be scheduled on the same day of the radium-223 
dichloride/placebo injection.  
Deleted text: 
Administration of bisphosphonates or denosumab should be done at least 2 hours before or 
after radium-223 dichloride/placebo administration. 
 
Section 7.2.1.1 Radium-223 dichloride 
This section was changed as a result of modification 3. 
Old text: 
The alpha particle emitting radiopharmaceutical BAY-88-8223 is a ready-to-use, sterile, non-
pyrogenic, clear and colorless aqueous solution of radium-223 dichloride for IV 
administration.  Radium-223 dichloride is an alpha particle emitter with a physical half-life of 
11.4 days.  The product is isotonic and has a pH of 6.0 to 8.0.  The radioactive concentration 
at the reference date is 1000 kBq/mL.  The product has a pre-calibration of 14 days.  When 
administered on a day other than the reference day, the volume should be corrected according 
to the physical decay table supplied with each shipment. 
 
The volume per vial is 6 mL, corresponding to 6 MBq at the calibration reference day.  
Radium-223 dichloride has a shelf life of 28 days from production day, when stored at 
ambient temperature.  The shelf life has been demonstrated for temperatures from cold 
storage (2°C to 8°C) up to 40°C.  In addition, it has been shown that the product quality is not 
jeopardized upon freezing.   
New text: 
The alpha particle emitting radiopharmaceutical BAY-88-8223 is a ready-to-use, sterile, non-
pyrogenic, clear and colorless aqueous solution of radium-223 dichloride for IV 
administration.  Radium-223 dichloride is an alpha particle emitter with a physical half-life of 


 
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11.4 days.  The product is isotonic and has a pH of 6.0 to 8.0.  The radioactive concentration 
at the reference date is 1000 kBq/mL (1100 kBq/ mL after implementation of NIST update).  
The product has a pre-calibration of 14 days.  When administered on a day other than the 
reference day, the volume should be corrected according to the physical decay table supplied 
with each shipment. 
The volume per vial is 6 mL, corresponding to 6 MBq (6.6 MBq after implementation of 
NIST update) at the calibration reference day.  Radium-223 dichloride has a shelf life of 28 
days from production day, when stored at ambient temperature.  The shelf life has been 
demonstrated for temperatures from cold storage (2°C to 8°C) up to 40°C.  In addition, it has 
been shown that the product quality is not jeopardized upon freezing.   
 
Section 7.4.1 Dose calibration  
This section was changed as a result of modification 3. 
Added text: 
As of Amendment 4, 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 [52]) 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 [53]), 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 [53]) in place at the time of implementation.  The 
current dial setting (NIST 2010 [52]) 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 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. 
 


 
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Section 7.4.3 Radium-223 dose calculation 
This section was changed as a result of modifications 3 and 9.  
Old text: 
The dosage of radium-223 dichloride is 50 kBq/kg body weight.  The total activity to be 
injected will be calculated volumetrically using the subject’s body weight within 3 days of 
injection (kg), the 50 kBq/kg 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 
according to the recommended formula below: 
Body weight (kg) x 50 kBq/kg = volume to be injected (mL) 
 
 
 
DK x 1000 kBq/mL 
New text: 
The dosage of radium-223 dichloride is 50 kBq/kg body weight (55 kBq/kg after 
implementation of NIST update).  The total activity to be injected will be calculated 
volumetrically using the subject’s body weight within 5 days of injection (kg), the 50 kBq/kg 
(55 kBq/kg after implementation of NIST update) dosage level, and the decay correction 
factor (DK) to correct for physical decay of radium-223.  A table with DKs according to 
physical decay of the study medication will be provided with each vial of radium-223 
dichloride.  The total amount (volume to be drawn into the syringe) to be administered to a 
subject should be calculated according to the recommended formula below: 
Body weight (kg) x 50 kBq/kga = volume to be injected (mL) 
  
 
DK x 1000 kBq/mLb 
a 55 kBq/kg after implementation of NIST update  
b 1100 kBq/mL after implementation of NIST update  
 
Section 7.4.6 Dose adjustments, delays, and treatment discontinuations 
This section was changed as a result of modification 7. 
Old text: 
Thrombocytopenia:  In case of thrombocytopenia NCI-CTCAE Grade 3 to 4, study drug 
administration should be delayed until recovery to CTCAE Grade 1 (minimum subjects with 
a platelet count 75 x 109 /L) or better before next study drug administration.  
New text: 
Thrombocytopenia:  In case of thrombocytopenia NCI-CTCAE Grade 2 to 4, study drug 
administration should be delayed until recovery to CTCAE Grade 1 (minimum subjects with 
a platelet count 75 x 109 /L) or better before next study drug administration.  
 


 
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Section 8.1.2 Permitted concomitant therapy 
This section was changed as a result of modification 2 and 17. 
Old text: 
 All subjects are expected to have been on therapy with either denosumab or 
bisphosphonates for at least 1 month before the start of study treatment and to 
continue on this therapy during the course of the study, with no change to therapy 
expected during the treatment phase of the study, except for toxicity reasons.  
Injection of bisphosphonates should be done at least 2 hours before or after study drug 
administration. 
 Subjects enrolled in the current study will start treatment with the single hormone 
agent after randomization either before or simultaneously to the first injection of 
radium-223 dichloride/placebo.  For subject’s convenience injections of fulvestrant 
may be scheduled on the same day of the radium-223 dichloride or placebo injection.  
Subjects already receiving treatment with a single hormone agent prior to study entry 
cannot be enrolled. 
New text: 
 All subjects are expected to have been on therapy with either denosumab or 
bisphosphonates for at least 1 month before the start of study treatment and to 
continue on this therapy during the course of the study, with no change to therapy 
expected during the treatment phase of the study, except for toxicity reasons.   
 Subjects enrolled in the current study must start treatment with the single hormone 
agent either within 15 days prior to randomization or after randomization (either 
before or simultaneously to the first injection of radium-223 dichloride/placebo).  For 
subject’s convenience injections of fulvestrant may be scheduled on the same day of 
the radium-223 dichloride or placebo injection.   
Section 8.1.1 Prohibited concomitant therapy 
This section was changed as a result of modification 19. 
Old text: 
Other cancer treatment with established efficacy in breast cancer except hormonal treatments 
should not be used during the treatment period. 
New text: 
Other cancer treatment with established efficacy in breast cancer except hormonal treatments 
or the permissible therapies mentioned in Section 8.1.2 should not be used during the 
treatment period. 
Section 9.1 Tabular schedule of evaluations 
This section was changed as a result of modifications 8, 9, 10, 11, 14, 16, and 18. 
Old text: 


 
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Table 9-1:  Schedule of assessments 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random. 
1 to 3 wk 
pre-Dose 1 
C1, Day 1 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 wk 
until 
SSE; 
q12 wk 
after 
SSEf 
q4 wk 
until SSE; 
q12 wk 
after 
SSEg 
 
 
Window (days): 
 
 
±7 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
±7 
±7 
±7 
 
BPI-SFi 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
Vital signsp 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Physical examinationr 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
Hematologys 
Xt 
 
Xu 
X 
Xu 
X 
Xu 
 
Xu 
Xu 
Xu 
X 
X 
 
X 
 
Clinical chemistryv 
Xt 
 
Xw 
X 
Xw 
X 
Xw 
 
Xw 
Xw 
Xw 
X 
X 
 
X 
 


 
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New text: 
Table 9-1:  Schedule of assessments 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random. 
 
C1, Day 1 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 wk 
until 
SSE; 
q12 wk 
after 
SSEf 
q4 wk 
until SSE; 
q12 wk 
after 
SSEg 
 
 
Window (days): 
 
 
 
±3 
± 7 
±3 
± 7 
±3 
± 7 
± 7 
± 7 
± 7 
±7 
±7 
±7 
±7 
 
BPI-SFi 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
Vital signsp 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xhh 
 
X 
 
 
Physical examinationr 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Xhh 
 
X 
 
 
Hematologys 
Xt 
 
Xu 
X 
Xu 
X 
Xu 
 
Xu 
Xu 
Xu 
X 
Xhh 
 
X 
 
Clinical chemistryv 
Xt 
 
Xw 
X 
Xw 
X 
Xw 
 
Xw 
Xw 
Xw 
X 
Xhh 
 
X 
 
 


 
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Old text: 
i. BPI-SF will be dispensed to the subject at Screening and the visit just before Cycle 1, 
Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1; Cycle 6, 
Day 1; EOT; and follow-up clinic visits. 
 
o. At screening an individual analgesic consumption diary will be dispensed to the subject 
just the visit before Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; 
Cycle 5, Day 1; Cycle 6, Day 1; EOT; and follow-up clinic visits.  Subjects will be 
asked to record analgesic use daily for one week (6 days prior to visit plus day of 
visit).  Pain medication will also be assessed at each treatment and follow-up visit by 
study site; subjects should be requested to bring all pain medication to each visit.  
Analgesic use will be recorded in the appropriate eCRF page. 
 
q. Subject’s weight should be re-checked prior to each injection to calculate appropriate 
drug dosing.  At all sites, weight is to be taken only once for each dose and it should 
be measured within 72 hours prior to dosing.  For US sites using the central PRD 
depot only, the subject weight for the dose day must be reported in a timely manner 
to the country PRD depot to allow adequate time for the 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 to avoid 2 pre-dose clinic 
visits.  
 
u. Blood sample for hematology must be taken, analyzed, and evaluated within the 72 
hours prior to each study drug administration.  
 
w. Blood sample for clinical chemistry must be taken within 72 hours prior to each study 
drug administration, but may be evaluated after the administration.   
 
x. PT, INR, and PTT: Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, 
dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to participate in 
the study if no underlying abnormality in coagulation parameters exists per prior 
history; weekly evaluation of INR/PTT will be required until stability is achieved for 
anticoagulants that require their monitoring as per local label.  
y. Pre-menopausal women must have a negative serum pregnancy test performed within 
7 days prior to randomization, prior to each study drug administration 3 and EOT.  
Post-menopausal women (as defined in Section 6.1) are not required to undergo a 
pregnancy test.  A plasma/serum estradiol assay is required within 7 days prior to 
randomization in pre-menopausal women with radiotherapy ovarian ablation or 
medical ovarian suppression and post-menopausal women age <55 years and one year 
or more of amenorrhea. 
z. Blood and/or urine sample for exploratory evaluation of biomarkers, prior to radium-
223 dichloride/placebo administration.  Serum and plasma samples will be collected 


 
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at Cycle 1, Day 1; Cycle 4, Day 1; and EOT or disease progression, whichever 
occurs first.  Urine samples will be collected at Cycle 1, Day 1; Cycle 4, Day 1; and 
EOT visits (or at the time of disease progression, whichever occurs earlier). 
New text: 
i. BPI-SF will be dispensed to the subject at the visit just before Cycle 1, Day 1; Cycle 
2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1; Cycle 6, Day 1; EOT; 
and follow-up clinic visits. 
o. An individual analgesic consumption diary will be dispensed to the subject just the visit 
before Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 
1; Cycle 6, Day 1; EOT; and follow-up clinic visits.  Subjects will be asked to record 
analgesic use daily for one week (6 days prior to visit plus day of visit).  Pain 
medication will also be assessed at each treatment and follow-up visit by study site; 
subjects should be requested to bring all pain medication to each visit.  Analgesic use 
will be recorded in the appropriate eCRF page. 
 
q. Subject’s weight should be re-checked prior to each injection to calculate appropriate 
drug dosing.  At all sites, weight is to be taken only once for each dose and it should 
be measured within 5 days prior to dosing.  For US sites using the central PRD 
depot only, the subject weight for the dose day must be reported in a timely manner 
to the country PRD depot to allow adequate time for the 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 to avoid 2 pre-dose clinic 
visits.  
 
u. Blood sample for hematology must be taken, analyzed, and evaluated within the 5 
days prior to each study drug administration.  
 
w. Blood sample for clinical chemistry must be taken within 5 days prior to each study 
drug administration, and must be evaluated prior to the administration.   
 
x. PT, INR, and PTT: Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, 
dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to participate in 
the study if no underlying abnormality in coagulation parameters exists per prior 
history; weekly evaluation of INR/PTT will be required until stability is achieved for 
anticoagulants that require their monitoring as per local label. Blood sample for 
coagulation tests must be taken and evaluated within 5 days prior to each study drug 
administration.  
y. Pre-menopausal women must have a negative serum pregnancy test performed within 
7 days prior to randomization, prior to each study drug administration (taken and 
evaluated within 5 days prior to administration), and EOT.  Post-menopausal women 
(as defined in Section 6.1) are not required to undergo a pregnancy test.  A 
plasma/serum estradiol assay is required within 7 days prior to randomization in 


 
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pre-menopausal women with radiotherapy ovarian ablation or medical ovarian 
suppression and post-menopausal women age <55 years and one year or more of 
amenorrhea. 
z. Blood and/or urine sample for exploratory evaluation of biomarkers, prior to radium-
223 dichloride or placebo administration.  Serum and plasma samples will be 
collected within 5 days of dosing at Cycle 1, Day 1; Cycle 4, Day 1; and EOT visits 
or disease progression, whichever occurs first.  Urine samples will be collected at 
Cycle 1, Day 1; Cycle 4, Day 1; and EOT visits or disease progression, whichever 
occurs first. 
Added text: 
hh. Performed every 12 weeks 
 
Section 9.2.1 Screening period (Visit 0 to 1) 
This section was changed as a result of modification 8. 
Old text: 
One week prior to randomization, the subject should be given a subject diary to be used for 
subject questionnaires and the analgesic consumption and should receive training in its use.  
Subjects will then complete the following assessments: 
BPI-SF questionnaire will be completed only once prior to randomization to assess WPS in 
the last 24 hours: a worst pain score of 0 to 1 on the BPI-SF Question #3 (worst pain in the 
last 24 hours) will be considered asymptomatic, and a WPS of 2 to 3 will be considered 
mildly symptomatic.   
New text: 
One week prior to randomization, the subject should be given a subject diary to be used for 
subject questionnaires and the analgesic consumption and should receive training in its use. 
 
Section 9.2.3 Treatment period 
This section was changed as a result of modification 2, 9 and 10. 
Old text: 
 All subjects will receive background standard of care hormonal treatment for breast 
cancer.  Subjects enrolled in the current study will start treatment with the single 
hormone agent after randomization either before or simultaneously to the first 
injection of radium-223 dichloride/placebo.  For subject’s convenience, injections of 
fulvestrant may be scheduled on the same day of the radium-223 dichloride/placebo 
injection.  Subjects already receiving treatment with a single hormone agent prior to 
study entry cannot be enrolled. 
 


 
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It is the responsibility of the unblinded person to calculate the required volume of study drug 
(i.e., dose of radium-223 dichloride/placebo) for the subject based on the subject’s body 
weight within 3 days of administration and the reference date of the received study 
medication (Section 7.4.3). 
For US sites using the central PRD depot ONLY, the subject weight for the dose day must be 
reported to the country PRD depot in a timely manner to allow adequate time for the PRD 
preparation and delivery.  The subject’s weight measurement, order confirmation call to the 
IXRS, and prescription for the central PRD depot are to be performed 3 days prior to 
injection.  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 blood samples for clinical chemistry and hematology should be taken within 3 days before 
each study drug administration, and the hematology parameters must be evaluated before each 
study drug administration (within 3 days). 
Before the first administration of radium-223 dichloride/placebo (within 3 days), the ANC 
should be ≥1.5 x 109/L, the platelet count ≥100 x 109/L, and Hb ≥8.0 g/dL. 
 
New text: 
 All subjects will receive background standard of care hormonal treatment for breast 
cancer.  Subjects enrolled in the current study must start treatment with the single 
hormone agent either within 15 days prior to randomization or after randomization 
(either before or simultaneously to the first injection of radium-223 
dichloride/placebo).  For subject’s convenience, injections of fulvestrant may be 
scheduled on the same day of the radium-223 dichloride/placebo injection.   
 
 It is the responsibility of the unblinded person to calculate the required volume of 
study drug (i.e., dose of radium-223 dichloride/placebo) for the subject based on the 
subject’s body weight within 5 days of administration and the reference date of the 
received study medication (Section 7.4.3). 
 
For US sites using the central PRD depot ONLY, the subject weight for the dose day must be 
reported to the country PRD depot in a timely manner to allow adequate time for the PRD 
preparation and delivery.  The subject’s weight measurement, order confirmation call to the 
IXRS, and prescription for the central PRD depot are to be performed 5 days prior to 
injection.  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. 
 


 
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The blood samples for clinical chemistry and hematology should be taken within 5 days 
before each study drug administration, and the hematology parameters must be evaluated 
before each study drug administration (within 5 days). 
Before the first administration of radium-223 dichloride/placebo (within 5 days), the ANC 
should be ≥1.5 x 109/L, the platelet count ≥100 x 109/L, and Hb ≥8.0 g/dL. 
 
Section 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each 
visit) 
This section was changed as a result of modification 9, 10, 11, and 15. 
Old text: 
 Record weight (kg), within 3 days prior to dosing 
 
 Blood draw for hematology evaluation (within 72 hours before radium-223 dichloride 
or placebo administration): hematocrit, Hb, platelet counts, RBC counts, WBC 
counts, and WBC.  Results to be assessed and documented prior to study drug 
treatment.  The Hb values need to be confirmed to be at least 8 g/dL prior to each 
dose.  If blood is drawn the day of the administration of radium-223 
dichloride/placebo, results must be available prior to study drug administration. 
 
 Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, 
creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin (blood 
sample for clinical chemistry must be taken within 72 hours prior to each study drug 
administration).  
 A coagulation panel (blood sample to be taken within 72 hours prior to each study 
drug administration): PT, PTT, and INR. 
 Pregnancy test: pre-menopausal women must have a negative serum pregnancy test 
performed within 72 hours before radium-223 dichloride or placebo administration.  
Post-menopausal women (as defined in Section 6.1) are not required to undergo a 
pregnancy test. 
 Blood draw and urine sample for exploratory biomarker analysis: serum, plasma, and 
urine samples will be collected at Visit 2 (Cycle 1, Day 1) and Visit 8 (Cycle 4, 
Day 1). 
 
 For US sites using the central PRD depot ONLY, the subject weight for the dose day 
must be reported to the country PRD depot in a timely manner to allow adequate time 
for the PRD preparation and delivery.  The subject’s weight measurement, order 
confirmation call to the IXRS, and prescription for the central PRD depot are to be 
performed 3 days prior to injection.  All efforts should be made to measure weight at 


 
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the same visit with the pre-dose laboratory assessments in order to avoid 2 pre-dose 
clinic visits.  
New text: 
 Record weight (kg), within 5 days prior to dosing 
 
 Blood draw for hematology evaluation (must be taken and evaluated within 5 days 
before radium-223 dichloride or placebo administration): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC.  Results to be assessed and documented 
prior to study drug treatment.  The Hb values need to be confirmed to be at least 
8 g/dL prior to each dose.  If blood is drawn the day of the administration of radium-
223 dichloride/placebo, results must be available prior to study drug administration. 
 
 Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, 
creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin (blood 
sample for clinical chemistry must be taken and evaluated within 5 days prior to each 
study drug administration).  
 A coagulation panel (blood sample to be taken and evaluated within 5 days prior to 
each study drug administration): PT, PTT, and INR. 
 Pregnancy test: pre-menopausal women must have a negative serum pregnancy test 
performed and evaluated within 5 days before radium-223 dichloride or placebo 
administration.  Post-menopausal women (as defined in Section 6.1) are not required 
to undergo a pregnancy test. 
 Blood draw and urine sample for exploratory biomarker analysis: serum, plasma, and 
urine samples will be collected within 5 days of Visit 2 (Cycle 1, Day 1) and within 5 
days of Visit 8 (Cycle 4, Day 1). 
 
 For US sites using the central PRD depot ONLY, the subject weight for the dose day 
must be reported to the country PRD depot in a timely manner to allow adequate time 
for the PRD preparation and delivery.  The subject’s weight measurement, order 
confirmation call to the IXRS, and prescription for the central PRD depot are to be 
performed 5 days prior to injection.  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.  
 
Section 9.2.3.3 End of treatment visit 
This section was changed as a result of modification 10, 11, and 15. 


 
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Old text: 
 Blood draws for hematology (within 72 hours of the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC.   
 Blood draws for clinical chemistry (within 72 hours of the visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin. 
 A coagulation panel (within 72 hours of the visit): PT, PTT, and INR. 
 Pregnancy test (within 72 hours of the visit): pre-menopausal women must have a 
negative serum pregnancy test.  Post-menopausal women (as defined in Section 6.1) 
are not required to undergo a pregnancy test. 
 Blood draw and urine sample for exploratory biomarker analysis (serum, plasma, and 
urine samples will be collected at the EOT or at the time of disease progression, 
whichever occurs earlier) 
New text: 
 Blood draws for hematology (within 5 days prior to the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC.   
 Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin. 
 A coagulation panel (within 5 days of the visit): PT, PTT, and INR. 
 Pregnancy test (within 5 days of the visit): pre-menopausal women must have a 
negative serum pregnancy test.  Post-menopausal women (as defined in Section 6.1) 
are not required to undergo a pregnancy test. 
 Blood draw and urine sample for exploratory biomarker analysis (serum, plasma, and 
urine samples will be collected within 5 days or at the time of disease progression, 
whichever occurs earlier) 
 
Section 9.2.4.1 Active follow-up with clinic visits 
This section was changed as a result of modifications 10 and 14 
Old text: 
The following procedures/evaluations should be performed at these visits. 
 Record vital signs:  blood pressure, heart rate, respiratory rate, and temperature  
 Perform full physical examination: A full physical examination must include the 
evaluation of head, eyes, ears, nose, throat, cardiovascular, respiratory, 
gastrointestinal, dermatological, musculoskeletal, and neurological systems. 
 


 
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 Blood draws for hematology (within 72 hours of the visit):  hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, WBC differential  
 Blood draws for clinical chemistry (within 72 hours of visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin  
 Radiological tumor assessment: to be performed until radiological disease progression 
is documented. 
New text: 
The following procedures/evaluations should be performed at these visits. (Note that vital 
signs measurement, full physical examination, blood draws, and radiological tumor 
assessment are only to be performed every 12 weeks ±7 days) 
 Record vital signs (every 12 weeks):  blood pressure, heart rate, respiratory rate, and 
temperature  
 Perform full physical examination (every 12 weeks): A full physical examination 
must include the evaluation of head, eyes, ears, nose, throat, cardiovascular, 
respiratory, gastrointestinal, dermatological, musculoskeletal, and neurological 
systems. 
 
 Blood draws for hematology every 12 weeks (within 5 days of the visit):  hematocrit, 
Hb, platelet counts, RBC counts, WBC counts, WBC differential  
 Blood draws for clinical chemistry every 12 weeks (within 5 days of the visit): Na, K, 
Cl, Ca, ALT, AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin 
(total), total cholesterol, and albumin  
 Radiological tumor assessment: to be performed every 12 weeks until radiological 
disease progression is documented 
 
Section 9.2.4.3 End of active follow-up 
This section was changed as a result of modification 10 and 18. 
Old text: 
 Blood draws for hematology (within 72 hours of the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC differential  
 Blood draws for clinical chemistry (within 72 hours of the visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin 
 


 
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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/placebo.  For all deaths, the date of death information will be collected 
in the end-of-follow-up page of the eCRF. 
New text: 
 Blood draws for hematology (within 5 days of the visit): hematocrit, Hb, platelet 
counts, RBC counts, WBC counts, and WBC differential  
 Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Cl, Ca, ALT, 
AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin  
 
For subjects who die >30 days after the administration of last study treatment, submission of 
the AE complementary pages of the eCRF is not required unless the death is considered 
related to radium-223 dichloride/placebo.  For all deaths, the date of death information will 
be collected in the end-of-follow-up page of the eCRF. 
 
Section 9.2.6 Radiological assessment: tumor and response evaluation 
This section was changed as a result of modification 12. 
Added text: 
All digitized images/scans (both baseline and post-baseline) will be collected for 
retrospective analysis. 
 
Section 9.4.2.2 Secondary efficacy endpoints 
This section was changed as a result of modification 1. 
Old text: 
Time to pain progression is defined as the interval from randomization to the first date 
a subject experiences pain progression based on WPS.  Pain progression is defined as an 
increase of 2 or more points in the “Worst pain in 24 hours” score from baseline observed at 
2 consecutive evaluations ≥4 weeks apart  
New text: 
Time to pain progression will be evaluated in subjects with baseline WPS ≤ 8.  Time to pain 
progression is defined as the interval from randomization to the first date a subject 
experiences pain progression based on WPS.  Pain progression is defined as an increase of 2 
or more points in the “Worst pain in 24 hours” score from baseline observed at 2 consecutive 
evaluations ≥4 weeks apart  


 
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Added text: 
Pain improvement is defined for subjects evaluable for pain improvement, i.e. subjects with 
baseline WPS > 3, as a 2-point decrease or more in WPS from baseline over 2 consecutive 
measurements conducted at least 4 weeks apart.  
Pain improvement rate is defined as the number of subjects with pain improvement as 
defined above, divided by the total number of subjects evaluable for pain improvement (i.e., 
subjects with baseline WPS>3). Both pain improvement rate at all visits and by visit will be 
considered. 
 
Section 9.7.2.1 Urine, plasma, and serum based biomarker analysis 
This section was changed as a result of modification 11. 
Old text: 
Blood samples will be obtained from all subjects at the following time points: (1) Cycle 1, 
Day 1 (Visit 2) and Cycle 4, Day 1 (Visit 8) prior to radium-223 dichloride or placebo 
administration, and at EOT visit or disease progression, whichever occurs first.  At these time 
points, urine samples will also be collected. 
New text: 
Blood samples will be obtained from all subjects at the following time points: (1) Cycle 1, 
Day 1 (Visit 2) and Cycle 4, Day 1 (Visit 8) within 5 days of the visit prior to radium-223 
dichloride or placebo administration, and within 5 days of the EOT visit or disease 
progression, whichever occurs first.  At these time points, urine samples will also be 
collected. 
 
Section 10.1 General considerations 
This section was changed as a result of modification 4. 
Old text: 
Prior SREs (1 versus 2): for the purpose of prior SREs stratification, any procedure which is 
related to an SRE, such as orthopedic surgery to treat a pathological bone fracture, should not 
be counted as a separate event. 
New text: 
Prior SREs (1 versus 2): for the purpose of prior SREs stratification, separate SREs are those 
that occur at least 21 days apart from each other. Any procedure which is related to an SRE, 
such as orthopedic surgery to treat a pathological bone fracture or multiple doses of radiation 
during a course of treatment, should not be counted as a separate event. In case of bone pain 
that occurs in several anatomical locations and requires separate EBRT sessions, it should be 
counted as one event if the EBRT sessions are administered within a period of 21 days. 
 


 
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Section 14. Reference list 
This section was changed as a result of modification 3 and 13. 
Added text: 
52 Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation 
counting. Appl Radiat Isot. 2010;68(7-8):1523-8. 
53 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. 
54 Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann 
Acad Med Singapore. 1994;23:129-38. 
 
Appendix 16.6 BPI-SF 
This section was changed as a result of modification 13. 
Added text: 
The severity of pain and its impact on daily functions will be self-assessed by the study 
subjects using the BPI-SF (54) 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.  
The BPI-SF will be self-administered by the subject at Dose 1, Day 1 (before the start of 
study treatment), at each treatment visit, at the end of treatment visit and follow-up clinic 
visits. 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 


 
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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 her 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 her.  
How should the Questionnaire be introduced?  
A sample script for introducing the questionnaire 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 complete this questionnaire about your health on the day of each 
clinic visit. 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. 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 her 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  
At the beginning of each visit, please check that 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 her whether she had any difficulty completing 
the questionnaire. If the subject says that she had trouble understanding a question, ask her 
why she had difficulty with that item. Re-read the question for her 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 


 
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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. 


 
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15.4 Amendment 5 
Amendment 5 (dated 11 Mar 2016) is an amendment to the Version 4.0 of the protocol, dated 
29 JUL 2015.  Changes to the protocol include: 
 Updated text for estradiol assay as postmenopausal ranges and detection limit for 
serum/plasma estradiol assay vary per laboratory. 
 Deleted text for exclusion of bilateral and 2 distinct breast cancers. 
 Clarified data collection for pain medication in alignment with completion of the 
BPI-SF questionnaire. 
 Added text for completion of PRO Questionnaire Information Sheet by study staff for 
when BPI questionnaire is required to be completed. 
 Clarified the process for unblinded personnel to obtain subject’s treatment 
assignment. 
 Clarified the drug order process at sites in the US. 
 Clarified radium-223 administration timelines. 
 Changed the SRE definition used for eligibility to make in line with the SRE 
definition used in prior studies with other bone targeted agents (denosumab, 
bisphosphonates). 
 Updated text to be consistent with rest of protocol. 
 Updated time period for recording of analgesic use in diary. 
 Added text as biomarkers are to be collected before study drug dosing. 
 Added PRO Questionnaire Information Sheet for completeness. 
 Updated text for clarification. 
 Revised definition of pain progression. 
 Added separate collection of opiate use to allow calculation of time to opiate use. 
 Removed progression as a separate assessment because progression is assessed 
radiologically as per tumor assessment schedule. 
 Clarified that clinical chemistry assessment will include bone marrow ALP only if 
that testing can be performed locally. 
 Clarified timing of technetium-99m bone scans and CT scans. 
 Updated study medical expert and contact information. 
 Added sampling for CTCs, which are believed to represent a surrogate for tumor cells 
and can be used as a surrogate to demonstrate efficacy of the drug by enumeration of 
CTCs but also as a source of tumor molecular characterizations. 


 
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15.4.1 Overview of changes to the study 
Modification 1 
Updated text for estradiol assay as postmenopausal ranges and detection limit for 
serum/plasma estradiol assay vary per laboratory.  
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion Criteria 
 
Modification 2 
Deleted text for exclusion of bilateral and 2 distinct breast cancers.  Eligible patients for this 
study must have stage IV (Any T, Any N, M1) metastatic disease and be considered 
candidates for second or further line of therapy.  None of the recent studies (i.e. BOLERO, 
PALOMA) in metastatic setting excluded patients with such conditions.   
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.2  Exclusion Criteria 
 
Modification 3 
Clarified data collection for pain medication in alignment with completion of the BPI-SF 
questionnaire. 
Sections affected include: 
 8.1.2 Permitted concomitant therapy 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 9.4.2.2 Secondary efficacy endpoints 
 
Modification 4 
Added text for completion of PRO Questionnaire Information Sheet by study staff for when 
BPI questionnaire is required to be completed. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 


 
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 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 
Modification 5 
Clarified the process for unblinded personnel to obtain subject’s treatment assignment. 
Section affected includes: 
 7.3 Treatment assignment 
 
Modification 6 
Clarified the drug order process at sites in the US. 
Section affected includes: 
 7.3 Treatment assignment 
 
Modification 7 
Clarified radium-223 administration timelines. 
Section affected includes: 
 7.2.1.1 Radium-223 dichloride 
 
Modification 8 
Changed the SRE definition used for eligibility to make in line with the SRE definition used 
in prior studies with other bone targeted agents (denosumab, bisphosphonates).   
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion Criteria 
 
Modification 9 
Updated text to be consistent with rest of protocol. 
Section affected includes: 
 Figure 5-1: Study design schematic 


 
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Modification 10 
Updated time period for recording of analgesic use in diary. 
Section affected includes: 
 9.1 Tabular schedule of evaluations 
 
Modification 11 
Added text as biomarkers are to be collected before study drug dosing. 
Sections affected include: 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 
Modification 12 
Added PRO Questionnaire Information Sheet for completeness. 
Sections affected include: 
 16.8 Patient Reported Questionnaire Information Sheet 
 
Modification 13 
Updated text for clarification. 
Sections affected include: 
 6. Study population 
 9.1 Tabular schedule of evaluations 
 9.2.6 Radiological assessment 
 9.4.2.2 Secondary efficacy endpoints 
 9.4.2.3 Exploratory efficacy endpoints 
 9.6.1.3 Assessments and documentation of adverse events 
 9.7.2 Biomarker assessments 
 
Modification 14 
Revised definition of pain progression. 
Sections affected include: 
 List of abbreviations 
 9.4.2.2 Secondary efficacy endpoints 


 
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Modification 15 
Added separate collection of opiate use to allow calculation of time to opiate use. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 
Modification 16 
Removed progression as a separate assessment because progression is assessed radiologically 
as per tumor assessment schedule. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.2 Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 
Modification 17 
Clarified that clinical chemistry assessment will include bone marrow ALP only if that 
testing can be performed locally. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 9.2.1 Screening period (Visits 0 to 1) 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.2 Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 


 
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 9.2.4.3 End of active follow-up 
 9.3.3 Other baseline characteristics 
 
Modification 18 
Clarified timing of technetium-99m bone scans and CT scans. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 9.2.6 Radiological assessment: tumor and response evaluation 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.3 End of active follow-up 
 
Modification 19 
Updated study medical expert and contact information. 
Section affected includes: 
 Title page 
 
Modification 20 
Added sampling for CTCs, which are believed to represent a surrogate for tumor cells and 
can be used as a surrogate to demonstrate efficacy of the drug by enumeration of CTCs but 
also as a source of tumor molecular characterizations. 
Sections affected include: 
 List of Abbreviations 
 9.1 Tabular schedule of evaluations 
 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each visit) 
 9.2.3.3 End of treatment visit 
 9.7.2.2 Collection of Circulating Tumor Cells for Biomarker Analyses 


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 
age ≥55 years and one year or more of amenorrhea,  
 
age <55 years and one year or more of amenorrhea with a plasma/serum 
estradiol assay <20 pg/mL, within 7 days of randomization  
 
bilateral ovariectomy 
 
10. Subjects must have experienced no more than 2 skeletal-related events (SREs) prior to 
study entry defined as: External beam radiotherapy (EBRT) for bone pain, pathological bone 
fracture (excluding major trauma), spinal cord compression, and/or orthopedic surgical 
procedure.  Subjects with no prior SREs are not permitted.  
New text: 
5. Documentation of menopausal status: post-menopausal or pre-menopausal subjects are 
eligible. 
 
Note: In premenopausal subjects, ovarian radiation or treatment with a luteinizing 
hormone-releasing hormone (LH-RH) agonist/antagonist is permitted for induction of 
ovarian suppression if the plasma/serum estradiol assay is within local laboratory 
postmenopausal range at screening, performed within 7 days of randomization. 
o 
Pre-menopausal subjects with or without ovarian radiation or concomitant 
treatment with an LH-RH agonist/antagonist must have a negative pregnancy test 
at screening and agree to use an adequate method of contraception as 
recommended by their treating physicians 
o 
Post-menopausal status is defined either by:  
 
age ≥55 years and one year or more of amenorrhea,  
 
age <55 years and one year or more of amenorrhea with a plasma/serum 
estradiol assay within local laboratory postmenopausal range, performed 
within 7 days of randomization  
 
bilateral ovariectomy 
 
10. Subjects must have experienced no more than 2 skeletal-related events (SREs) prior to 
study entry defined as: Need for external beam radiotherapy (EBRT) to bone, pathological 
bone fracture (excluding major trauma), spinal cord compression, and/or orthopedic surgical 
procedure.  Subjects with no prior SREs are not permitted.  
 


 
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Synopsis: Diagnosis and main criteria for inclusion and exclusion, Section 6.2 Exclusion 
criteria 
This was changed as a result of modification 2. 
Old text: 
3. Subjects with any of the following cancers: 
o 
iInflammatory breast cancer 
o 
Bilateral breast cancer or a history of 2 distinct breast cancers 
New text: 
3. Subjects with inflammatory breast cancer 
 
Section: List of abbreviations 
This was changed as a result of modification 14 and 20. 
Added text: 
IPM 
Increase in pain management 
 
CTC 
Circulating tumor cell 
 
Section: Figure 5-1 Study design schematic 
This was changed as a result of modification 9. 
Old text: 
Subjects who discontinue treatment, had an EOT visit, and can travel to the investigational 
site will be followed until the subject can no longer travel to the clinic, dies, is lost to follow 
up, or withdrawals informed consent and actively objects to collection of further data. The 
maximum duration of the active follow up is until study termination. 
New text: 
Subjects who discontinue treatment, had an EOT visit, and can travel to the investigational 
site will be followed until the subject can no longer travel to the clinic, experiences an SSE 
and radiological progression, dies, is lost to follow up, or withdrawals informed consent and 
actively objects to collection of further data. The maximum duration of the active follow up is 
until study termination. 
 


 
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Section 6. Study population 
This was changed as a result of modification 13. 
Old text: 
Approximately 227 subjects with HER2 negative, hormone receptor positive breast cancer 
with bone metastases will be enrolled and treated. 
New text: 
Approximately 227 subjects with HER2 negative, hormone receptor positive breast cancer 
with bone metastases will be randomized. 
 
Section 7.2.1.1 Radium-223 dichloride 
This was changed as a result of modification 7. 
Old text: 
It is important to note that, in general (unless otherwise agreed), in cases where study drug 
has been ordered, the time window for administration should be within 3 days of the day of 
receipt.  If administration must be postponed more than 3 days after receipt, replacement of 
the drug order is required. 
New text: 
It is important to note that, in general (unless otherwise agreed), in cases where study drug 
has been ordered, the time window for administration should be within 3 days of the planned 
treatment day.  If administration must be postponed more than 3 days, replacement of the 
drug order is required. 
 
Section 7.3 Treatment assignment 
This was changed as a result of modifications 5 and 6. 
Old text: 
The IXRS will provide only the randomization number to the caller, i.e., blinded personnel, 
but not the assigned treatment.  A confirmation e-mail containing randomization number and 
treatment will be sent to the unblinded staff member who will be responsible for preparing 
the study drug for the subject for the first administration.  When the subject is allocated to 
radium-223 dichloride, the unblinded person will use IXRS to send an order to the 
manufacturer for drug shipment.  The timing for the drug order should be based on the 
planned subject visit date.  If the subject is allocated to placebo, the unblinded person at the 
study site will be responsible for providing saline corresponding to the IXRS treatment day.  
This should not be made available before to avoid unblinding the subject and blinded study 
personnel.  


 
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New text: 
The IXRS will provide only the randomization number to the caller, i.e., blinded personnel, 
but not the assigned treatment.  A confirmation e-mail containing randomization number will 
be sent to the unblinded personnel who will have to log into IXRS in order to know the 
treatment arm assigned to the patient.  The unblinded personnel will be responsible for 
preparing the study drug for the subject for the first administration.  For US only, if a subject 
is allocated to radium-223 dichloride, the unblinded personnel will fax shipment request to 
Cardinal Health for pre-filled syringe.  The timing for the drug order should be based on the 
planned subject visit date.  If the subject is allocated to placebo, the unblinded person at the 
study site will be responsible for providing saline corresponding to the IXRS treatment day.  
This should not be made available before to avoid unblinding the subject and blinded study 
personnel.  
 
Section 8.1.2 Permitted concomitant therapy 
This was changed as a result of modification 3. 
Old text: 
 Analgesic use will be captured via a subject diary and the eCRF (analgesic consumption 
diary and recorded analgesics, respectively, see schedule of assessments, Table 9-1).  
Subjects will be asked to track their analgesic use on an analgesic consumption diary for 
1 week prior to their clinic visit.  Any medication taken for pain, whether for palliation of 
bone pain or relief of other type of pain, and any changes should be recorded in the eCRF 
at each visit.  Note that EBRT treatment should be recorded in the eCRFs until end of the 
active follow-up period without clinic visits. 
New text: 
 Analgesic use will be captured via a subject diary (analgesic consumption diary) and the 
eCRF (24-hour analgesics use page and regular analgesics concomitant medication page, 
see schedule of assessments, Table 9-1).  Subjects will be asked to track their analgesic 
use on an analgesic consumption diary for 24 hours prior to their clinic visit.  Any 
medication taken for pain, whether for palliation of bone pain or relief of other type of 
pain, and any changes should be recorded in the eCRF at each visit.  Note that EBRT 
treatment should be recorded in the eCRFs until end of the active follow-up period 
without clinic visits. 
 


 
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Section 9.1 Tabular schedule of evaluations 
This was changed as a result of modifications 4, 10, 13, 15, 16, 17, 18, and 20. 
Old text: 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random. 
 
C1, Day 11 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 
wk 
until 
SSE; 
q12 
wk 
after 
SSEf 
q4 
wk 
until 
SSE; 
q12 
wk 
after 
SSEg 
 
 
Window 
(days): 
 
 
 
±3 
± 
7 
±3 
± 
7 
±3 
± 
7 
± 
7 
± 7 
± 7 
±7 
±7 
±7 
±7 
Technetium-
99m bone 
scanaa 
Xbb 
 
 
 
 
 
Xaa 
 
 
 
Xaa  
Xaa 
Xaa 
 
Xaa 
 
Chest, 
abdominal and 
pelvic CT 
scanaa,cc,dd,ee 
X 
 
 
 
 
 
Xaa 
 
 
 
Xaa 
Xaa 
Xaa 
 
Xaa 
 
Progression 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
New text: 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
Active  
Follow-up 
 
End of Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
With 
Clinic 
Visits 
W/O 
Clinic 
Visits 
Visit: 
0-1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random. 
 
C1, Day 11 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dosee 
q4 
wk 
until 
SSE; 
q12 
wk 
after 
SSEf 
q4 
wk 
until 
SSE; 
q12 
wk 
after 
SSEg 
 
 
Window (days): 
 
 
 
±3 
± 
7 
±3 
± 
7 
±3 
± 
7 
± 
7 
± 
7 
± 7 
±7 
±7 
±7 
±7 
 
Record opiate use  
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 


 
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Whole Blood for 
CTCsii 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
  
 
 
 
Technetium-99m 
bone scanaa,bb 
X 
X 
Chest, abdominal 
and pelvic CT 
scanaa,cc,dd,ee 
X 
X 
Old text: 
i. BPI-SF will be dispensed to the subject at the visit just before Cycle 1, Day 1; Cycle 2, 
Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1; Cycle 6, Day 1; EOT; and follow-up 
clinic visits. 
 
o. An individual analgesic consumption diary will be dispensed to the subject just the visit 
before Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1; 
Cycle 6, Day 1; EOT; and follow-up clinic visits.  Subjects will be asked to record analgesic 
use daily for one week (6 days prior to visit plus day of visit).  Pain medication will also be 
assessed at each treatment and follow-up visit by study site; subjects should be requested to 
bring all pain medication to each visit.  Analgesic use will be recorded in the appropriate 
eCRF page. 
 
v. Sodium, potassium, chloride, calcium, aspartate aminotransferase, alanine 
aminotransferase, lactate dehydrogenase, bone alkaline phosphatase, serum creatinine, 
phosphate, blood urea nitrogen, bilirubin (total), total cholesterol, and albumin. 
 
aa. Radiological tumor evaluation must be performed 8 weeks (±7 days) after the first 
radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 
(radiological progression) is documented. If radiologic soft tissue or visceral progression in 
absence of bone progression (according to mRECIST 1.1 criteria) is observed, bone imaging 
and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS.  This schedule is to be maintained and will not be shifted because of 
treatment interruptions/delays.  Scans will be read locally.  The time window for the scans is 
±7 days. 
New text: 
i. BPI-SF will be dispensed to the subject at the visit just before Cycle 1, Day 1; Cycle 2, 
Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1; Cycle 6, Day 1; EOT; and follow-up 
clinic visits.  Additionally PRO Questionnaire Information Sheet is to be completed by 
clinical staff based on discussion with patient, even if patient does not complete the BPI-SF 
questionnaire. 
 
o. An individual analgesic consumption diary will be dispensed to the subject just the visit 
before Cycle 1, Day 1; Cycle 2, Day 1; Cycle 3, Day 1; Cycle 4, Day 1; Cycle 5, Day 1; 


 
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Cycle 6, Day 1; EOT; and follow-up clinic visits.  Subjects will be asked to record analgesic 
use 24 hours prior to their clinic visit. 
v. Sodium, potassium, chloride, calcium, aspartate aminotransferase, alanine 
aminotransferase, lactate dehydrogenase, bone alkaline phosphatase (if testing is available 
and can be performed locally), serum creatinine, phosphate, blood urea nitrogen, bilirubin 
(total), total cholesterol, and albumin. 
 
aa. Radiological tumor evaluation must be performed 8 weeks (±7 days) after the first 
radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 
(radiological progression) is documented. If radiologic soft tissue or visceral progression in 
absence of bone progression (according to mRECIST 1.1 criteria) is observed, bone imaging 
and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS till bone progression.  This schedule is to be maintained and will not be 
shifted because of treatment interruptions/delays.  Scans will be read locally.  The time 
window for the scans is ±7 days. 
 
ii. Details of sampling are described in the Laboratory Manual. Blood samples for analysis of 
circulating tumor cells will be collected within 5 days of Visits 2, 4, 6, 8, 9, 10  (ie, Day 1 of 
Cycles 1 through 6) prior to study drug dosing, and within 5 days of the EOT visit or disease 
progression, whichever occurs first. 
 
Section 9.2.1 Screening period (Visits 0 to 1) 
This was changed as a result of modification 17. 
Old text: 
 Blood draw for clinical chemistry: sodium (Na), potassium (K), chloride (Cl), calcium 
(Ca), ALT, AST, lactate dehydrogenase (LDH), bone ALP, serum creatinine, phosphate, 
blood urea nitrogen (BUN), total bilirubin, total cholesterol, and albumin. 
New text: 
 Blood draw for clinical chemistry: sodium (Na), potassium (K), chloride (Cl), calcium 
(Ca), ALT, AST, lactate dehydrogenase (LDH), bone ALP (if testing is available and can 
be performed locally), serum creatinine, phosphate, blood urea nitrogen (BUN), total 
bilirubin, total cholesterol, and albumin. 
 


 
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Section 9.2.3.1 Visits 2, 4, 6, 8, 9, and 10 (Day 1 of Cycles 1 through 6 ±7 days at each 
visit)  
This was changed as a result of modifications 3, 4, 11, 15, 16, 17, 18, and 20. 
Old text: 
BPI-SF questionnaire will be completed prior to any other study assessments/procedures and 
should be checked for completion at the visit 
 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in by the 
subjects for one week (6 days prior to visit plus day of visit) 
o Analgesic use during the last 24 hours recorded in eCRF, by site, assessing subject 
pain medication.  Subject should bring all pain medication to each visit 
New text: 
BPI-SF questionnaire will be completed prior to any other study assessments/procedures and 
should be checked for completion at the visit. Additionally PRO Questionnaire 
Information Sheet is to be completed by clinical staff based on discussion with patient, 
even if patient does not complete the BPI-SF questionnaire. 
 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in by the 
subjects for 24 hours prior to visit.  The analgesic use for 24 hours prior to the visit 
will be recorded by the investigator on the eCRF. 
Added text: 
 Record opiate use 
Old text: 
 Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, serum 
creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin (blood 
sample for clinical chemistry must be taken and evaluated within 5 days prior to each 
study drug administration). 
 
 Blood draw and urine sample for exploratory biomarker analysis: serum, plasma, and 
urine samples will be collected within 5 days of Visit 2 (Cycle 1, Day 1) and within 
5 days of Visit 8 (Cycle 4, Day 1). 


 
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New text: 
 Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP (if testing 
is available and can be performed locally), serum creatinine, phosphate, BUN, total 
bilirubin, total cholesterol, and albumin (blood sample for clinical chemistry must be 
taken and evaluated within 5 days prior to each study drug administration). 
 
 Blood draw and urine sample for exploratory biomarker analysis: serum, plasma, and 
urine samples will be collected within 5 days of Visit 2 (Cycle 1, Day 1) and within 
5 days of4 Visit 8 (Cycle 4, Day 1) prior to study drug dosing. 
Deleted text: 
 At Visit 6 and Visit 10 (Cycle 3, Day 1 and Cycle 6, Day 1) only (see also Section 9.2.6): 
o A chest/abdominal/pelvic CT or MRI.  The same imaging modalities are to be used as 
were used at baseline.   
o Bone technetium-99m scan with careful identification of all disease-related hotspots.  
All visible bone lesions must also be imaged with conventional anatomical imaging 
procedures, such as SPECT-CT/MRI or CT or MRI scan (with or without contrast 
media).  All new bone lesions or progression of existing bone lesion(s) identified on a 
technetium-99m bone scan will need confirmatory CT or MRI imaging.  In case of a 
new lesion or of progression of existing bone lesion(s) observed on a bone scan that is 
not confirmed by CT/MRI, progression will not be declared until the CT/MRI 
confirmation of progression occurs.  A CT/MRI confirmatory scan must take place 6 
to 8 weeks after the new lesion or progression of existing lesion(s) was observed on 
bone scan.  Modified RECIST version 1.1 (mRECIST 1.1) criteria will be applied to 
declare a PFS event. 
 
In case of new bone lesions or progression of existing bone lesions is identified on 
CT/MRI but not on a technetium-99m bone scan, progression will be declared at the 
time of the lesion identification or progression was observed on the CT/MRI scan. 
 
FDG PET scan, if performed as part of standard of care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See also 
Appendix 16.2). 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
o The time window for the scans is ±7 days.  
o For radiologic progression confirmed during the treatment period: 


 
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 If radiologic soft tissue or visceral progression in absence of bone progression 
(according to mRECIST 1.1 criteria) is observed, bone imaging and MRI/CT 
scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS 
Record progression 
Added text: 
 Blood draw for analysis of circulating tumor cells (CTCs) collected within 5 days of 
Visits 2, 4, 6, 8, 9, 10 (Day 1 of Cycles 1 through 6), prior to study drug dosing. 
 Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2. 
 
Section 9.2.3.2 Visits 3, 5, and 7 (Day 15 of Cycles 1, 2, and 3 ±3 days at each visit) and 
unscheduled visits 
This was changed as a result of modification 16 and 17. 
Old text: 
 Blood draw for clinical chemistry: Na, K, Cl, Ca, ALT, AST, LDH, bone ALP, serum 
creatinine, phosphate, BUN, total bilirubin, total cholesterol, and albumin. 
New text: 
 Blood draw for clinical chemistry is only required at Visit 3 (Cycle 1, Day 15) and Visit 5 
(Cycle 2, Day 15): Na, K, Cl, Ca, ALT, AST, LDH, bone ALP (if testing is available and 
can be performed locally), serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin. 
Deleted text: 
Record progression 
 
Section 9.2.3.3 End of treatment visit 9.2.4.1 Active follow-up with clinic visits 
This was changed as a result of modifications 3, 4, 15, 16, 17, 18, and 20. 
Old text: 
 BPI-SF questionnaire will be completed prior to any other study assessments/procedures 
and should be checked for completion at the visit 
 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in by the 
subjects for one week (6 days prior to visit plus day of visit) 


 
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o Analgesic use during the last 24 hours recorded in eCRF, by site, assessing subject 
pain medication.  Subject should bring all pain medication to each visit 
New text: 
 BPI-SF questionnaire will be completed prior to any other study assessments/procedures 
and should be checked for completion at the visit. Additionally PRO Questionnaire 
Information Sheet is to be completed by clinical staff based on discussion with patient, 
even if patient does not complete the BPI-SF questionnaire. 
 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in by the 
subjects for 24 hours prior to visit.  The analgesic use for 24 hours prior to the visit 
will be recorded by the investigator on the eCRF. 
Added text: 
 Record opiate use 
Old text: 
 Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Cl, Ca, ALT, AST, 
LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total cholesterol, 
and albumin 
Record progression 
 Radiological tumor assessment – to be performed only if prior assessment has been done 
more than 8 weeks prior to EOT visit.  mRECIST 1.1 criteria will be applied to declare a 
PFS event. 
o A chest/abdominal/pelvic CT or MRI.   
o Bone technetium-99m scan with careful identification of all disease-related hotspots.  
All visible bone lesions must also be imaged with conventional anatomical imaging 
procedures such as SPECT-CT/MRI or CT or MRI scan (with or without contrast 
media).  All new bone lesions or progression of existing bone lesion(s) identified on a 
technetium-99m bone scan will need confirmatory CT or MRI imaging.  In case of a 
new lesion or of progression of existing bone lesion(s) observed on a bone scan that is 
not confirmed by CT/MRI, progression will not be declared until the CT/MRI 
confirmation of progression occurs.  A CT/MRI confirmatory scan must take place 6 
to 8 weeks after the new lesion or progression of existing lesion(s) was observed on 
bone scan. 
 
In case of new bone lesions or progression of existing bone lesions is identified on 
CT/MRI but not on a technetium-99m bone scan, progression will be declared at the 
time of the lesion identification or progression was observed on the CT/MRI scan. 


 
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FDG PET scan, if performed as part of standard of care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See also 
Appendix 16.2). 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
o The time window for the scans is ±7 days.  
o For confirmed radiologic progression: 
o If radiologic soft tissue or visceral progression in absence of bone progression 
(according to mRECIST 1.1 criteria) is observed, bone imaging and MRI/CT scan of 
the chest, abdomen, and pelvis should continue to allow assessment of bone-specific 
rPFS 
New text: 
 Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Cl, Ca, ALT, AST, 
LDH, bone ALP (if testing is available and can be performed locally), serum creatinine, 
phosphate, BUN, bilirubin (total), total cholesterol, and albumin 
 Blood draw for analysis of CTCs (within 5 days of the visit). 
 Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2 
 
Section 9.2.4.1 Active follow-up with clinic visits 
This was changed as a result of modifications 3, 4, 15, 16, 17, 18, and 20. 
Old text: 
 BPI-SF questionnaire will be completed prior to any other study assessments/procedures 
and should be checked for completion at the visit 
 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in by the 
subjects for one week (6 days prior to visit plus day of visit) 
o Analgesic use during the last 24 hours recorded in eCRF, by site, assessing subject 
pain medication.  Subject should bring all pain medication to each visit 


 
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New text: 
 BPI-SF questionnaire will be completed prior to any other study assessments/procedures 
and should be checked for completion at the visit. Additionally PRO Questionnaire 
Information Sheet is to be completed by clinical staff based on discussion with patient, 
even if patient does not complete the BPI-SF questionnaire. 
 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in by the 
subjects for 24 hours prior to visit.  The analgesic use for 24 hours prior to the visit 
will be recorded by the investigator on the eCRF. 
Added text: 
 Record opiate use 
Old text: 
Blood draws for clinical chemistry every 12 weeks (within 5 days of the visit):  Na, K, Cl, Ca, 
ALT, AST, LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin 
Radiological tumor assessment: to be performed every 12 weeks until radiological disease 
progression is documented 
o A chest/abdominal/pelvic CT or MRI.  The same imaging modalities are to be used as 
were used at baseline.  
o Bone technetium-99m scan with careful identification of all disease-related hotspots 
and associated SPECT-CT/MRI or CT/ MRI scan (with or without contrast media). 
 
FDG PET scan, if performed as part of standard of care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See also 
Appendix 16.2). 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
o The time window for the scans is ±7 days.  
o If a subject experiences radiological progression during the active follow-up period 
with visits: 
 If radiologic soft tissue or visceral progression in absence of bone progression 
(according to mRECIST 1.1 criteria), is observed, bone imaging and MRI/CT scan 


 
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of the chest, abdomen, and pelvis should continue to allow assessment of bone-
specific rPFS. 
New text: 
 Blood draws for clinical chemistry every 12 weeks (within 5 days of the visit):  Na, K, Cl, 
Ca, ALT, AST, LDH, bone ALP (if testing is available and can be performed locally), 
serum creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin 
 Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2. 
Deleted text: 
 Record progression 
 
Section 9.2.4.3 End of active follow-up 
This was changed as a result of modifications 3, 4, 15, 16, 17, and 18. 
Old text: 
BPI-SF questionnaire will be completed prior to any other study assessments/procedures and 
should be checked for completion at the visit 
 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in by the 
subjects for one week (6 days prior to visit plus day of visit) 
o Analgesic use during the last 24 hours recorded in eCRF, by site, assessing subject 
pain medication.  Subject should bring all pain medication to each visit 
New text: 
 BPI-SF questionnaire will be completed prior to any other study assessments/procedures 
and should be checked for completion at the visit. Additionally PRO Questionnaire 
Information Sheet is to be completed by clinical staff based on discussion with 
patient, even if patient does not complete the BPI-SF questionnaire 
 
 Recording of analgesic use will be performed by:  
o Analgesic use recorded via the analgesic concomitant medication eCRF  
o Analgesic consumption diary (completion to be checked by site) to be filled in by the 
subjects for 24 hours prior to visit.  The analgesic use for 24 hours prior to the visit 
will be recorded by the investigator on the eCRF. 


 
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Added text: 
 Record opiate use 
Old text: 
 Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Cl, Ca, ALT, AST, 
LDH, bone ALP, serum creatinine, phosphate, BUN, bilirubin (total), total 
cholesterol, and albumin 
Radiological tumor assessment to be performed only for subjects who had no previously 
documented progression 
o A chest/abdominal/pelvic CT or MRI.  The same imaging modalities are to be used as 
were used at baseline.  An abdominal/pelvic MRI will be accepted instead of 
abdominal/pelvic CT only if MRI abdomen/pelvis was performed at baseline. 
o Bone technetium-99m scan with careful identification of all disease-related hotspots 
and any confirmatory SPECT-CT/MRI or CT or MRI scan (with and without contrast 
media). 
 
FDG PET scan, if performed as part of standard of care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can 
document that the CT is of identical diagnostic quality to a diagnostic CT. (See also 
Appendix 16.2). 
o FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. 
o The time window for the scans is ±7 days. 
Record progression 
New text: 
 Blood draws for clinical chemistry (within 5 days of the visit): Na, K, Cl, Ca, ALT, AST, 
LDH, bone ALP (if testing is available and can be performed locally), serum 
creatinine, phosphate, BUN, bilirubin (total), total cholesterol, and albumin 
 Radiological tumor assessments: please refer to Section 9.2.6 and Appendix 16.2 
 
Section 9.2.6 Radiological assessment: tumor and response evaluation 
This was changed as a result of modifications 13 and 18. 
Old text: 
Radiological tumor evaluation, using the mRECIST 1.1 guidelines (See Section 16.2), must 
be performed within 3 weeks prior to randomization, at 8 weeks (±7 days) after the first 
radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 


 
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(radiological progression) is documented.  If radiologic soft tissue or visceral progression in 
absence of bone progression (according to mRECIST 1.1 criteria) is observed, bone imaging 
and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS. 
This schedule is to be maintained and will not be shifted because of treatment 
interruptions/delays.  Subjects who discontinue study treatment for reasons other than disease 
progression will continue to undergo tumor response evaluations until PD is documented 
(radiological progression). 
 
FDG PET scan, if performed as part of standard of care imaging, can be used as an adjunct to 
CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT component of the 
scan can be used for tumor measurements only if the site can document that the CT is of 
identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m bone 
scintigraphy if it is the standard of care at the institution, provided the same bone imaging 
modality is used throughout the study. The same lesions identified at baseline must be 
evaluated at follow-up assessments using the same technique and preferably by the same 
Investigator/radiologist. 
New text: 
Radiological tumor evaluation, using the mRECIST 1.1 guidelines (See Section 16.2), must 
be performed as follows (see also Figure 9–1): 
 Within 3 weeks prior to randomization,  
 8 weeks (±7 days) after the first radium-223 dichloride/placebo administration  
 Every 12 weeks (±7 days) thereafter until PD (radiological progression) is documented.   
A technetium-99m bone scan and CT or MRI (chest/abdomen/pelvis and any additional sites 
of disease, as applicable) should be performed at all the above mentioned timepoints. 
This schedule is to be maintained and will not be shifted because of treatment 
interruptions/delays.   


 
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Figure 9-1:  Radiological tumor evaluation schedule 
 
If radiologic soft tissue or visceral progression in absence of bone progression (according to 
mRECIST 1.1 criteria) is observed, bone imaging and MRI/CT scan of the chest, abdomen, 
and pelvis should continue to allow assessment of bone-specific rPFS until bone progression 
occurs  or start of a new anticancer treatment. 
If radiologic bone progression occurs prior to occurrence of visceral metastases, MRI/CT 
scan of the chest, abdomen, and pelvis should continue until occurrence of visceral metastasis 
or start of a new anticancer treatment after the end of the current study treatment. This will 
allow assessment of time to visceral metastases onset. 
Subjects who discontinue study treatment for reasons other than disease progression will 
continue to undergo tumor response evaluations until PD is documented (radiological 
progression). 
 
Note: FDG PET scan, if performed as part of standard of care imaging, can be used as an 
adjunct to CT/MRI in line with RECIST 1.1 guidelines. If FDG PET/CT scan, the CT 
component of the scan can be used for tumor measurements only if the site can document that 
the CT is of identical diagnostic quality to a diagnostic CT. (See also Appendix 16.2). 
A technetium-99m bone scan with careful identification of all disease-related hotspots should 
be performed for all patients at the above mentioned timepoints. All visible bone lesions must 
also be imaged with conventional anatomical imaging procedures such as CT or MRI scan.  
During the study a new bone lesion or progression of existing bone lesion/s initially identified 
on a technetium-99m bone scan must be confirmed by CT or MRI.  If confirmed by CT/MRI, 
the date of occurrence of the new lesion or of progression of existing bone lesion/s will be the 
date it was initially detected (by technetium-99m bone scan) even if the confirmation by 
CT/MRI was done at a subsequent scan.  (See also Section 16.2). 
Note: FDG PET/CT or NaF PET/CT scan is acceptable as an alternative to technetium-99m 
bone scintigraphy if it is the standard of care at the institution, provided the same bone 
imaging modality is used throughout the study. The same lesions identified at baseline must 


 
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be evaluated at follow-up assessments using the same technique and preferably by the same 
Investigator/radiologist. 
Added text: 
For details on radiological tumor assessment please also refer to Section 16.2. 
 
Section 9.3.3 Other baseline characteristics 
This was changed as a result of modification 17. 
Old text: 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol, ALT, AST, LDH, bone ALP, serum 
creatinine, phosphate, BUN, total bilirubin, and albumin 
New text: 
o Clinical chemistry: Na, K, Cl, Ca, total cholesterol, ALT, AST, LDH, bone ALP (if testing 
is available and can be performed locally), serum creatinine, phosphate, BUN, total 
bilirubin, and albumin 
 
Section 9.4.2.2 Secondary efficacy endpoints 
This was changed as a result of modifications 3, 13, and 14.  
Old text: 
Time to opiate use for cancer pain is defined as the interval from the date of randomization 
to the date of opiate use.  Subjects who have no opiate use at the time of analysis will be 
censored at the last known date of no opiate use.  Subjects with no on-study assessment or no 
baseline assessment will be censored at the date of randomization. 
Time to opiate use will be determined by analgesic use captured via subject analgesic 
consumption diary and/or the eCRF (analgesic consumption diary and recorded analgesics, 
respectively, see Table 9-1 Schedule of assessments). 
Time to pain progression will be evaluated in subjects with baseline WPS ≤ 8.  Time to pain 
progression is defined as the interval from randomization to the first date a subject 
experiences pain progression based on WPS.  Pain progression is defined as an increase of 2 
or more points in the “Worst pain in 24 hours” score from baseline observed at 2 consecutive 
evaluations ≥4 weeks apart 
OR 
initiation of short- or long-acting opioid use for pain. 
Assessments will occur on the day of the visit.  An evaluable pain assessment interval 
requires completion of a minimum of 4 out of 7 questions.  Subjects who have not 
experienced pain progression at the time of analysis will be censored on the last date the 
subject was known to have not progressed. Subjects with no on-study assessment or no 
baseline assessment will be censored at the date of randomization. 


 
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Pain improvement is defined for subjects evaluable for pain improvement, i.e. subjects with 
baseline WPS > 3, as a 2-point decrease or more in WPS from baseline over 2 consecutive 
measurements conducted at least 4 weeks apart. 
Pain improvement rate is defined as the number of subjects with pain improvement as 
defined above, divided by the total number of subjects evaluable for pain improvement (i.e., 
subjects with baseline WPS>3). Both pain improvement rate at all visits and by visit will be 
considered. 
New text: 
Time to opiate use for cancer pain is defined as the interval from the date of randomization 
to the date of opiate use.  Subjects who have no opiate use at the time of analysis will be 
censored at the last assessment date of no opiate use.  Subjects with no on-study assessment 
or no baseline assessment will be censored at the date of randomization. 
Time to opiate use will be determined by analgesic use captured via different eCRF pages (24 
hour analgesic use page, analgesic concomitant medication page and opiate use page, 
respectively, see Table 9-1 Schedule of assessments).  
Time to pain progression is defined as the interval from randomization to the first date 
a subject experiences pain progression based on WPS and analgesics use.  Time to pain 
progression will be evaluated in subjects with baseline WPS ≤ 8.  Pain progression is defined 
as an increase of 2 or more points in the “Worst pain in 24 hours” score from baseline 
observed at 2 consecutive evaluations ≥4 weeks apart 
OR 
an increase in pain management (IPM) with respect to baseline, whichever occurs first.   
Assessments will occur on the day of the visit.  An evaluable pain assessment interval 
requires completion of a minimum of 4 out of 7 questions.  Subjects who have not 
experienced pain progression at the time of analysis will be censored on the last post-baseline 
pain assessment date the subject was known to have not progressed. Subjects with no 
on-study assessment or no baseline assessment will be censored at the date of randomization. 
Pain improvement is defined for subjects evaluable for pain improvement, i.e. subjects with 
baseline WPS ≥ 2, as a 2-point decrease or more in WPS from baseline over 2 consecutive 
measurements conducted at least 4 weeks apart, without an IPM. 
Pain improvement rate is defined as the number of subjects with pain improvement as 
defined above, divided by the total number of subjects evaluable for pain improvement (i.e., 
subjects with baseline WPS≥ 2). Pain improvement rate at week 12, EOT and any visit will 
be considered. 
 


 
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Section 9.4.2.3 Exploratory efficacy endpoints 
This was changed as a result of modification 13. 
Old text: 
Time to bone ALP progression is defined as the time (days) from the date of randomization 
to the date of first bone ALP progression.  Bone ALP progression is defined as a 25% 
increase from the baseline value, at least 12 weeks from baseline in subjects with no bone 
ALP decline from baseline; or a 25% increase above the nadir value, which is confirmed by 
a second value obtained 3 or more weeks later in subjects with an initial bone ALP decline 
from baseline. 
New text: 
Time to bone ALP progression is defined as the time (days) from the date of randomization 
to the date of first bone ALP progression.  Bone ALP progression is defined as a 25% 
increase from the baseline value, at least 12 weeks from baseline in subjects with no bone 
ALP decline from baseline; or a 25% increase above the nadir value, which is confirmed by 
a second value obtained 4 or more weeks later in subjects with an initial bone ALP decline 
from baseline. 
 
Section 9.6.1.3 Assessments and documentation of adverse events 
This was changed as a result of modification 13. 
Old text: 
All AEs and SAEs occurring after the EOT visit until the EOS must be documented and 
reported if considered to be related to study medication or to study-related procedures. 
New text: 
All AEs and SAEs occurring beyond 30 days after the last dose of study treatment must be 
documented and reported if considered to be related to study medication or to study-related 
procedures. 
 
Section 9.7.2 Biomarker assessments 
This was changed as a result of modification 13. 
Old text: 
Biomarker analyses planned within this study may include predictive, prognostic, and 
pharmacodynamic biomarkers analyzed from serum and urine.  Serum, urine, and biomarker 
analyses will be dependent upon the availability of appropriate biomarker assays and may be 
deferred or not performed, if during or at the end of the study, it becomes clear that the 
analysis will have no scientific value, or there are not enough samples or not enough 
responders to allow for adequate biomarker evaluation.  In the event the study is terminated 


 
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early or does not reach a positive primary endpoint, completion of the biomarker assessments 
will be based on justification and intended utility of the data. 
New text: 
Biomarker analyses planned within this study may include predictive, prognostic, and 
pharmacodynamic biomarkers analyzed from serum and urine.  Serum, urine, and biomarker 
analyses will be dependent upon the availability of appropriate biomarker assays and may be 
deferred or not performed, if during or at the end of the study, it becomes clear that the 
analysis will have no scientific value, or there are not enough samples or not enough 
responders to allow for adequate biomarker evaluation.  In the event the study is terminated 
early or does not reach a positive primary endpoint, completion of the biomarker assessments 
will be based on justification and intended utility of the data.  Exploratory biomarker data 
including CTC analysis will be reported in a separated biomarker report. 
 
Section 9.7.2.2 Collection of Circulating Tumor Cells for Biomarker Analyses 
This was changed as a result of modification 20. 
Added text: 
9.7.2.2 Collection of Circulating Tumor Cells for Biomarker Analyses 
Circulating Tumor Cells (CTCs) are believed to represent a surrogate for tumor cells and can 
be used as surrogate to demonstrate efficacy of the drug by enumeration of CTCs, but also as 
source of tumor molecular characterization.  
Blood samples will be obtained from all subjects at the following time points: (1) Cycle 1, 
Day 1 (Visit 2) and every subsequent cycle, Day 1 within 5 days of the visit prior to 
radium-223 dichloride or placebo administration, and within 5 days of the EOT visit or 
disease progression, whichever occurs first. 
 
Section 16.8 Patient Reported Questionnaire Information Sheet 
This was changed as a result of modification 12. 
Added text: 
Subject Number   ___ ___ ___ ___ ___/___ ___ ___ ___ 
Visit: _____________ 
Instructions: 
 
This information sheet is to be completed by the study nurse/investigator. 
 
This information sheet must be competed for all patients at each visit in which the 
protocol requires the questionnaire to be administered, whether or not the 
questionnaire was completed by the patient. 
 
When the patient returns the questionnaire 
o Please complete this information sheet. 


 
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o Please check that the patient has answered all the questions and no question 
has more than one answer. 
 
1. Was the questionnaire provided to the patient at this  
    visit? 
     1 No  
 
      2 Yes 
If YES, please continue 
If NO, please go to question 5 
 
2. Date questionnaire completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
d d m m y y y y 
 
3. Was the questionnaire provided prior to clinical  
    examination? 
     1 No  
 
        2 Yes 
 
4. Were all questions answered? 
     1 No  
 
        2 Yes 
 
If YES, please STOP 
 
If NO, please continue 
 
5. If No, specify reason questionnaire/questions was not answered: 
 
Patient felt too ill 
 
Patient refused to complete questionnaire for reason other than illness 
 
Patient did not keep appointment 
 
Questionnaire not administered due to institution error 
 
Questionnaire not available in the appropriate language 
 
 
Other, please specify: 
 
 


 
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15.5 Amendment 6 
Amendment 6 (dated 11 JUL 2016) is an amendment to the Version 5.0 of the protocol, dated 
11 MAR 2015.  Changes to the protocol include: 
 Modified inclusion/exclusion criteria to allow entry of patients with visceral 
metastases.   
 Deleted BPI-SF text to avoid redundancy with Appendix 16.6. 
 Added text for visceral metastases at baseline, for consistency with modification 1. 
 Removed timeframe for prior chemotherapy administered for adjuvant/neo-adjuvant 
disease.   
 Removed timeframe for CT/MRI confirmatory scan for consistency with 17096 and 
to avoid an additional scan and associated radiation without affecting outcome. 
 Updated company name. 
 Added text for consistency within protocol. 
15.5.1 Overview of changes to the study 
Modification 1 
Modified inclusion/exclusion criteria to allow entry of patients with visceral metastases. 
Inclusion of patients with visceral metastases improves enrollment without significantly 
impacting the patient population.  This modification allows entry of patients with 
asymptomatic visceral metastases with good organ function. The inclusion of asymptomatic 
visceral disease should have negligible impact on the primary endpoint of SSE-FS. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.1 Inclusion criteria 
 6.2 Exclusion criteria 
 16.2 Response evaluation criteria in solid tumors (RECIST 1.1) 
 
Modification 2 
Deleted BPI-SF text to avoid redundancy with Appendix 16.6. 
Sections affected include: 
 9.4.2.2 Secondary efficacy endpoints 
 


 
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Modification 3 
Added text for visceral metastases at baseline, for consistency with modification 1. 
Sections affected include: 
 9.4.2.3 Exploratory efficacy endpoints 
 
Modification 4 
Removed timeframe for prior chemotherapy administered for adjuvant/neo-adjuvant disease. 
More recent data from chemotherapy combination studies with Xofigo shows good safety 
profile of the combination. In addition, long term safety follow up data from ALSYMPCA 
showed good safety profile for patients that received subsequent chemotherapy. At the time 
of the current study set up this data was not available. 
Sections affected include: 
 Synopsis: Diagnosis and main criteria for inclusion and exclusion 
 6.2 Exclusion criteria 
 
Modification 5 
Removed timeframe for CT/MRI confirmatory scan for consistency with 17096 and to avoid 
an additional scan and associated radiation without affecting outcome. 
Sections affected include: 
 16.2 Response evaluation criteria in solid tumors (RECIST 1.1) 
 
Modification 6 
Updated company name. 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. 
Sections affected include: 
 Header 
 Title page 
 


 
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Modification 7 
Added text for consistency within protocol. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 


 
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15.5.2 Changes to the protocol text 
Changes to the protocol text are highlighted as specified at the beginning of Section 15.5.1. 
Header 
This was changed as a result of modification 6. 
Deleted text: 
 
 
Title page 
This was changed as a result of modification 6. 
Old text: 
Bayer HealthCare AG, D-51368 Leverkusen, Germany 
New text: 
Bayer AG, D-51368 Leverkusen, Germany  
US territory: Bayer Healthcare Pharmaceuticals Inc.,  
100 Bayer Boulevard, P.O. Box 915 
Whippany NJ 07981-0915 USA 
 
Synopsis: Diagnosis and main criteria for inclusion and exclusion, Section 6.1 Inclusion 
criteria 
This was changed as a result of modification 1. 
Old text: 
6. Subjects with bone dominant disease with at least 2 skeletal metastases identified at 
baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI). 
Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph nodes) is 
allowed. 
 
14. Laboratory requirements:  
o Absolute neutrophil count (ANC) ≥1.5 x 109/L  
o Platelet count ≥100 x 109/L without platelet transfusion within 4 weeks 
prior to randomization 
o Hemoglobin ≥9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or 
erythropoietin within 4 weeks prior to randomization 


 
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o Total bilirubin level ≤1.5 x institutional upper limit of normal (ULN) 
(except for subjects with documented Gilbert’s disease) 
o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 x institutional ULN.  AST and ALT values above the ULN must not 
be related to liver metastases 
o Creatinine ≤1.5 x ULN 
o Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73m2 according 
to the Modification of Diet in Renal Disease (MDRD) abbreviated formula 
(Note: please refer to local labelling for administration of full dose of 
bisphosphonates) 
o International normalized ratio of prothrombin time (INR) and partial 
thromboplastin time (PTT) or activated PTT ≤1.5 x ULN at study entry.  
Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, 
dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to 
participate in the study if no underlying abnormality in coagulation 
parameters exists per prior history; weekly evaluation of INR/PTT will be 
required until stability is achieved for anticoagulants that require their 
monitoring as per local label. 
o Serum albumin >30 g/L 
New text: 
6. Subjects with bone dominant disease with at least 2 skeletal metastases identified at 
baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI). 
Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph nodes) and/or 
visceral metastases is allowed. 
 
14. Laboratory requirements:  
o Absolute neutrophil count (ANC) ≥1.5 x 109/L  
o Platelet count ≥100 x 109/L without platelet transfusion within 4 weeks 
prior to randomization 
o Hemoglobin ≥9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or 
erythropoietin within 4 weeks prior to randomization 
o Total bilirubin level ≤1.5 x institutional upper limit of normal (ULN) 
(except for subjects with documented Gilbert’s disease) 
o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 x institutional ULN. 
o Creatinine ≤1.5 x ULN 
o Estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73m2 according 
to the Modification of Diet in Renal Disease (MDRD) abbreviated formula 


 
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(Note: please refer to local labelling for administration of full dose of 
bisphosphonates) 
o International normalized ratio of prothrombin time (INR) and partial 
thromboplastin time (PTT) or activated PTT ≤1.5 x ULN at study entry.  
Subjects treated with warfarin, heparin, enoxaparin, rivaroxaban, 
dabigatran, apixaban, or aspirin (e.g. ≤100 mg daily) will be allowed to 
participate in the study if no underlying abnormality in coagulation 
parameters exists per prior history; weekly evaluation of INR/PTT will be 
required until stability is achieved for anticoagulants that require their 
monitoring as per local label. 
o Serum albumin >30 g/L 
o Pulse oximetry O2 saturation >92% if lung metastases are present 
 
Synopsis: Diagnosis and main criteria for inclusion and exclusion, Section 6.2 Exclusion 
criteria 
This was changed as a result of modification 1 and 4. 
Old text: 
4. History and/or presence of confirmed visceral metastases 
5. Subjects who have either received chemotherapy for metastatic disease or are considered 
by the treating Investigator to be appropriate candidates for chemotherapy as current 
treatment for metastatic breast cancer are excluded.  Chemotherapy administered for 
adjuvant/neo-adjuvant disease is acceptable provided it was administered at least 1 year 
prior to study entry. 
6. Subjects with any previous untreated or concurrent cancer that is distinct in primary site or 
histology from the cancer under study, except treated basal cell carcinoma or superficial 
bladder tumor (Ta and Tis, American Joint Committee on Cancer, 7th edition).  Subjects 
surviving a cancer that was curatively treated and without evidence of disease for more 
than 3 years before enrollment are allowed.  All cancer treatments must be completed at 
least 3 years prior to study entry (i.e., signature date of ICF). 
7. Subjects with known or history of brain metastases or leptomeningeal disease: subjects 
with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 
28 days prior to randomization to exclude active brain metastasis.  Imaging of the central 
nervous system is otherwise not required 
8. 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. 
9. Prior treatment with radium-223 dichloride 


 
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10. Prior hemibody external radiotherapy.  Subjects who received other types of prior 
external radiotherapy are allowed provided that bone marrow function is assessed and 
meets the protocol requirements for hemoglobin, ANC, and platelets. 
11. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-
188 
12. ECOG Performance Status ≥2 
13. Blood transfusions, platelet transfusions or use of erythropoietin within 4 weeks prior to 
randomization.   
14. 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 randomization 
15. Treatment with an investigational drug or with any anti-cancer treatments not permitted 
by the protocol, within 4 weeks prior to randomization 
16. Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed 
Paget’s disease of bone) 
17. Any other serious illness or medical condition such as, but not limited to: 
o Any uncontrolled infection 
o Cardiac failure New York Heart Association Class III or IV 
o Crohn’s disease or ulcerative colitis 
o Bone marrow dysplasia 
18. Previous assignment to treatment in this study 
19. Breastfeeding women 
20. Known hypersensitivity to the active substance or to any of the excipients of radium-223 
dichloride 
21. Known presence of osteonecrosis of jaw 
New text: 
5. Subjects who have either received chemotherapy for metastatic disease or are considered 
by the treating Investigator to be appropriate candidates for chemotherapy as current 
treatment for metastatic breast cancer are excluded.  Chemotherapy administered for 
adjuvant/neo-adjuvant disease is acceptable. 
6. Subjects with any previous untreated or concurrent cancer that is distinct in primary site or 
histology from the cancer under study, except treated basal cell carcinoma or superficial 
bladder tumor (Ta and Tis, American Joint Committee on Cancer, 7th edition).  Subjects 
surviving a cancer that was curatively treated and without evidence of disease for more 
than 3 years before enrollment are allowed.  All cancer treatments must be completed at 
least 3 years prior to study entry (i.e., signature date of ICF). 


 
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7. Subjects with known or history of brain metastases or leptomeningeal disease: subjects 
with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 
28 days prior to randomization to exclude active brain metastasis.  Imaging of the central 
nervous system is otherwise not required 
8. 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. 
9. Prior treatment with radium-223 dichloride 
10. Prior hemibody external radiotherapy.  Subjects who received other types of prior 
external radiotherapy are allowed provided that bone marrow function is assessed and 
meets the protocol requirements for hemoglobin, ANC, and platelets. 
11. Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-
188 
12. ECOG Performance Status ≥2 
13. Blood transfusions, platelet transfusions or use of erythropoietin within 4 weeks prior to 
randomization.   
14. 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 randomization 
15. Treatment with an investigational drug or with any anti-cancer treatments not permitted 
by the protocol, within 4 weeks prior to randomization 
16. Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed 
Paget’s disease of bone) 
17. Any other serious illness or medical condition such as, but not limited to: 
o Any uncontrolled infection 
o Cardiac failure New York Heart Association Class III or IV 
o Crohn’s disease or ulcerative colitis 
o Bone marrow dysplasia 
18. Previous assignment to treatment in this study 
19. Breastfeeding women 
20. Known hypersensitivity to the active substance or to any of the excipients of radium-223 
dichloride 
21. Known presence of osteonecrosis of jaw 
22. Patients with immediately life-threatening visceral disease, for whom chemotherapy is the 
preferred treatment option. 
23. Lymphangitic carcinomatosis. 


 
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24. Patients with ascites requiring paracentesis within 2 weeks prior to study entry (signature 
of informed consent) and during the screening period. 
 
Section 9.1 Tabular schedule of evaluations 
This was changed as a result of modification 7. 
Old text: 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
Active  
Follow-up 
 
End of 
Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clini
c 
Visit
s 
W/O 
Clinic 
Visits 
With 
Clini
c 
Visit
s 
W/O 
Clini
c 
Visit
s 
Visit: 
0-
1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random
 
C1, Day 11 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dose
e 
q4 
wk 
until 
SSE; 
q12 
wk 
after 
SSEf 
q4 wk 
until 
SSE; 
q12 
wk 
after 
SSEg 
 
 
Window (days): 
 
 
 
±
3 
± 
7 
±3 
± 
7 
±
3 
± 
7 
± 
7 
± 7 
± 7 
±7 
±7 
±7 
±7 
 
Technetium-99m 
bone scan aa,bb 
X 
X 
New text: 
Study Period 
Screeninga 
Randomization 
Treatmentb,c 
 
Active  
Follow-up 
 
End of 
Active 
Follow-up 
Radium-223 dichloride or Placebo 
EOT 
visit 
With 
Clini
c 
Visit
s 
W/O 
Clinic 
Visits 
With 
Clini
c 
Visit
s 
W/O 
Clini
c 
Visit
s 
Visit: 
0-
1 
- 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
- 
- 
- 
- 
Cycle: 
- 
- 
1 
2 
3 
4 
5 
6 
- 
- 
- 
- 
- 
Timing: 
3 wk pre-
random
 
C1, Day 1 
C1, Day 15d 
C2, Day 1 
C2, Day 15 
C3, Day 1 
C3, Day 15 
C4, Day 1 
C5, Day 1 
C6, Day 1 
4 wk 
post-
last 
dose
e 
q4 
wk 
until 
SSE; 
q12 
wk 
after 
SSEf 
q4 wk 
until 
SSE; 
q12 
wk 
after 
SSEg 
 
 
Window (days): 
 
 
 
±
3 
± 
7 
±3 
± 
7 
±
3 
± 
7 
± 
7 
± 7 
± 7 
±7 
±7 
±7 
±7 
 


 
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Technetium-99m 
bone scan or FDG 
PET/CT or NaF 
PET/CT, same 
technique for all 
assessmentsaa,bb 
X 
X 
 
Section 9.1 Tabular schedule of evaluations 
This was changed as a result of modification 7. 
Old text: 
aa. Radiological tumor evaluation must be performed 8 weeks (±7 days) after the first 
radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 
(radiological progression) is documented. If radiologic soft tissue or visceral progression in 
absence of bone progression (according to mRECIST 1.1 criteria) is observed, bone imaging 
and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS till bone progression.  This schedule is to be maintained and will not be 
shifted because of treatment interruptions/delays.  Scans will be read locally.  The time 
window for the scans is ±7 days. 
New text: 
aa. Radiological tumor evaluation must be performed 8 weeks (±7 days) after the first 
radium-223 dichloride/placebo administration and every 12 weeks thereafter until PD 
(radiological progression) is documented. If radiologic soft tissue or visceral progression in 
absence of bone progression (according to mRECIST 1.1 criteria) is observed, bone imaging 
and MRI/CT scan of the chest, abdomen, and pelvis should continue to allow assessment of 
bone-specific rPFS until bone progression occurs or start of a new anticancer treatment.  This 
schedule is to be maintained and will not be shifted because of treatment interruptions/delays.  
Scans will be read locally.  The time window for the scans is ±7 days. 
 
Section 9.4.2.2 Secondary efficacy endpoints 
This was changed as a result of modification 2. 
Old text: 
Pain improvement rate is defined as the number of subjects with pain improvement as 
defined above, divided by the total number of subjects evaluable for pain improvement (i.e., 
subjects with baseline WPS ≥2). Pain improvement rate at week 12, EOT and any visit will 
be considered. 
The BPI-SF (Section 16.6) is a short, self-administered questionnaire with 9 items, which was 
designed to evaluate the intensity of, and the impairment caused by pain.  Questions #2 
(locating areas of pain on a diagram) and question #7 (regarding use of pain medication) of 
the BPI-SF questionnaire will not be answered, as they do not affect the global pain score.  
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 


 
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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 (does not interfere) to 10 (completely 
interferes) rating scales. 
The items are aggregated into 2 dimensions: (1) Pain severity index, using the mean of the 
4 items on the pain intensity, and (2) Function interference index, using the mean of the 
7 pain interference items.  All 4 severity items must be completed for aggregating the pain 
severity index.  The function interference index is scored as the mean of the item scores 
multiplied by 7, given that more than 50% or 4 of 7 of the items have been completed. 
New text: 
Pain improvement rate is defined as the number of subjects with pain improvement as 
defined above, divided by the total number of subjects evaluable for pain improvement (i.e., 
subjects with baseline WPS ≥2). Pain improvement rate at week 12, EOT and any visit will 
be considered. 
 
Section 9.4.2.3 Exploratory efficacy endpoints 
This was changed as a result of modification 3. 
Old text: 
Time to visceral metastases onset is defined as the time (days) from the date of 
randomization to the date of the first scan showing visceral metastatic disease.  
New text: 
Time to visceral metastases onset is defined as the time (days) from the date of 
randomization to the date of the first scan showing visceral metastatic disease. Subjects with 
visceral metastases at baseline will be censored at randomization date. 
 
Section 16.2 Response evaluation criteria in solid tumors (RECIST 1.1) 
This was changed as a result of modifications 1 and 5. 
Old text: 
Visceral lesions: Malignant finding in visceral organs: lung, liver, brain, etc.  
Note: patients with visceral lesions will not be considered eligible for this study.  
Measurable lesions: Lesions that, at baseline, meet the requirements for being reproducibly 
quantifiable (see section below for detailed definition of measurable lesions). 
 
 A new bone lesion or progression of existing bone lesion/s initially identified on a 
technetium-99m bone scan must be confirmed by CT or MRI.  If confirmed by CT/MRI, 
the date of occurrence of the new lesion or of progression of existing bone lesion/s will be 


 
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the date it was initially detected (by technetium-99m bone scan) even if the confirmation 
by CT/MRI was done at a subsequent scan.  A CT/MRI confirmatory scan must take 
place 6 to 8 weeks after the new lesion or progression of existing lesion/s was observed 
on bone scan 
New text: 
Visceral lesions: Malignant finding in visceral organs: lung, liver, brain, etc.  
Measurable lesions: Lesions that, at baseline, meet the requirements for being reproducibly 
quantifiable (see section below for detailed definition of measurable lesions). 
 
 A new bone lesion or progression of existing bone lesion/s initially identified on a 
technetium-99m bone scan must be confirmed by CT or MRI.  If confirmed by CT/MRI, 
the date of occurrence of the new lesion or of progression of existing bone lesion/s will be 
the date it was initially detected (by technetium-99m bone scan) even if the confirmation 
by CT/MRI was done at a subsequent scan. 


 
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15.6 Amendment 7 
Amendment 7 (dated 18 MAY 2017) is an amendment to the Version 6.0 of the protocol, 
dated 11 JUL 2016.  Changes to the protocol include: 
 Updated study medical expert and contact information 
 Added text to provide tolerance limits for permitted radiation. 
 Text was updated to provide clarity to study sites. 
 Text was added for consistency with Table 9-1: Schedule of assessments. 
 Clarified sites at which CTCs are collected. 
 Added interim data review. 
 Updated text for independent radiological review. 
 Added text for the establishment of an independent unblinded data review committee. 
 Reformatted page for signature of the sponsor’s medically responsible person. 
15.6.1 Overview of changes to the study 
Modification 1 
Updated study medical expert and contact information. 
Sections affected include: 
 Title page 
 
Modification 2 
Added text to provide tolerance limits for permitted radiation. 
Sections affected include: 
 7.4.4 Study drug dose preparation 
 
Modification 3 
Text was updated to provide clarity to study sites. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 
Modification 4 
Text was added for consistency with Table 9-1: Schedule of assessments.  Although monthly 
visits might not be possible for some patients, tumor assessments as per time schedule 


 
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described in Section 9.2.6 might be feasible and will allow collection of data for disease 
response assessment related to some efficacy endpoints (radiological PFS, radiological bone 
specific PFS, etc.). 
Sections affected include: 
 9.2.4.2 Active follow-up without clinic visits 
 
Modification 5 
Clarified sites at which CTCs are collected. 
Sections affected include: 
 9.7.2.2 Collection of circulating tumor cells for biomarker analyses 
 
Modification 6 
Added interim data review. 
Sections affected include: 
 10.5 Planned interim data review  
 
Modification 7 
Updated text for independent radiological review. 
Sections affected include: 
 9.2.6 Radiological assessment: tumor and response evaluation  
 13.1.2 Independent radiological review 
 
Modification 8 
Added text for the establishment of an independent unblinded data review committee. 
Sections affected include: 
 List of abbreviations 
 13.1.3 Independent Data Review Committee 
 
Modification 9 
Added text for the establishment of an independent unblinded data review committee. 
Section affected includes: 
 Signature of the sponsor’s medically responsible person 


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Added text: 
IDRC 
Independent Data Review Committee 
 
Section 7.4.4 Study drug dose preparation 
This was changed as a result of modification 2. 
Old text: 
The study medication will be administered as a slow bolus IV injection.  After administration, 
the equipment used in connection with the preparation and administration of drug, are to be 
treated as radioactive waste and should be disposed in accordance with hospital procedure for 
the handling of radioactive material and according to local laws.  Written information about 
radium-223 dichloride and instructions for the handling and injection of radioactive material 
will be provided to study personnel. 
New text: 
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, are to be treated as radioactive waste and should be disposed in 
accordance with hospital procedure for the handling of radioactive material and according to 
local laws.  Written information about radium-223 dichloride and instructions for the 
handling and injection of radioactive material will be provided to study personnel. 
 
Section 9.1 Tabular schedule of evaluations 
This was changed as a result of modification 3. 
Old text: 
ii. Details of sampling are described in the Laboratory Manual.  Blood samples for analysis of 
circulating tumor cells will be collected within 5 days of Visits 2, 4, 6, 8, 9, 10  (ie, Day 1 of 
Cycles 1 through 6) prior to study drug dosing, and within 5 days of the EOT visit or disease 
progression, whichever occurs first. 
New text: 
ii. Details of sampling are described in the Laboratory Manual.  Blood samples for analysis of 
circulating tumor cells will be collected within 5 days of Day 1 of Cycles 1 through 6 prior to 
study drug dosing, and within 5 days of the EOT visit or disease progression, whichever 
occurs first. 
 
Section 9.2.4.2 Active follow-up without clinic visits 
This was changed as a result of modification 4. 


 
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Added text: 
If possible, Radiological tumor assessments as per timepoints and guidelines specified in 
Section 9.2.6 and Appendix 16.2 to be performed as applicable. 
 
Section 9.2.6 Radiological assessment: tumor and response evaluation 
This was changed as a result of modification 7. 
Deleted text: 
All digitized images/scans (both baseline and post-baseline) will be collected for 
retrospective analysis. 
 
Section 9.7.2.2 Collection of circulating tumor cells for biomarker analyses  
This was changed as a result of modification 5. 
Old text: 
Blood samples will be obtained from all subjects at the following time points: (1) Cycle 1, 
Day 1 (Visit 2) and every subsequent cycles, Day 1 within 5 days of the visit prior to 
radium-223 dichloride or placebo administration, and within 5 days of the EOT visit or 
disease progression, whichever occurs first. 
New text: 
Blood samples will be obtained from all subjects at sites in France, Germany, Israel, Spain, 
and the United Kingdom at the following time points: (1) Cycle 1, Day 1 (Visit 2) and every 
subsequent cycles, Day 1 within 5 days of the visit prior to radium-223 dichloride or placebo 
administration, and within 5 days of the EOT visit or disease progression, whichever occurs 
first. 
 
Section 10.5 Planned interim data review  
This was changed as a result of modification 6. 
Old text: 
There is no formal interim analysis for efficacy planned for the primary endpoint SSE-FS.  At 
the final analysis for SSE-FS, the secondary endpoints will be analyzed as well, but no alpha 
adjustment will be applied for secondary endpoints. 
New text: 
An administrative interim data review will be performed when approximately 40 rPFS events 
are reached. The interim data review will be primarily focused on the rPFS, and the results 
will inform on future radium-223 clinical development plans in this indication.  An 
independent unblinded data review committee will be formed.  


 
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No formal statistical testing will be performed for either SSE-FS or rPFS at the time of this 
interim review. Only summary statistics will be produced. There is no plan to stop the trial 
due to superior efficacy; therefore, no alpha adjustment is applied for this interim look at the 
primary endpoint of SSE-FS. The study will remain blinded after the interim data review.  
Details of the interim data review will be provided in the statistical analysis plan. 
 
Section 13.1.2 Independent radiological review 
This was changed as a result of modification 7. 
Old text: 
This study will have no central review.  However, all digitized images/scans (both baseline 
and post-baseline) will be collected for retrospective analysis. 
New text: 
This study will have no central review.   
 
Section 13.1.3 Independent Data Review Committee (IDRC) 
This was changed as a result of modification 8. 
Added text: 
An independent unblinded data review committee will be established.  
The IDRC will conduct a one-time unblinded review of the data. IDRC review will be 
supported by an independent unblinded statistical analysis center, as further described in the 
IDRC operational plan. 
 


 
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15.7 Amendment 8 
Amendment 8 (dated 03 APR 2018) is an amendment to the Version 7.0 of the protocol, 
dated 23 MAY 2017.  Changes to the integrated protocol include: 
 New request that bone fractures and bone associated events (e.g., osteoporosis) need 
to be reported as (S)AEs, including during long-term follow-up, regardless of the 
investigator’s causality assessment. 
 Addition of possibility to transition to long-term follow-up study for subjects who 
have completed at a minimum the end of treatment visit or 30 days from last study 
treatment dose, whichever is latest 
 Updated sponsor’s medically responsible person 
 Clarification to AE and SAE reporting requirements during active follow-up in the 
Schedule of Assessments 
 Minor clarifications 
15.7.1 Overview of changes 
15.7.1.1 Modification 1 
Bone fractures and bone associated events (e.g., osteoporosis) need to be reported as (S)AEs, 
including during long-term follow-up, regardless of the investigator’s causality assessment. 
Sections affected include: 
 Synopsis 
 5.1.1 Study periods and duration 
 9.1 Tabular schedule of evaluations 
 9.2.4.1 Active follow-up with clinic visits 
 9.2.4.2 Active follow-up without clinic visits 
 9.2.4.3 End of active follow-up 
 9.6.1.3 Assessments and documentation of adverse events 
 9.6.1.4 Reporting of serious adverse events 
Rationale: 
The ERA 223 study, a phase III randomized trial in prostate cancer patients examining 
radium‐223 dichloride vs 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 


 
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bone associated events (e.g., osteoporosis) occurring during study and in the follow-up period 
should be documented regardless of the investigator’s causality assessment. 
15.7.1.2 Modification 2 
Clarification of transition to long-term extension study, to allow collection of long term 
safety data 
Sections affected include: 
 Synopsis 
 5.1.1 Study periods and duration 
 5.3 End of study 
 9.2.5 End of Study 
Rationale: 
To allow collection of long-term safety data, subjects who have completed at a minimum the 
end of treatment visit or 30 days from last study treatment dose, whichever is latest, may be 
transitioned into a separate long‐term follow‐up study. Until the transition to the long‐term 
follow up study, subjects will continue to follow all the required procedures and visits 
described in the current protocol. 
15.7.1.3 Modification 3 
The sponsor’s medically responsible person has changed and signature page was updated to 
reflect this. 
Sections affected include: 
 Signature of the sponsor’s medically responsible person 
15.7.1.4 Modification 4 
Clarification of footnotes in the schedule of assessment to reflect consistency with the body 
text. The AEs and SAEs reporting requirements during active follow-up apply regardless of 
whether the patient has clinic visits or not.  The footnotes previously indicated these reporting 
requirements applied only in the case without clinic visits, which is inconsistent with the 
active follow up description in Section 9.2.4.1. 
Sections affected include: 
 9.1 Tabular schedule of evaluations 
 
15.7.1.5 Minor clarifications 
For Word-related technical reasons, numbered footnotes have been replaced with a summary 
of changes at the start of each amended section. 


 
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15.7.2 Changes to the protocol text 
Changes to the protocol text are provided in a separate tracked changes document. 


 
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16. Appendices 
16.1 National Cancer Institute-Common Terminology Criteria, version 4.03 
This study will utilize the NCI-CTCAE v4.03 for toxicity and SAE reporting.  A copy of the 
CTCAE v4.03 can be downloaded from the website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.  All 
appropriate treatment areas should have access to a copy of the CTCAE v4.03. 


 
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16.2 Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 
Section modified by Amendment 2 (Section 15.2) and Amendment 6 (Section 15.5). 
Disease response and progression will be evaluated in this study using a modified version of 
RECIST version 1.1 (51).  The modification refers to bone lesions assessment: all bone 
lesions are considered non measurable and new bone lesions identified by bone scan will 
need to be confirmed by further imaging (CT/MRI).  
Definitions: 
Bone lesions: Malignant findings in skeleton.  
Soft tissue lesions: Malignant finding in soft tissue (skin, subcutaneous, muscle, fat, lymph 
nodes). 
Visceral lesions: Malignant finding in visceral organs: lung, liver, brain, etc. 
Measurable lesions: Lesions that, at baseline, meet the requirements for being reproducibly 
quantifiable (see section below for detailed definition of measurable lesions).  
Non-measurable lesions:  Lesions that, at baseline, do not meet the below-described 
requirements.  These lesions cannot be chosen for quantitative assessment, and must be 
assessed qualitatively only. 
Target lesions: Lesions that are chosen at baseline (from the set of measurable lesions) for 
quantitative assessment throughout the trial, using rules outlined below.  A lesion that has 
been selected as a target lesion remains a target lesion for the rest of the study. 
Non-target lesions: Lesions that are not chosen at baseline for quantitative assessment, and 
must be assessed qualitatively throughout the trial.  A lesion that has been selected as a non-
target lesion remains a non-target lesion for the rest of the study. 
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. 
All measurements must be recorded in millimeters (or decimal fractions of centimeters). 
For measurements of tumors other than lymph nodes, the longest unbroken diameter seen on 
an axial slice is recorded.  
Lymph nodes must always be measured in the short axis (the longest measurement on an 
axial slice perpendicular to the longest diameter of the lymph node).  Lymph nodes less than 
10 mm in short axis diameter are defined as normal. 
CT/MRI of chest/abdomen/pelvis and any additional sites of disease (if clinically indicated) 
will be performed for all subjects.  
In addition, all subjects will have their bone disease assessed by technetium-99m bone scan 
with careful identification of all disease-related hotspots.  


 
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If FDG PET/CT or FDG PET scan is performed as part of the standard of practice imaging, 
the results of the FDG PET scan can be used as a complement to CT scanning in the 
assessment of disease progression – based on occurrence of new lesions – as per the RECIST 
1.1 algorithm (See section on New lesions in this appendix). 
FDG PET/CT or NAF PET/CT scan is acceptable as an alternative to technetium-99m bone 
scintigraphy if it is the standard of care at the institution, provided the same bone imaging 
modality is used throughout the study. 
Clinical lesions might be assessed clinically only as per the following rules: clinical lesions 
will only be considered measurable when they are superficial (e.g., skin nodules, palpable 
lymph nodes) and ≥10 mm diameter as assessed using calipers.  For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended. 
Baseline Assessment: 
Identifying measurable disease: 
Non-nodal malignant lesions: Measurable lesions are those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI.  If scans 
with slice thickness greater than 5mm are used, the minimum size should be twice the 
slice thickness. 
 10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
Malignant lymph nodes: To be considered pathologically enlarged, a lymph node must be 
≥10 mm in short axis when assessed by CT scan.  To be considered measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan.  
Tumor lesions situated in a previously irradiated area are not considered measurable unless 
there has been demonstrated progression in the lesion. 
Identifying non-measurable disease: 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with short axis 10 to 14 mm) are considered non-measurable 
disease.  
Bone lesions: 
Bone lesions (blastic, lytic, mixed type) will be considered non-measurable lesions.   
Selection of target and non-target lesions:  
At baseline, lesions are divided into those that will be followed quantitatively (target lesions) 
and those that will be followed qualitatively (non-target lesions). 


 
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Target lesions: 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and be recorded 
and measured at baseline.  These lesions should be selected on the basis of their size (lesion 
with the longest diameter/short axis for lymph nodes), be representative of all involved 
organs, and should be suitable for reproducible repeated measurements.  
For the purposes of this selection, all lymph nodes should be regarded as a single organ.  If 
there are multiple chains/regions, one from each should be selected. 
The sum of the diameters (longest diameter for non-nodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated by adding all target lesion diameters/short axis 
(for lymph nodes) and reported as the baseline sum of diameters.  The baseline sum of 
diameters will be used as the reference measurement when looking for evidence of objective 
response at later visits. 
If there are more than 5 measurable lesions, those not selected as target lesions will be 
considered together with non-measurable disease as non-target lesions. 
Non-target lesions: 
Non-target lesions include all non-measurable lesions, plus any measurable lesions over and 
above the maximum 5 listed as target lesions.  
Bone lesions are considered non-measurable and therefore should all be classified as 
non-target lesions.   
Post-baseline assessment: 
At every response assessment visit after baseline, the Investigator will assess the following:  
 target lesions selected at baseline, and  
 non-target lesions selected at baseline, and   
 search for new lesions.  
The lesion assessments are then combined into an assessment of the entire subject at that visit 
(called the visit response or the overall response). 
Target lesion assessment: 
The Investigator will measure each target lesion in the same manner as at baseline.  
Malignant lymph nodes will be measured in short axis diameter.  
If a lesion decreases in size to the point where it is still present, but cannot be measured 
accurately, a default value of 5 mm should be recorded for its diameter.  
If a lesion has disappeared, a value of 0 mm should be recorded for its diameter. 
If a lesion has split into distinct fragments, the longest diameter of each fragment should be 
measured, and the diameters added together.  


 
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If 2 lesions have merged, the longest diameter of the entire resulting lesion should be 
measured. 
The sum of diameters will be calculated by adding all target lesion diameters/short axis (for 
lymph nodes).  
The sum of diameters is always compared to 2 reference points: the baseline sum of 
diameters, and the smallest sum of diameters seen during the study (also called the nadir).  
The baseline may actually be the nadir, if there has been no reduction in the sum of diameters 
during the study.  The target lesion response is then classified as follows in Table 16–1. 
 
Table 16–1:  Target lesion response 
Response 
Response characteristics 
Complete response (CR) 
Complete disappearance of target lesions 
All target lymph nodes <10 mm 
Partial response (PR) 
At least a 30% decrease in the sum of diameters 
from baseline 
Progressive disease (PD) 
At least a 20% increase in the sum of diameters 
from the smallest value seen during the trial 
(including baseline), with at least a 5 mm absolute 
increase in the sum 
Stable disease (SD) 
Neither enough shrinkage to qualify as PR, nor 
enough growth to qualify as PD 
Non-evaluable (NE) 
One or more target lesions not evaluated because 
of imaging issues, coverage, or change in imaging 
technique 
Please note that when lymph nodes are included as target lesions, a CR may occur even when 
the sum of diameters is not zero, since a normal lymph node will have a diameter greater than 
zero but less than 10 mm. 
 
Non-target lesion assessment: 
Non-target lesions are assessed as a whole.  After examining each non-target lesion, the 
Investigator will classify the non-target lesion response as follows in Table 16–2. 
 


 
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Table 16–2:  Non-target lesion response 
Response 
Response characteristics 
Complete response (CR) 
Complete disappearance of all non-target lesions  
All non-target lymph nodes <10 mm 
Progressive disease (PD) 
Unequivocal progression of non-target lesions as 
a whole. 
 Subjective call by expert reviewer 
 Evaluated as a group, not lesion by lesion 
Non-CR/Non-PD 
Non-target lesions still present, without 
unequivocal progression 
Non-evaluable (NE) 
One or more non-target lesions not evaluated 
because of imaging issues, coverage, or change 
in imaging technique 
 
 
To achieve unequivocal progression in subjects with measurable disease on the basis of the 
non-target disease, there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of stable disease (SD) or partial response (PR) in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of 
therapy.  A modest ‘increase’ in the size of one or more non-target lesions is usually not 
sufficient to qualify for unequivocal progression. 
New lesions: 
Any new lesion that is considered unequivocally malignant is evidence of progression, with 
no minimum size requirement.  
An individual radiological event will be adjudicated in retrospect as progression at the time it 
was first detected by imaging techniques, even if strict criteria were fulfilled only on 
subsequent radiological testing.  This means that if a new lesion is not unequivocal at the 
time of initial detection, but later becomes unequivocal, the date of progression will be the 
date it was first detected. 
Specific considerations for new bone lesions and for unequivocal progression of existing 
bone lesions: 
The finding of a new bone lesion or progression of existing bone lesions should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor: some new bone lesions 
or unequivocal increase in size of existing lesions may be simply healing or flare of 
pre-existing lesions. 
The following rules will apply: 
 A new bone lesion or progression of existing bone lesion/s initially identified on a 
technetium-99m bone scan must be confirmed by CT or MRI.  If confirmed by 
CT/MRI, the date of occurrence of the new lesion or of progression of existing bone 


 
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lesion/s will be the date it was initially detected (by technetium-99m bone scan) even 
if the confirmation by CT/MRI was done at a subsequent scan. 
 A new bone lesion or progression of existing bone lesions initially identified by 
CT/MRI (and not visible on a technetium-99m bone scan) will not need further 
confirmation by CT/MRI unless not considered unequivocal at time of initial 
documentation.  The date of occurrence of new lesion or progression of existing 
lesions will be the date it was initially detected by CT/MRI. 
New lesions and FDG PET imaging 
New lesions on the basis of FDG PET imaging can be identified according to the following 
algorithm: 
 (-) FDG PET at baseline and (+) FDG PET at follow-up = Progressive Disease (PD) 
based on a new lesion 
 No FDG PET at baseline and (+) FDG PET at follow-up = PD if the new lesion is 
confirmed on CT. If a subsequent CT confirms the new lesion, the date of PD is the 
date of the initial FDG PET scan. 
 No FDG PET at baseline and (+) FDG PET at follow-up corresponding to a pre-
existing lesion on CT that is not progressing is not PD 
Note: A ‘positive’ FDG PET scan lesion means one with uptake greater than twice that of the 
surrounding tissue on the attenuation corrected image 
Visit response: 
The response of the target lesions, the response of the non-target lesions, and the presence or 
absence of new lesions are combined into the visit response for the entire subject at this visit, 
using the tables below. 
 


 
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Table 16–3:   Visit Response:  Subjects with target lesions (with or without non-target 
lesions) 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
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 
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 = non-evaluable; PD = progressive disease; PR = partial 
response; SD = stable disease. 
 
The following text descriptions of the visit response are logically equivalent to the tables 
above.  
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 (SD):  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 (PD):  At least a 20% increase in the sum of diameters of target lesions 
from 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 also constitute PD.  Ascites or pleural effusion 
will be recorded as disease progression only if proven malignant. 
In the absence of target disease, the following will apply (Table 16–4). 
 


 
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Table 16–4:  Time Point Response:  Subjects with non-target lesions only 
Non-Target Lesions 
New Lesionsa 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PDb 
Not all evaluated 
No 
NE 
Unequivocal PDc 
Yes or no 
PD 
Any 
Yes 
PD 
Abbreviations: CR  complete response; NE  non-evaluable; PD  progressive disease. 
a New lesions must be unequivocal (see bone lesions specifications) 
b “Non-CR/non-PD” is preferred over “stable disease”  
c “Unequivocal PD”:  Subjective call by expert reviewer.  Evaluated as a group, not lesion by lesion 
 


 
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16.3 Calculation for glomerular filtration rate  
Section modified by Amendment 1 (Section 15.1). 
In accordance with established nephrology practice and guidelines, renal function at baseline 
and throughout the study will be assessed by means of the estimated GFR, calculated using 
the abbreviated MDRD study formula.  
This equation of 4 variables (serum creatinine level, age, sex, and ethnicity) is recommended 
by the National Kidney Foundation for use in individuals 18 years or older.  The formula can 
be found at the following web site:  
http://www.kidney.org/professionals/kdoqi/gfr_calculator. 
 


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


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


 
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16.6 BPI-SF 
Section modified by Amendment 4 (Section 15.3). 
The severity of pain and its impact on daily functions will be self-assessed by the study 
subjects using the BPI-SF (54) 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.  
The BPI-SF will be self-administered by the subject at Dose 1, Day 1 (before the start of 
study treatment), at each treatment visit, at the end of treatment visit and follow-up clinic 
visits. 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 her 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 her.  
How should the Questionnaire be introduced?  
A sample script for introducing the questionnaire is given below.  


 
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“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 complete this questionnaire about your health on the day of each 
clinic visit. 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. 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 her 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  
At the beginning of each visit, please check that 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 her whether she had any difficulty completing 
the questionnaire. If the subject says that she had trouble understanding a question, ask her 
why she had difficulty with that item. Re-read the question for her 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. 


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SAP_000.pdf: 
 
Document Type: 
Statistical Analysis Plan 
Official Title: 
A phase II randomized, double-blind, placebo-controlled trial 
of radium-223 dichloride versus placebo when administered 
to metastatic HER2 negative hormone receptor positive breast 
cancer subjects with bone metastases treated with hormonal 
treatment background therapy 
NCT Number: 
NCT02258464 
Document Date: 
12 Aug 2019 
 


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Statistical Analysis Plan 
Protocol No.: BAY 88-8223 / 16298 
Page: 
1 of 
32
 
Integrated Statistical Analysis Plan 
A phase II randomized, double-blind, placebo-controlled trial of radium-223 dichloride versus 
placebo when administered to metastatic HER2 negative hormone receptor positive breast 
cancer subjects with bone metastases treated with hormonal treatment background therapy 
For this study, the SAP and subsequent SAP amendment were released as follows: 
• Original statistical analysis plan, Version 1.0, dated 29 APR 2016 
• Amendment 1 (based on integrated protocol amendment7) forming integrated statistical 
analysis plan Version 2.0, dated 25 OCT 2017 
• Amendment 2 (based on integrated protocol amendment 8) forming integrated statistical 
analysis plan version 3.0, dated 4 JAN 2019 
• Amendment 3 (based on integrated protocol amendment 8) forming integrated statistical 
analysis plan version 4.0, dated 12 AUG 2019 
This document integrates the original statistical analysis plan and all global amendments. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Protocol No.: BAY 88-8223 / 16298 
Page: 
2 of 
32
A phase II randomized, double-blind, placebo-controlled trial of radium-223 
dichloride versus placebo when administered to metastatic HER2 negative 
hormone receptor positive breast cancer subjects with bone metastases 
treated with hormonal treatment background therapy  
Short title: Study of radium-223 dichloride versus placebo and hormonal treatment as 
background therapy in subjects with bone predominant HER2 negative hormone receptor 
positive metastatic breast cancer 
BSP Study drug 
BAY 88-8223 / Radium-223 dichloride / Xofigo® 
Study purpose: 
This is a randomized, double-blind, placebo-controlled phase II study 
to evaluate the clinical benefit of radium-223 dichloride versus placebo 
when administered to metastatic HER2 negative hormone receptor 
positive breast cancer subjects with bone metastases treated with 
hormonal treatment background therapy 
Clinical study phase: II 
Date: 
12AUG2019 
Study No.: 
 
BAY 88-8223 / 16298 Version: 
V4.0 
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
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Statistical Analysis Plan 
Protocol No.: BAY 88-8223 / 16298 
    Page:  3 of 32 
 
Table of Contents 
 
1. 
Introduction ............................................................................................................................. 7 
2. 
Study Objectives ...................................................................................................................... 8 
3. 
Study Design ........................................................................................................................... 9 
4. 
General Statistical Considerations ......................................................................................... 11 
4.1 
General Principles .......................................................................................................... 11 
4.2 
Handling of Dropouts ..................................................................................................... 11 
4.3 
Handling of Missing Data .............................................................................................. 11 
4.4 
Interim Analyses and Data Monitoring .......................................................................... 12 
4.4.1 
Interim Analyses ............................................................................................. 12 
4.4.2 
Data Monitoring.............................................................................................. 12 
4.4.3 
Data Rules ....................................................................................................... 12 
4.5 
Validity Review .............................................................................................................. 12 
5. 
Analysis Sets ......................................................................................................................... 12 
6. 
Statistical Methodology ......................................................................................................... 13 
6.1 
Population characteristics ............................................................................................... 13 
6.1.1 
Disposition of subjects .................................................................................... 13 
6.1.2 
Demographic and baseline characteristics ...................................................... 13 
6.1.3 
Medical history ............................................................................................... 14 
6.1.4 
Prior, concomitant and post-treatment medications ....................................... 14 
6.2 
Efficacy Analysis ........................................................................................................... 15 
6.2.1 
Primary efficacy variables .............................................................................. 15 
6.2.2 
Secondary efficacy variables .......................................................................... 17 
6.2.3 
Exploratory efficacy variables ........................................................................ 22 
6.2.4 
Subgroup analyses .......................................................................................... 24 
6.2.5 
Brief Pain Inventory-Short Form (BPI-SF) .................................................... 25 
6.2.6 
Other variables ................................................................................................ 26 
6.3 
Safety Analysis ............................................................................................................... 26 
6.3.1 
Extent of exposure .......................................................................................... 26 
6.3.2 
Adverse events ................................................................................................ 26 
6.3.3 
Deaths ............................................................................................................. 27 
6.3.4 
Clinical laboratory evaluations ....................................................................... 28 
6.3.5 
Other safety measures ..................................................................................... 28 
6.4 
Pharmacokinetics ........................................................................................................... 29 
6.5 
Biomarker analyses ........................................................................................................ 29 
6.6 
Sample size estimation ................................................................................................... 29 
6.7 
Additional analyses planned to be reported outside the main report ............................. 29 
6.8 
Change of analysis ......................................................................................................... 29 
6.8.1 
Efficacy endpoints .......................................................................................... 29 
6.8.2 
Other endpoints ............................................................................................... 30 
7. 
Document history and changes in the planned statistical analysis ........................................ 30 
8. 
References ............................................................................................................................. 31 
9. 
Appendices ............................................................................................................................ 31 
9.1 
Overall tumor response .................................................................................................. 31 


Statistical Analysis Plan 
Protocol No.: BAY 88-8223 / 16298 
    Page:  4 of 32 
 
 
Table of tables 
Table 1: Symptomatic Skeletal Event Free Survival (SSE-FS) censoring rules. ................................................... 16 
Table 2: Radiological progression free survival censoring rules ........................................................................... 20 
Table 3: Time to first on-study SSE censoring rule ............................................................................................... 22 
Table 4: Time to first visceral metastases onset censoring rule ............................................................................. 23 
Table 5: Overall tumor response ............................................................................................................................ 31 
 


Statistical Analysis Plan 
Protocol No.: BAY 88-8223 / 16298 
    Page:  5 of 32 
 
Abbreviations 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
BHA 
Denosumab or bisphosphonates 
BMI 
Body Mass Index 
BPI-SF 
Brief Pain Inventory – Short Form  
CT 
Computed tomography 
CTCAE  
Common Terminology Criteria for Adverse Events; version 4.03 
EBRT 
External beam radiation therapy 
ECOG 
Eastern Co-operative Oncology Group  
ECOG PS 
Eastern Co-operative Oncology Group Performance Status 
eCRF 
Electronic case report form 
EOT 
End of Treatment 
GCP 
Good Clinical Practice 
HR 
Hazard ratio 
ICF 
Informed consent form 
IDMC 
Independent data monitoring committee 
ITT 
Intent-to-treat 
IV 
Intravenous 
IXRS 
Interactive Voice/Web Response System 
kBq 
KiloBecquerel; SI unit of radioactivity 
kg 
Kilogram 
mCi 
Millicuries 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
OS 
Overall survival 
PD 
Progressive disease 
PS 
Performance status 
rPFS 
Radiological progression-free survival 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SSE 
Symptomatic skeletal event 
SSE-FS 
Symptomatic skeletal event-free survival 
WHO 
World Health Organization 
WHO-DD 
World Health Organization Drug Dictionary 
WPS 
Worst pain subscale 
 
 
 


Statistical Analysis Plan 
Protocol No.: BAY 88-8223 / 16298 
    Page:  6 of 32 
 
 
 
Definitions of terms 
 
Radium-223 
dichloride  
The investigational product, a targeted alpha particle emitting 
radiopharmaceutical, is a ready-to-use solution for intravenous injection 
containing the drug substance radium-223 dichloride. The active moiety is 
the alpha particle emitting nuclide radium-223, present as a divalent cation 
(223Ra2+).  
Dose  
Doses are given as kiloBecquerel (kBq) per kilogram body weight, with the 
corresponding dose given in millicurie (mCi) per kilogram in parenthesis. 
The term “dose” is used to describe the quantity of radioactivity from 
radium-223 administered.  
 
 
 
 
 
 


Statistical Analysis Plan 
Protocol No.: BAY 88-8223 / 16298 
    Page:  7 of 32 
 
1. Introduction 
Presence of estrogen receptor (ER) and/or progesterone receptor (PR) is one of the most 
important prognostic/predictive factors in breast cancers. Patients with hormone receptor positive 
disease and HER2-negative disease are candidates for endocrine therapy. Bone is a frequent site 
of metastatic spread with approximately 65% to 75% of patients with metastatic breast cancer 
having skeletal involvement [1]. Due to the disrupted bone remodeling process, patients with 
metastatic bone lesions are at risk of increased morbidity including skeletal-related events (SRE), 
such as bone pain requiring intervention (i.e., radiotherapy or surgery), pathologic fractures, 
spinal cord compression, as well as symptomatic hypercalcemia and bone marrow infiltration. 
These events will ultimately impair the patient’s quality of life (QoL) and functional 
independence. 
Radium-223 dichloride solution for injection is a novel alpha particle-emitting 
radiopharmaceutical. The bone targeting property of radium-223 is similar to that of other earth 
alkaline elements, like calcium or strontium-89. However, the radiation characteristics of an 
alpha particle-emitting radionuclide appear to be more advantageous than of a beta-emitting 
radionuclide. The alpha particle range from radium-223 dichloride is less than 100 micrometers 
(less than 10 cell diameters), which limits damage to the surrounding normal tissue. 
In the phase III, double-blind, randomized, BC1-06, ALSYMPCA (Alpharadin in Symptomatic 
Prostate Cancer) study, a total of 922 subjects with CRPC and symptomatic bone metastases 
were randomized to receive 6 injections of radium-223 dichloride (50 kBq/kg IV, based on NIST 
2010 standardization [2]) or matching placebo every 4 weeks. Based on data of an interim 
analysis (n=809), radium-223 dichloride significantly improved overall survival (OS compared 
to placebo (the median OS was 14.0 versus 11.2 months, respectively; Hazard ratio [HR]= 0.695; 
p=0.00185). Symptomatic skeletal events (SSE) were lower in the radium-223 dichloride arm, 
and time to first SSE was significantly delayed (the median time to SSE was 13.6 months, versus 
8.4 months, respectively; HR=0.610; p=0.00046). Adverse events of any grade were reported in 
88% of the subjects who received radium-223 dichloride versus 94% in the placebo arm (Grade 
3/4 AEs were reported for 51% and 59% of subjects, respectively). 
In an open-label, multicenter, single-arm, phase IIa study (BC1-09), 23 subjects with metastatic 
breast cancer with bone dominant disease were administered 4 injections of radium-223 
dichloride (50 kBq/kg IV, based on NIST 2010 standardization[2]) every 4 weeks. The primary 
efficacy endpoints were the change in urine levels of N-terminal telopeptide (NTX) and bone 
alkaline phosphatase (ALP) from baseline at Week 16. Median urine NTX levels were reduced 
by 20% (from 36 to 29 nmo1 bone collagen equivalents [BCE]/mmo1 creatinine; p=0.03) and 
33% (from 36 to 23 nmo1 BCE/mmo1 creatinine; p=0.0124) at Week 8 and Week 16, 
respectively; 17/23 and 9/13 subjects (for whom data were available) had a decrease in urine 
NTX at Week 8 and Week 16, respectively. Median bone ALP levels were reduced by 33% 
(from 22.1 to 12.1 ng/mL; p=0.0001) at Week 8 and 42% (from 22.1 to 10.94 ng/mL; p=0.04) at 
Week 16. Bone ALP levels were reduced in 20/22 subjects at Week 8 and in 10/12 subjects (for 
whom data were available) at Week 16. Radium-223 dichloride was found to be safe and well 
tolerated. 


Statistical Analysis Plan 
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The treatment options for patients with bone dominant metastasis of breast cancer are still 
limited.  
Radium-223 dichloride has shown significant anti-tumor activity in a phase III study in subjects 
with bone predominant metastatic CRPC and in a phase II metastatic breast cancer study. The 
safety profile and tolerability for radium-223 dichloride appear to be acceptable in this study 
population. 
For a more detailed introduction, please refer to the clinical study protocol. 
The original protocol, version 1.0, is dated 13 MAY 2014. This statistical analysis plan (SAP) 
version 4.0 (amendment 3), describes the analyses to be included in the clinical study report for 
study 16298. It is based on the SAP version 1.0, dated 29 APR 2016, the version 2.0 (amendment 
1), dated 25 OCT 2017, the version 3.0 (amendment 2), dated 04 JAN 2019 and the integrated 
clinical study protocol version 8.0 (amendment 8), dated 03 APR 2018.1 
2. Study Objectives 
The objective of this study is to assess the efficacy and safety of radium-223 dichloride in 
subjects with HER2 negative, hormone receptor positive breast cancer with bone metastases 
treated with hormonal treatment background therapy.  
The primary endpoint is:  
• symptomatic skeletal event-free survival (SSE-FS).  
The secondary endpoints are: 
• OS;  
• time to opiate use for cancer pain;  
• time to pain progression;  
• pain improvement rate;  
• time to cytotoxic chemotherapy;  
• radiological progression free survival (rPFS); 
• Safety, acute and long term, including new primary malignancies and hematopoietic 
reserve for tolerability of subsequent chemotherapy.  
The exploratory endpoints are: 
                                                 
1 As of Amendment 3. 


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• time to first on-study SSE;  
• time to bone ALP progression;  
• bone ALP response at Week 12 and end of treatment (EOT);  
• bone-specific rPFS; 
• resource utilization;  
• biomarker assessments,  
• time to visceral metastases onset.  
3. Study Design 
This study is an international phase II, randomized, double-blind, placebo-controlled, parallel 
group study of radium-223 dichloride versus placebo administered on top of the hormonal 
treatment and supportive care as background treatment in subjects with HER2 negative, hormone 
receptor positive breast cancer with bone metastases.  Randomization will be stratified by: 
• Geographical regions (Europe/North America [including Israel] versus Asia) 
• Previous lines of hormone therapy in metastatic setting (1 versus 2 or more): for the 
purpose of counting the number of prior lines of hormone therapy, only a change of the 
hormone agent due to progression is counted as a new line of therapy.  A switch of 
hormone therapy from one agent to another due to toxicity or other reasons (e.g., 
subject’s preference) in absence of progressive disease (PD) at the time of switch will be 
counted as one line, although 2 different agents have been administered. 
• Prior SREs (1 versus 2): for the purpose of prior SREs stratification, separate SREs are 
those that occur at least 21 days apart of each other. Any procedure which is related to an 
SRE, such as orthopedic surgery to treat a pathological bone fracture or multiple doses of 
radiation during a course of treatment, should not be counted as a separate event. In case 
of bone pain that occurs in several anatomical locations and requires separate external 
beam radiotherapy (EBRT) sessions, it should be counted as one event if the EBRT 
sessions are administered within a period of 21 days. 
 
This study will be conducted at approximately 160 investigative study sites and approximately 
227 subjects will be enrolled. 
The study will comprise 4 periods: screening, randomization, treatment, and the follow-up period 
(active follow-up with clinic visits and active follow-up without clinic visits). 


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Investigational treatment consists of up to 6 cycles of radium-223 dichloride 55 kBq/kg  body 
weight  (based on updated 2015 NIST standardization[3]1) (Arm A) or placebo (Arm B) each 
separated by an interval of 4 weeks. All subjects will receive hormonal treatment with a single 
agent and supportive care as background treatment according to the local standard of practice. 
These treatments will also continue after completion of radium-223 dichloride or placebo. 
Subjects will be assessed for efficacy and safety endpoints at each treatment visit and will be 
evaluated every 12 weeks for radiological progression. Symptomatic skeletal events should be 
recorded until end of active follow-up, independent of whether the subject starts a new anti-
cancer therapy (i.e., chemotherapy, other). 
Subjects who discontinued or completed the radium-223 dichloride or placebo treatment, did not 
experience an SSE and radiological progression during the treatment period, had an EOT visit, 
and can travel to the clinic will enter an active follow-up period with clinic visits.  During this 
period, clinic visits are to occur as follows: 
• For subjects who have not experienced an SSE during the treatment period, visits will 
continue with the same frequency as during treatment (every 4 weeks ±7 days) until the 
subject has an SSE.  After the occurrence of the SSE, the subjects will be switched to a 
frequency of visits every 12 weeks ±7 days at the next scheduled visit.  
• For subjects who experienced an SSE during the treatment or this period, visits will occur 
every 12 weeks ±7 days.  The subjects will continue to be followed for radiological 
progression and long-term safety. 
• Subjects who miss 2 consecutive follow-up visits will be considered unable to travel to 
the site and will enter the active follow-up without clinic visits. 
Subjects from the treatment period or the active follow-up period with clinic visits who can no 
longer travel to the clinic site or those who experienced an SSE and radiological progression will 
be followed for survival, treatment-related AEs and SAEs, and the initiation of other anti-cancer 
therapies, and SSEs, with phone calls as follows: 
• For subjects who did not experience an SSE during treatment or the previous follow up 
period, the frequency of the phone calls will be every 4 weeks ±7 days until the subject 
has an SSE.  After the occurrence of the SSE, the subjects will be switched to a frequency 
of phone calls every 12 weeks ±7 days at the next scheduled phone call. 
• For subjects who experienced an SSE during treatment or the previous follow-up period, 
the frequency of the phone calls will be every 12 weeks ±7 days. 
A schematic of the study design is presented in protocol Section 5.   
                                                 
1 Updated dose per revised NIST standardization. The amount of radioactivity in the 
administered dose is unchanged from the 2010 standardization; only the numerical value of the 
dose changed due to the revised standard. 


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4. General Statistical Considerations 
4.1 General Principles 
The statistical evaluation will be performed by using the software package SAS version 9.2 or 
higher (SAS Institute Inc., Cary, NC, USA). Unless otherwise noted, data will be analyzed by 
descriptive statistical methods: The number of data available and missing data, mean, standard 
deviation, minimum, quartiles, median, and maximum will be calculated for metric data. 
Frequency tables will be generated for categorical data. 
Definition of efficacy and safety endpoints, analysis strategies, structure of analysis datasets and 
layout of analysis data displays are following Bayer Healthcare Pharmaceuticals (BHP) standards: 
Xofigo Project Standards, the Therapeutic Area Oncology Standards (TAS) and the Global 
Medical Standards (GMS), respectively. Where the given ordering reflects the priority of the 
different standards, means specifications of the latter ones have to be followed only if not specified 
in standards mentioned before.  
4.2 Handling of Dropouts 
A “dropout” is defined as a subject who has been randomized and discontinues study participation 
prematurely for any reason. Subjects withdrawn from study treatment will not be replaced. Refer 
to Section 6.3 in the study protocol for withdrawal of subjects from study. 
All efficacy analyses are based on the ITT population, which comprises all randomized subjects, 
including subjects who withdraw regardless of the reason for withdrawal. See following chapters 
for more details on deriving efficacy endpoints in case of missing data. 
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 eCRF. Except as 
noted, missing data will not be imputed or carried forward in any statistical analysis. 
Safety baseline is defined as the available value at last visit prior to or on first administration 
date of radium-223 dichloride. If values are missing at the baseline (Visit 2), data recorded at  
screening visit will be considered as baseline value. If screening record is also missing,  the 
baseline value will be left as missing. 
No imputation will be performed for missing lesion assessment and tumor response. For 
example, if a subject misses a scan visit and PD is documented at the next available scan visit, 
the actual visit date of the first documented PD will be used to calculate rPFS. 


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The partial missing date used for derivation of time to event, adverse event and concomitant 
medication partial missing start/stop dates will be imputed and the imputation rule will be 
specified in the analysis dataset specification. 
4.4 Interim Analyses and Data Monitoring 
4.4.1 
Interim Analyses 
An administrative interim data review will be performed when approximately 40 rPFS events are 
reached. The interim data review will be primarily focused on the rPFS, and the results will inform 
on future radium-223 clinical development plans in this indication. An independent unblinded data 
review committee will be formed. 
No formal statistical testing will be performed for either SSE-FS or rPFS at the time of this interim 
review. Only summary statistics will be produced. The number of patients randomized,  number 
censored, number of events, median rPFS and its 80% and 95% CI, and rPFS event rate at 6, 9 and 
12 months will be presented. A Kaplan-Meier curve will be generated for each treatment group.  
There is no plan to stop the trial due to superior efficacy; therefore, no alpha adjustment is applied 
for this interim look at the primary endpoint of SSE-FS. The study will remain blinded after the 
interim data review.  
Treatment-related AEs, study drug-related TEAEs, TE, AEs of interest, and serious AEs, lab 
toxicities are planned to be reported. The summaries of the safety data will be completed for the 
Safety analysis population (SAF). 1 
4.4.2 
Data Monitoring 
An Independent Data Monitoring Committee (IDMC) will not be applied to this study.  
4.4.3 Data Rules 
A data cut-off date for the final analysis of SSE-FS will be based on  the number of events 
required for the primary endpoint SSE-FS that have occurred. 
4.5 Validity Review 
The results of validity review meetings will be documented in the Validity Review Reports.  
5. Analysis Sets 
Intent-to-treat analysis (ITT) population 
                                                 
1 As of Amendment 1. 


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The primary population for all efficacy analyses is the Intent-to-treat analysis (ITT) population, 
which is defined as all randomized subjects. Subjects will be analyzed as randomized.  
Safety analysis (SAF) population 
The population for safety analysis (SAF) population is comprised of all randomized subjects who 
received at least one dose of study medication (Radium-223 dichloride or placebo) and will be 
used for all safety analyses. Subjects will be analyzed as treated. Using a conservative approach, 
subjects randomized to the placebo arm will be analyzed under the Radium-223 dichloride arm if 
the subject received at least one dose of Radium-223 dichloride treatment whereas subjects 
randomized to the Radium-223 dichloride arm will still be analyzed under the Radium-223 
dichloride arm regardless of receiving at least one dose of placebo. Only in a case where a 
subject randomized to the Radium-223 dichloride arm received only placebo treatment would the 
subject be analyzed under the placebo arm.  
6. Statistical Methodology 
The formal statistical analyses will be both descriptive and inferential. Summaries will be 
provided for each of the treatment groups. 
 
6.1 Population characteristics 
For this analysis, only descriptive statistics will be provided (no testing performed). The results 
will be displayed by treatment group for the ITT population. 
6.1.1 
Disposition of subjects 
The number of subjects enrolled and included in each of the ITT and safety populations will be 
tabulated by region, country, and center. A summary table will also be presented for the number 
of subjects enrolled and the number and percentage of subjects in each of the defined 
populations. The reasons for subjects excluded from each of the analysis populations will also be 
tabulated. In addition, the number of subjects who were screened, randomized, treated and 
discontinued will be summarized by treatment group. Reasons for discontinuation of study 
treatment will be tabulated. 
6.1.2 
Demographic and baseline characteristics 
All demographic and baseline characteristics will be summarized for the ITT population using 
descriptive statistics such as frequency and proportion (for categorical variables), mean, median 
and standard deviation (for continuous variables).  
These will include, but may not be limited to:  
• Demographics and baseline characteristics:                                                                      
Sex, race, ethnicity, age calculated at the date of randomization using date of birth, age 


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categories ( ≥55, <55) 1, Geographical region (Europe/North America [including Israel] 
versus Asia), baseline weight, height, body mass index, systolic blood pressure (BP), 
diastolic BP, heart rate, respiration rate. 
• Baseline cancer characteristics:                                                                                   
Eastern Cooperative Oncology Group (ECOG) performance status, menopausal status, 
histology, stage at initial diagnosis (TNM), grading (American Joint Committee on 
Cancer [AJCC]) at initial diagnosis, status of primary tumor at study entry, TNM 
classification of breast cancer at study entry, progesterone receptor status, estrogen 
receptor status, HER2/neu status (Immunohistochemistry[IHC]), HER2/neu status 
(Fluorescence in situ hybridization[FISH])/( Chromogenic in situ hybridization[CISH]) /( 
HER2 gene amplification ISH (other validated assay)) 2, time since initial diagnosis, time 
since initial diagnosis to metastatic disease, time since initial diagnosis to bone 
metastases, time since first progression, time since most recent progression, previous 
lines of hormone therapy in metastatic setting (1 versus 2 or more), and prior SREs (1 
versus 2), cancer pain assessment3. 
6.1.3 
Medical history 
The dictionary for coding is MedDRA version 17 or most recent version. By treatment-group 
summary statistics (frequency and percentage) will be provided by system organ class and 
preferred term for ITT analysis set.  
6.1.4 
Prior, concomitant and post-treatment medications 
The dictionary used for coding medications is World Health Organization Drug Dictionary 
(WHO-DD). The following categories of medications will be summarized 
• Systemic anti-cancer therapies: frequency of subjects for each drug category, prior and 
post study medication.  
• Diagnostic and Therapeutic Procedures: frequency of subjects by procedure, prior, during 
and post study medication.  
• Radiotherapies: frequency of subjects by field and intent, prior, during therapy and post 
study medication. 
• Myelosupressive systemic anti-cancer therapy during follow up: frequency of subjects for 
each drug category. 
• Analgesics: frequency of subjects for each drug category, prior and post study 
medication. 
• Denosumab or bisphosphonates (BHA): frequency of subjects for each drug category, 
prior study medication. 
                                                 
1 As of Amendment 1. 
2 As of Amendment 1. 
3 As of Amendment 1. 


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• Other prior and concomitant medications: frequency of subjects for each drug category.  
 
6.2 Efficacy Analysis 
All comparisons of the treatment groups with respect to the primary and secondary efficacy 
variables will be based on the ITT population.  
The duration for the time-to-event variables is calculated by event/censoring date – reference 
date + 1. Time-to-event analysis reference date is randomization date except for time to opiate 
use for cancer pain, time to pain progression, pain improvement rate. These pain efficacy 
endpoints baseline is defined as last available value prior to first administration of radium-223 
dichloride since the data are not collected at screening visit. For all other efficacy endpoints, the 
baseline is defined as the last available value prior to or on the date of randomization.  
6.2.1 
Primary efficacy variables 
6.2.1.1 Definition of SSE-FS: 
The primary efficacy endpoint is symptomatic skeletal event-free survival (SSE-FS). It is defined 
as the time from date of randomization to occurrence of one of the following, whichever happens 
earlier: 
 
(1) An on-study SSE, which is defined as: 
a. the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms 
b. the occurrence of new symptomatic pathological bone fractures (vertebral or non-
vertebral) 
c. the occurrence of spinal cord compression 
d. a tumor related orthopedic surgical intervention. 
 
(2) Death from any cause  
 
Note: Any EBRT or orthopedic surgery related to a prior skeletal related event but 
administered after signature of the informed consent form (ICF) will not be counted as an on-
study SSE. 
 
For event date, the actual procedure date instead of date of symptom will be used to calculate the 
SSE-FS.  
 
The censoring rules for SSE-FS are summarized in Table 1.


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Table 1: Symptomatic Skeletal Event Free Survival (SSE-FS) censoring rules. 
 
Situation 
End Date  
Censored Reason for 
Censoring 
No post-baseline SSE 
assessment and no death 
Date of 
Randomization 
Yes 
No post-baseline 
SSE assessment and 
no death 
Subject had an SSE event 
Date of first SSE 
No* 
N/A 
Death without prior SSE 
(<9 weeks between last SSE 
assessment and death) # 
Date of death 
No* 
N/A 
Death without prior SSE (≥ 
9 weeks between last SSE 
assessment and death) # 
Last SSE assessment 
before the missing 
SSE assessments# 
Yes 
≥ 9 weeks between 
last SSE 
assessments 
immediately prior to 
death 
Neither SSE nor death at data 
cutoff  
Last SSE assessment  Yes 
Neither SSE nor 
death 
Symptomatic Skeletal Event Free Survival (SSE-FS) = End Date – Date of Randomization +1  
*The earliest end date in the table is used in calculating the SSE-FS 
#: use randomization date instead of last SSE assessment date if no post-baseline SSE assessment. 
SSE events immediately after missing SSE assessments are still counted as events in the analysis of SSE-FS. 
 
6.2.1.2 Analysis of SSE-FS: 
The primary analysis of SSE-FS will be performed when approximately 119 subjects have SSE-
FS.  
Since differences are expected between the values of the stratification variables entered by the 
investigator at the time of randomization (IVRS) and those derived from information collected 
on the eCRF, the analysis will be performed using both assignments to the strata. However, the 
primary stratified analyses for the efficacy endpoints will be based on the stratification 
information entered in IVRS. Stratification factors collected on the eCRF (considered the ‘true’ 
information) will be used for sensitivity analyses. In rare circumstances, if eCRF data cannot be 
accurately documented, then IVRS data will be used. 
The null hypothesis that both treatment groups have the same SSE-FS distribution will be tested 
against the alternative hypothesis that the distribution of SSE-FS time in radium-223 dichloride 
is different from the placebo group.  
H0: SSE-FSXofigo = SSE-FS Placebo, versus 
HA: SSE-FSXofigo > SSE-FS Placebo1 
                                                 
1 As of Amendment 1. 


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The SSE-FS will be compared using a stratified log-rank test with a one-sided alpha of 0.1 (2-
sided alpha of 0.2), stratified by the same stratification factors as randomization: geographical 
regions, previous lines of hormone therapy in metastatic setting and prior SREs, based on the 
stratification data in IVRS.  
The product-limit estimates of the survival distribution functions (Kaplan-Meier) will be 
presented for each treatment group: N, total censored, total failed, time to event (median and its 
80% CI, 25th and 75th percentile, range), probability of event-free survial at pre-specified months. 
A Kaplan-Meier curve will be generated for each treatment group. 
The hazard ratio (radium-223 dichloride / placebo) for SSE-FS and its 80% and 95% confidence 
intervals (CIs) will be calculated using a univariate Cox model, stratified by the same factors as 
stated above. 
The Kaplan-Meier (KM) estimates for SSE-FS and KM curves will also be presented for each 
treatment group. The median and SSE-FS rates at time points such as 3 months, 6 months, etc., 
together with corresponding 80% CIs will also be calculated by treatment group. Subgroup 
analysis will be performed for subjects who have no opiate use at baseline1. 
The contribution of each component of the composite SSE between the arms will be evaluated. 
Descriptive statistics will be presented. 
Sensitivity analyses will be conducted for the following scenarios2: 
• SSE-FS will be evaluated using stratification factors derived from the information 
collected on the eCRF. 
6.2.2 
Secondary efficacy variables 
The secondary efficacy variables are specified below:  
• Overall survival (OS) 
• Time to opiate use for cancer pain 
• Time to pain progression 
• Pain improvement rate 
•  Time to cytotoxic chemotherapy 
• rPFS  
6.2.2.1 Definition 
Overall survival is defined as the time from the date of randomization to the date of death due to 
any cause.  The OS time for subjects alive at the time of analysis (or database cut-off date) will 
be censored at their last known alive date. For subjects whose last date of follow-up confirms the 
                                                 
1 As of Amendment 1. 
2 As of Amendment 3. 


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subject was alive at the data cut-off (i.e., based on the formal survival sweep), the subject will be 
censored at the data cut-off date. If a subject is lost to follow up and there was no contact after 
randomization, this subject will be censored at randomization date (OS = 1 day).  
Time to opiate use for cancer pain is defined as the interval from the date of radium-223 
dichloride treatment start to the date of start of opiate use.  Subjects who have no opiate use at 
the time of analysis (or database cut-off date) will be censored at the last opiate use assessment 
date.  Subjects with no on study assessment or no baseline assessment will be censored at 
radium-223 dichloride treatment start date (day 1). Subjects who have opiate use prior to radium-
223 dichloride treatment start will be censored at radium-223 dichloride treatment start date.  
Time to opiate use for cancer pain will be analyzed based on the information collected on the 
analgesic concomitant medication; analgesics use 24 hour page and opiate use eCRF pages, 
whichever is the earliest.  
Time to pain progression is defined as the interval from radium-223 dichloride  treatment start 
to the first date a subject experiences pain progression based on worst pain subscale (WPS) and 
analgesic use.  Time to pain progression will be evaluated in subjects with baseline WPS ≤ 8. 
Pain progression is defined as an increase of 2 or more points in the “worst pain in 24 hours” 
score from baseline observed at 2 consecutive evaluations ≥4 weeks apart  
OR 
An increase in pain management with respect to baseline, whichever occurs first. 
An increase in pain management (IPM) is defined as.  
• For subjects taking no analgesics or a non-opioid at baseline, the initiation of any opioid 
would be considered an IPM. 
• For subjects taking a weak opioid at baseline, the initiation of any strong opioid would be 
considered an IPM. 
• For subjects taking a strong opioid at baseline, the initiation of an additional strong 
opioid would be considered an IPM 
• For subjects taking a weak opioid at baseline, the initiation of an additional weak opioid 
would be considered an IPM.1 
Pain intensity (worst pain score [WPS]) assessments will occur on the day of visit. Subjects who 
have not experienced pain progression at the time of analysis (or database cut-off date) will be 
censored at the last post-baseline pain assessment date the subject was known to have not 
progressed.  Subjects with no on-study assessment or no baseline assessment will be censored at 
radium-223 dichloride  treatment start date2.  
                                                 
1 As of Amendment 3. 
2 As of Amendment 1. 


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The increase in pain management is based on the analgesic use information collected on all 
eCRF pages including analgesic concomitant medication, 24-hour analgesic use page and opiate 
use eCRF page. 
Pain improvement is defined for subjects evaluable for pain improvement, i.e. subjects with 
baseline WPS≥ 2, as a 2-point decrease or more in WPS from baseline over 2 consecutive 
measurements conducted at least 4 weeks apart, without an increase in pain management. 
Pain improvement rate is defined as the number of subjects with pain improvement as defined 
above, divided by the total number of subjects evaluable for pain improvement (i.e., subjects 
with baseline WPS≥ 2).  
Time to cytotoxic chemotherapy is defined as the time from the date of randomization to the 
date of the first cytotoxic chemotherapy during follow up. Subjects who have not started 
cytotoxic chemotherapy during the study will be censored at last assessment for systemic anti-
cancer therapy.   
Radiological progression-free survival (rPFS) is defined as the time from the date of 
randomization to the date of first radiological progression or death (if death occurs before 
progression).  For subjects without documented radiological progression or death at the time of 
analysis (or database cut-off date), i.e., data cut-off, the rPFS time will be censored at the date of 
the last evaluable tumor assessment. Every effort will be made to obtain radiologic scans for 
documentation of progression.  
The radiological progression will be derived using algorithm in Table 5: Overall tumor response 
in appendix. Table 2 shows the end date and censoring rules for rPFS. 
Subjects with baseline superscan will continue to have post-baseline bone imaging by either 
anatomically limited or full body CT/MRI, and the CT/MRI imaging will be used for rPFS 
analysis for these subjects. If no confirmed  radiological progression is detected by bone imaging 
full-body CT/MRI at post-baseline and no death, then these subjects will be censored at the last 
full-body CT/MRI assessment date with clear radiological non-PD. Anatomically limited 
CT/MRI assessments identify results unknown. 


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Table 2: Radiological progression free survival censoring rules 
Situation 
End Date  
Censored Reason for Censoring 
Subject had a radiological 
assessment of PD (no missed 
radiological assessment) 
Date of first PD 
No 
N/A 
Death during the study (no 
missed radiological 
assessment) or before first 
radiological PD assessment 
Date of death 
No 
N/A 
Subjects with baseline 
superscan, then either 
radiological PD(regardless 
by anatomically limited or 
full body CT/MRI) or death 
at post-baseline 
Date of first PD or death 
No 
N/A 
Subjects with baseline 
superscan, then radiological 
non-PD (by full body 
CT/MRI) and no death at 
post-baseline 
Date of last full-body 
CT/MRI assessment with 
radiological non-PD(by 
full body CT/MRI)  
Or  
Date of randomization if 
no full body CT/MRI at 
post-baseline 
Yes1 
Radiological non-PD 
(by full body CT/MRI) 
and no death at post-
baseline 
Subjects without any 
evaluable post-baseline 
radiological tumor 
assessment. 
The randomization date 
Yes 
No baseline or post-
baseline tumor 
assessment. 
Subjects who had a death or 
disease progression 
immediately after two or more 
consecutive missed 
radiological assessments.  
Date of last radiological 
assessment before missed 
assessments. 
Yes 
Death or disease 
progression immediately 
after two or more 
consecutive missed 
radiological 
assessments. 
New protocol prohibited 
systemic anticancer treatment 
started prior to radiological PD 
or death 
Date of last radiological 
assessment prior to the 
change of therapy 
Yes 
New protocol prohibited 
systemic anticancer 
treatment started prior to 
radiological PD or death 
Subjects who discontinue or 
withdraw early from the study 
without documented 
radiological disease 
progression. 
Date of last evaluable 
radiological assessment 
Yes 
Discontinue or withdraw 
early from the study 
without documented 
radiological disease 
progression 
Radiological Progression Free Survival (rPFS) = End Date – Start Date +1 
Two consecutive missing radiological assessments are defined if the time interval between two consecutive radiological 
assessments is more than 26 weeks (2 × (12 +1) week) 2. 


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Table 2: Radiological progression free survival censoring rules 
# For patients with baseline superscan, radiological non-PD has to be identified by full-body CT/MRI. Anatomically 
limited CT/MRI assessments identify results unknown. 
The prohibited concomitant therapies during the treatment phase of study include:  
• Chemotherapy 
• Radiopharmaceuticals, such as strontium-89, samarium-153, rhenium-186, or rhenium-
188 
• Hemibody external radiotherapy 
• Other investigational drugs 
6.2.2.2 Analysis of secondary efficacy endpoints 
Time to event efficacy analysis will be performed to compare two treatment groups using a 
stratified log-rank test stratified by the same stratification factors as randomization. The hazard 
ratio (radium-223 dichloride / placebo) and its 80% and 95% CIs will be estimated from the Cox 
model, stratified by the same factors as for SSE-FS analysis. No alpha adjustment will be applied 
for secondary endpoints. 
The product-limit estimates of the survival distribution functions (Kaplan-Meier) will be 
presented for each treatment group: N, total censored, total failed, time to event (median and its 
80% CI, 25th and 75th percentile, range), probability of event-free survival at pre-specified 
months, such as 6, 12, 18, etc. months for OS. A Kaplan-Meier curve will be generated for each 
treatment group. 
The pain improvement rates will be calculated by treatment group with their 80% CI as well as 
the differences of pain improvement rates between treatment groups and the corresponding 80% 
CIs. Pain improvement rate at week 12, EOT and any visit will be considered. 
The comparison of pain improvement rate for all visits between the two treatment groups will be 
done using the “general association Cochran-Mantel-Haenszel statistic” stratified by the same 
stratification factors used in the SSE-FS analysis.   
Due to  inaccuracies in German translation of BPI-SF, the primary analyses of pain progression 
and pain improvement rates will be conducted with cleaned BPI-SF data only. Sensitivity 
analyses will be conducted for pain progression and pain improvement rates with all BPI-SF 
data, including uncleaned BPI-SF data.3  
                                                 
1 As of Amendment 1. 
2 As of Amendment 1. 
3 As of Amendment 3. 


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6.2.3 
Exploratory efficacy variables 
The exploratory efficacy variables are specified below:  
• Time to first on-study SSE 
• Time to bone ALP progression 
• Bone ALP response at week 12 and EOT  
•   Bone specific rPFS 
• Time to visceral metastases onset 
6.2.3.1 Definition 
Time to first on-study SSE is defined as the time from the date of randomization to the date of 
the first on-study SSE. For subjects without SSE at the time of analysis, time to first on-study 
SSE will be censored at the date of last assessment of SSE.  
The conventions for calculation of time to first on-study SSE are the same as for SSE-FS in 
section 6.2.1.1 except without considering death as an SSE event. The censoring rules for time to 
first on-study SSE are summarized in Table 3. 
Table 3:  Time to first on-study SSE censoring rule 
Situation 
End Date  
Censored 
Reason for Censoring 
No post-baseline SSE 
assessment 
Randomization date 
Yes 
No post-baseline SSE 
assessment 
Subject had an SSE event 
Date of first SSE 
No 
N/A 
No SSE and no death at 
data cutoff 
Last SSE assessment  Yes 
No SSE 
No SSE prior to death 
Last SSE assessment  Yes 
No SSE prior to death 
SSE events immediately after missing SSE assessments are still counted as events in the analysis of Time to 
first on-study SSE. 
 
Time to bone ALP progression is defined as the time from the date of randomization to the date 
of first bone ALP progression.  Bone ALP progression is defined as a ≥25% increase from the 
baseline value, at least 12 weeks from baseline in subjects with no bone ALP decline from 
baseline; or a ≥25% increase above the nadir value, which is confirmed by a second value 
obtained 3 or more weeks later in subjects with an initial bone ALP decline from baseline. 
Confirmation visit does not have to be adjacent to first visit with increase from nadir. Subjects 
without bone ALP progression at the time of analysis (or database cut-off date) will be censored 
at last bone ALP assessment. Subjects without baseline or post-baseline bone ALP values will be 
censored at date of randomization.  
For subjects who had a bone ALP progression immediately after two or more consecutive missed 
ALP assessments, time to bone ALP progression will be censored at the date of last bone ALP 
assessment before missed assessments. Two consecutive missing assessments is defined if the 
time interval between two consecutive ALP assessments is more than 10 weeks (2 × (4 weeks +1 


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week))during the treatment period, or 26 weeks (2 × (12 weeks +1 week)) during the active 
follow-up period1. 
Bone ALP response at week 12 and EOT is defined as a ≥30% reduction of the blood level at 
Week 12 and EOT, compared to the baseline value.  Confirmed bone ALP response is defined as 
a ≥30% reduction of the blood level, compared to the baseline value, confirmed by a second 
bone ALP value 4 or more weeks later.  
Bone specific rPFS is defined as the time from the date of randomization to the date of 
confirmed radiological progression detected by bone imaging or death (if death occurs before 
progression).  Subjects without confirmed radiological progression or death at the time of 
analysis (or database cut-off date) will be censored at their last evaluable radiological bone 
imaging assessment. If a new bone lesion or unequivocal increase in size of bone lesions is 
identified on bone scan, the lesion must also be confirmed by computed tomography/magnetic 
resonance imaging (CT/MRI).  If a new bone lesion or unequivocal increase in size of bone 
lesions is only visible on a CT/MRI and not visible on a technetium 99m bone scan, progression 
will be declared without further confirmation. The conventions for calculation of bone specific 
rPFS are the same as for rPFS in section 6.2.2.1 except that bone progression or death (if death 
occurs before progression) is considered as a bone specific rPFS event and bone tumor 
assessment is used to determine the event/censoring.  
Subjects with baseline superscan will continue to have post-baseline bone imaging by either 
anatomically limited or full body CT/MRI, and the CT/MRI imaging will be used for bone 
specific rPFS analysis for these subjects. If no confirmed  radiological progression is detected by 
bone imaging full-body CT/MRI at post-baseline, then these baseline superscan subjects will be 
censored at the last full-body CT/MRI assessment date with clear radiological non-PD. Baseline 
superscan subjects will be censored at date of randomization if no full body CT/MRI at post-
baseline. Anatomically limited CT/MRI assessments identify results unknown. 
Time to visceral metastases onset is defined as the time from the date of randomization to the 
date of the first scan showing visceral metastatic disease.  
The censoring rules for time to visceral metastases onset are summarized in Table 4. 
Table 4:  Time to first visceral metastases onset censoring rule 
Situation 
End Date  
Censored Reason for Censoring 
Subject had a visceral metastases 
Date of the first scan 
showing visceral 
metastatic disease 
No 
N/A 
Subjects without any evaluable 
post-baseline non-bone tumor 
assessment. 
The randomization 
date 
Yes 
No baseline or post-
baseline tumor 
assessment. 
Subjects who didn’t have visceral 
metastases at the time of analysis. 
Date of last evaluable 
non-bone tumor 
assessment 
Yes 
Death or disease 
progression immediately 
after two or more 
consecutive missed 
                                                 
1 As of Amendment 3. 


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radiological 
assessments. 
 
6.2.3.2 Analysis of exploratory efficacy endpoints 
Similar to the primary efficacy endpoint, time to event efficacy analysis will be performed to 
compare two treatment groups using a stratified log-rank test stratified by the same stratification 
factors as randomization. The hazard ratio (radium-223 dichloride / placebo) and its 80% and 
95% CIs will be estimated from the Cox model, stratified by the same factors as for SSE-FS 
analysis.  
The product-limit estimates of the survival distribution functions (Kaplan-Meier) will be 
presented for each treatment group: N, total censored, total failed, time to event (median and its 
80% CI, 25th and 75th percentile, range), rate of subjects who did not yet develop an event at pre-
specified months. A Kaplan-Meier curve will be generated for each treatment group. 
Sensitivity analysis of Time to bone ALP progression will be performed by dropping the 12 
week restriction in the definition. 
The bone ALP response at Week 12 and EOT will be calculated by treatment group with their 
80% CI as well as the differences of bone ALP response between treatment groups and the 
corresponding 80% CIs.  
The comparison of bone ALP response at Week 12 and EOT between two treatment groups will 
be done using the “general association Cochran-Mantel-Haenszel statistic” stratified by the same 
stratification factors used in the SSE-FS analysis.   
 
The change from baseline WPS to the Week 12 visit and EOT visit will be calculated. The 
missing values at Week 12 and /or EOT will remain missing (the previous value will not be 
carried forward). 
6.2.4 Subgroup analyses 
Descriptive statistics and hazard ratio estimates with 80% CIs will be provided for SSE-FS and 
rPFS at least within each category of the following variables, provided there are a sufficient 
number of events in total within the subgroup across the treatment groups.  
The list used for subgroup analyses for SSE-FS were updated and provided as below:  
• Age (≥55, <55) 1  
• Race  
• Geographical region (Europe/North America [including Israel] versus Asia)  
                                                 
1 As of Amendment 1. 


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• Baseline ECOG performance status  
• Previous lines of hormone therapy in metastatic setting  
• Visceral disease1 
• Prior SREs  
• Baseline total body weight 
• Baseline ideal body weight 
• BMI. 
The subgroup analyses for rPFS will be performed as below2: 
• Age (≥55, <55)  
• Geographical region (Europe/North America [including Israel] versus Asia)  
• Baseline ECOG performance status  
• Previous lines of hormone therapy in metastatic setting  
• Visceral disease 
• BMI 
 
6.2.5 Brief Pain Inventory-Short Form (BPI-SF) 
The BPI-SF is an 11-item, self-administered, clinically valid, reliable, and responsive measure 
developed to assess pain related to cancer. 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.  
The items are aggregated into 2 dimensions: (1) Pain severity index, and (2) Function 
interference index, using the mean of the 7 pain interference items. All 4 severity items must be 
completed for aggregating the pain severity index. The function interference index is scored as 
the mean of the item scores multiplied by 7, given that more than 50% or 4 of 7 of the items have 
been completed.  
Descriptive statistics for observed data will be presented at each assessment time point and for 
change from baseline by treatment group.  
                                                 
1 As of Amendment 1. 
2 As of Amendment 3. 
 


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6.2.6 Other variables 
6.2.6.1 Resource utilization 
Resource utilization data will be presented in the listing.1 
6.3 Safety Analysis 
The summaries of the safety data will be completed for the Safety analysis population (SAF). No 
formal statistical test will be performed for the safety variables. 
6.3.1 Extent of exposure 
Study medication and single standard of care hormonal treatment will be summarized for the 
SAF by treatment group, using descriptive statistics such as frequency and proportion (for 
categorical variables), mean, median, and standard deviation (for continuous variables). 
Summaries will include, but may not be limited to: 
• Duration of treatment Radium-223 dichloride: overall duration of study treatment, 
number of injections of study treatment, time between two consecutive injections, 
such as time between injections X and X+1, X=1, 2, …, 5, average time between 
injections. Overall duration of single standard of care hormonal treatment in study 
medication treatment period and follow up period, respectively. 
• Dosage of Radium-223 dichloride: total activity injected, total activity injected per 
body weight. Dosage of hormonal treatment will be summarized for safety 
population. 
• Dose modifications of Radium-223 dichloride: number of subjects with all 
injections performed successfully and without delay, number of injections not 
performed successfully, number of injections delay, reason for injections delay. 
Dose modification of hormonal treatment. 
6.3.2 
Adverse events  
All adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) Version 18 or most recent version. The intensity of an AE will be 
documented using National Cancer Institute (NCI) Common Terminology Criteria Adverse 
Event (CTCAE), version 4.03.   
A treatment-emergent AE is defined as any event arising or worsening after the start of study 
drug administration until 30 days after the last study medication intake. 
                                                 
1 As of Amendment 3 


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Summary statistics (frequency and percentage of subjects, not of events) will be presented by 
treatment group using MedDRA by worst grade for the following: 
• Incidence rate of pre-treatment AEs.  
• Incidence rate of treatment-emergent AEs. 
• Incidence rate of treatment-emergent drug-related AEs. 
• Incidence rate of treatment-emergent AEs with grades 3 or 4. 
• Incidence rate of treatment-emergent AEs with Grade 5. 
• Incidence rate of treatment-emergent AEs leading to permanent withdrawal of 
medication.  
• Incidence rate of treatment-emergent AEs leading to dose interruptions. 
• Incidence rate of treatment-emergent AEs leading to dose reductions (applies to 
background treatment and concomitant medication of interest). 
• Incidence rate of serious treatment-emergent adverse events. 
• Incidence rate of serious treatment-emergent drug-related adverse events. 
• Listing of treatment-emergent AEs leading to withdrawal: subject ID, investigator AE 
term, start and stop date of study drug administration, start and stop date of AE, drug 
related (yes/no), serious (yes/no), worst grade, outcome. 
• Listing of treatment-emergent serious AEs: subject ID, investigator AE term, worst 
grade, start and stop dates of study treatment, start and stop date of AE , drug related 
(yes/no), outcome, action taken.  
• In addition, descriptive summaries will be provided for long term safety endpoints 
including new primary malignancies and hematopoietic reserve for tolerability of 
subsequent chemotherapy.  
• Bone fractures and bone associated events will be reported, including during long-term 
follow-up, regardless of the investigator’s causality assessment.1 
6.3.3 
Deaths 
Deaths reported during the study period will be tabulated by treatment group. 
• Summary table of deaths (all deaths, all deaths during treatment and up to 30 days after 
last dose of study drug, all deaths later than 30 days after last dose of study medication) 
                                                 
1 As of Amendment 2. 


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• Listing of subjects who died during treatment and up to 30 days after last dose: subject 
ID, start and stop date of study medication, date of death, and cause of death. 
 
6.3.4 
Clinical laboratory evaluations 
Worst grades for hematological and biochemical toxicities will be calculated according to 
CTCAE, version 4.03 based on laboratory measurements. Summary statistics (frequency and 
percentage of subjects, not of events) will be presented by treatment group and NCI CTC worst 
grade for the following: 
• Hematological and Biochemical Toxicities: treatment-emergent events by worst CTCAE 
grade. 
• Change in worst grade from baseline for hematological and biochemical toxicity (worst 
grade under treatment- latest pre-treatment value).  
• Shift table from baseline to worst grade post-baseline for hematological and biochemical 
toxicity (worst grade under treatment- latest pre-treatment value). 
• By-subject listing of subjects with abnormal laboratory values. 
If more than one assessment occurred at any post-baseline visit (repeated measures at same 
visit), the last valid (non-missing) value will be used in the summaries. Unscheduled laboratory 
data will be listed but will not be included in the summary tables. CTC grading of some 
laboratory parameters require clinical information in addition to the laboratory values. However, 
laboratory CTC grades presented in the CSR will be based only on the numerical lab results. 
6.3.5 Other safety measures 
The last pre-treatment safety measurement, i.e., SBP, DBP, weight, body temperature, heart rate, 
respiration rate and electrocardiogram (ECG) will be used as “baseline value.” 
When more than one value is collected at the same visit, the value retained at that particular visit 
for summary statistics will be the average of the different measures reported for that visit. 
For each treatment group, vital signs will be tabulated and summarized by visit for observed 
values and changes from baseline using descriptive statistics, as appropriate.   
Summary statistics of ECG data will be reported at each visit for raw data and for changes from 
baseline. In addition, incidence rates of treatment-emergent ECG findings will be reported. 
The number and percentage of subjects in each ECOG category will be presented by visit. 
Changes from baseline in ECOG will be summarized in shift tables by treatment group and visit. 


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6.4 Pharmacokinetics  
No pharmacokinetic (PK) measurements will be performed in this study. 
6.5 Biomarker analyses  
Biomarker analyses planned within this study may include predictive, prognostic, and 
pharmacodynamic biomarkers analyzed from serum and urine. Summary statistics for 
biomarkers and their changes from baseline may be presented by visits and treatment depending 
on the availability of data.  
Biomarker analyses will be described in a separate analysis plan.  
6.6 Sample size estimation 
The sample size is based on the primary efficacy endpoint, SSE-FS.  
Assuming 1-sided alpha of 0.1 (2-sided alpha of 0.2), power of 90%, and a randomization ratio 
of 1:1 between the experimental and control arms, 119 events are required to detect a 60% 
increase in SSE-FS. The expected study duration is 24.0 months assuming subjects enroll at a 
rate of 20 subjects per month, an enrollment ramp-up time of 6 months, a dropout rate of 15% for 
the primary endpoint, exponentially distributed event time, 8.3 month median time for the 
control group and a 14.8 month long enrollment for a total of 227 patients in the two treatment 
groups combined. 
6.7 Additional analyses planned to be reported outside the main report 
Biomarker analyses if any will be reported in a separate report. 
6.8 Change of analysis1 
6.8.1 Efficacy endpoints 
The planned sensitivity analyses for all efficacy endpoints in previous sections will not be 
performed due to the study early termination, except for SSE-FS will be evaluated using 
stratification factors derived from the information collected on the eCRF. All confidence 
intervals for time to event results specificied in previous sections are calculated for 80% CI only. 
A hazard ratio with 2-sided 80% and 95% CI from a stratified Cox proportional hazards model 
will be performed as planned. 
The pain improvement rate will be summarized, however, the planned comparison of pain 
improvement rate using the “general association Cochran-Mantel-Haenszel statistic” will not be 
performed.  
                                                 
1 As of Amendment 2. 


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The list used for subgroup analyses for SSE-FS were updated and provided as below: 
• Age (≥55, <55)  
• Race  
• Geographical region (Europe/North America [including Israel] versus Asia)  
• Baseline ECOG performance status  
• Previous lines of hormone therapy in metastatic setting  
• Visceral disease 
• Prior SREs,  
• Baseline total body weight 
• Baseline ideal body weight 
• BMI 
The subgroup analyses for rPFS will be performed as below: 
• Age (≥55, <55)  
• Geographical region (Europe/North America [including Israel] versus Asia)  
• Baseline ECOG performance status  
• Previous lines of hormone therapy in metastatic setting  
• Visceral disease 
• BMI 
 
6.8.2 Other endpoints 
The following planned analysis will not be performed due to the study early termination. 
• Resource utilization (will be included in listing only) 
• Biomarker analyses 
• Area under curve (AUC) for pain severity index and function interference index 
7. Document history and changes in the planned statistical analysis 
• Signed SAP version 1.0 dated 29 APR 2016, according to protocol version 1.0 up to 
amendment 5, integrated protocol version 5.0, and dated 11 MAR 2016. 
• Signed SAP version 2.0 dated 25 OCT 2017, according to protocol version 1.0 up to 
amendment 7, integrated protocol version 6.0, and dated 23 MAY 2017. 
• Signed SAP version 3.0 dated 04 JAN 2019, according to protocol version 1.0 up to 
amendment 8, integrated protocol version 8.0, and dated 03 APR 2018. 
• Signed SAP version 4.0 dated 05 AUG 2019, according to protocol version 1.0 up to 
amendment 8, integrated protocol version 8.0, and dated 03 APR 2018. 


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8. References 
1. Rubens RD, Coleman RE. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE. Clinical 
oncology. New York: Churchill Livingstone, 1995:643-65.  
2. Cessna JT, Zimmerman BE. Standardization of radium-223 by liquid scintillation counting. 
Appl Radiat Isot. 2010;68(7-8):1523-8.  
3. 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. 
9. Appendices 
9.1 Overall tumor response 
Table 5: Overall tumor response 
Overall non-bone 
response according  
to modified 
RECIST 1.1  
Response of non-target 
bone lesions 
(including new bone 
lesions) 
Overall response  
(consider both non-
bone and bone 
response) 
The scan date used for 
censoring if overall response 
is non-PD (1st or last date) 
Complete response 
Complete response 
CR 
  
Partial response 
Complete response 
PR 
  
Stable disease 
Complete response 
SD 
  
Non CR/Non PD 
Complete response 
Non CR/Non PD 
  
Progressive disease 
Complete response 
PD 
Last assessment date prior to 
PD 
Not 
evaluable/Missing 
Complete response 
NE 
  
Complete response 
Non CR/Non PD 
PR 
  
Partial response 
Non CR/Non PD 
PR 
  
Stable disease 
Non CR/Non PD 
SD 
  
Non CR/Non PD 
Non CR/Non PD 
Non CR/Non PD 
  
Progressive disease 
Non CR/Non PD 
PD 
Last assessment date prior to 
PD 
Not 
evaluable/Missing 
Non CR/Non PD 
NE 
  
Complete response 
Unequivocal progression 
PD 
Bone response date 
Partial response 
Unequivocal progression 
PD 
Bone response date 
Stable disease 
Unequivocal progression 
PD 
Bone response date 
Non CR/Non PD 
Unequivocal progression 
PD 
Bone response date 
Progressive disease 
Unequivocal progression 
PD 
Bone response date 
Not 
evaluable/Missing 
Unequivocal progression 
PD 
Bone response date 
Complete response 
Not (all) 
evaluated/Missing 
NE 
  


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Table 5: Overall tumor response 
Overall non-bone 
response according  
to modified 
RECIST 1.1  
Response of non-target 
bone lesions 
(including new bone 
lesions) 
Overall response  
(consider both non-
bone and bone 
response) 
The scan date used for 
censoring if overall response 
is non-PD (1st or last date) 
Partial response 
Not (all) 
evaluated/Missing 
NE 
  
Stable disease 
Not (all) 
evaluated/Missing 
NE 
  
Non CR/Non PD 
Not (all) 
evaluated/Missing 
NE 
  
Progressive disease 
Not (all) 
evaluated/Missing 
PD 
Last assessment date prior to 
PD 
Not 
evaluable/Missing 
Not (all) 
evaluated/Missing 
NE/Missing 
  
Not applicable  
Complete response 
CR 
Bone response date 
Not applicable 
Non CR/Non PD 
Non CR/Non PD 
Bone response date 
Not applicable 
Unequivocal progression 
Unequivocal 
progression 
Bone response date 
Not applicable 
Not (all) evaluated 
Not (all) evaluated 
Bone response date 
Definitions: 
1. Not applicable = No non bone lesions at baseline and no new non bone lesions (no PD) 
2. Not evaluated = not all evaluated = Missing (new lesion must be absent) 
3. As per RECIST 1.1 paper: ""When no imaging/measurement is done at all at a particular time point, the patient 
is not evaluable (NE) at that time point. If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered NE at that time point"" (unless other arguments for PD)"