A Study of Alpharadin With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer (CRPC)

• Sponsor: Bayer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01106352
• Collaborator: (none)
• Enrollment: 70
• Locations: 7
• Arms: 2
• Duration (Months): 59
• Patients Per Site: 10
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The main purpose of this study is to establish a recommended dose of Alpharadin to be used in combination with docetaxel in patients with bone metastases from castration-resistant prostate cancer and to investigate safety and explore efficacy of the recommended dose.

Condition or Disease	Intervention/Treatment	Phase
Bone Metastases; Castration-Resistant Prostate Cancer	Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Drug: Docetaxel	Phase 1/Phase 2

Detailed Description

The trial was initially conducted and submitted by Algeta ASA. After acquiring Algeta, Bayer is now the sponsor.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/IIa Study of Safety and Efficacy of Alpharadin® With Docetaxel in Patients With Bone Metastasis From Castration-Resistant Prostate Cancer
• Study Start Date: Jul 1, 2010
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radium-223 dichloride (Xofigo, BAY88-8223) + docetaxel Alpharadin (Radium-223 dichloride) is administered intravenously as a bolus injection. In the randomized phase IIa part of the protocol, the dose established in the dose-escalation part of the protocol (Phase I) will be used, i.e. 5 doses of 50 kBq/kg b.w. every 6 weeks in combination with the approved step-down dose of docetaxel (60 mg/m^2) administered intravenously every 3 weeks with 5 mg prednisone twice a day continuously and pre-medication with dexamethasone.	Drug: Radium-223 dichloride (Xofigo, BAY88-8223); Alpharadin (Radium-223 dichloride) is administered intravenously as a bolus injection.; Drug: Docetaxel; Docetaxel (75 mg/m^2) will be administered intravenously every 3 weeks with 5 mg prednisone twice a day continuously and pre-medication with dexamethasone. Step-down to 60 mg/m^2 is allowed as per the approved docetaxel label.
Active Comparator: Docetaxel Docetaxel (75 mg/m2) will be administered intravenously every 3 weeks with 5 mg prednisone twice a day continuously and pre-medication with dexamethasone. Step-down to 60 mg/m^2 is allowed as per the approved docetaxel label.	Drug: Docetaxel; Docetaxel (75 mg/m^2) will be administered intravenously every 3 weeks with 5 mg prednisone twice a day continuously and pre-medication with dexamethasone. Step-down to 60 mg/m^2 is allowed as per the approved docetaxel label.

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With Dose-Limiting Toxicities - Dose Escalation Part [From randomization until 6 weeks post-injection in all dose cohort of dose-escalation part]

   DLT was defined as - Absolute neutrophil count grade greater than or equal to (>=) 4 (Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0: less than [<] 0.5 × 109 per Liter) lasting longer than 7 days without fever despite granulocyte colony-stimulating factor (G-CSF) support). Platelet count Grade >= 4 (CTCAE, v4.0: < 25× 109/L) lasting longer than 7 days. Diarrhea Grade >= 3 (CTAE, v4.0: increase of >= 7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care in activities of daily living) in spite of optimal use of antidiarrheal medication. Vomiting or constipation Grade >= 4 (CTCAE, v4.0: life-threatening consequences; urgent intervention indicated). Febrile neutropenia Grade >= 3 (CTCAE, v4.0).

2. Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Treatment-Emergent Serious Adverse Events (TESAE) With a CTCAE Grade of 3 or 4 [From start of study treatment to 6 weeks after study treatment (that is maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort) and 8 weeks for serious AEs]

   Treatment-emergent adverse event (TEAEs) were defined as events that occur following the first injection of study treatment, or that started prior to the first injection and worsened during treatment. An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An Serious Adverse Event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in patient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.

3. Change From Baseline in Serum Biochemistry (Albumin, Protein, Hemoglobin) During the Treatment Period [Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)]

   In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

4. Change From Baseline in Serum Biochemistry (Alkaline Phosphatase [AP], Alanine Aminotransferase [AAT], Lactate Dehydrogenase [LD]) During the Treatment Period [Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)]

   In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

5. Change From Baseline in Serum Biochemistry (Bilirubin, Creatinine) During the Treatment Period [Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)]

   In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

6. Change From Baseline in Serum Biochemistry (Calcium, Chloride, Magnesium, Potassium, Phosphate, Sodium, Urea) During the Treatment Period [Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)]

   In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

7. Change From Baseline in Serum Biochemistry (Platelets, Leukocytes, Lymphocytes, Neutrophils, Monocytes, Eosinophils, Basophils) During the Treatment Period [Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)]

   In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

8. Change From Baseline in Serum Biochemistry (Erythrocytes) During the Treatment Period [Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)]

   In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

9. Changes From Baseline in Systolic and Diastolic Blood Pressure During the Treatment Period [From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)]

   In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

10. Changes From Baseline in Respiratory Rate During the Treatment Period [From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)]

    In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

11. Changes From Baseline in Heart Rate During the Treatment Period [From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)]

    In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

12. Changes From Baseline in Weight During the Treatment Period [From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)]

    In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.

13. Number of Subjects With Physical Examination During the Treatment Period [From start of study treatment to 6 weeks after study treatment (i.e., maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)]

    Any physical examination finding that was classified by the investigator as a clinically significant change (compared with previous examination) was considered an AE, documented on the eCRF, and followed until the outcome was known. The below physical examination findings were recorded and reported. GDASC = General disorders and administration site conditions MND = Metabolism and nutrition disorders SSTD= Skin and subcutaneous tissue disorders MCTD = Musculoskeletal and connective tissue disorders IPPC = Injury, poisoning and procedural complications RTMD = Respiratory, thoracic and mediastinal disorders NBMU = Neoplasms benign, malignant and unspecified (include cysts and polyps) In the below table.

14. Number of Subjects With Signs of Long-Term Radiation Toxicity [From start of study treatment upto 12 months]

    Long-term radiation toxicity included incidence of potential late toxicity, such as new primary cancers and bone marrow changes (acute myelogenous leukemia, myelodysplastic syndrome, and aplastic anemia).

Other Outcome Measures

1. Exploratory Efficacy: Weighted Mean Area Under the Curve for Bone Turnover Biomarkers [From start of study treatment to 6 weeks after study treatment (maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)]

   Weighted mean area under the curve for the below bone turnover biomarkers were evaluated, ICTP = pyridinoline cross-linked carboxyterminal telopeptide P1NP = N-terminal peptide of procollagen type 1 uCTX-1 = urine C-telopeptide 1

2. Exploratory Efficacy: Time to Prostate-specific Antigen (PSA) Progression [12 months]

   Serum PSA progression defined as two consecutive increases in PSA over a previous reference value within 6 months of first study treatment, each measurement at least 1 week apart.

3. Exploratory Efficacy: Percent Change From Baseline in Circulating Tumor Cells at Day 85 [Baseline, Day 85, expanded safety cohort]

   CTCs were measured to follow the evolution of the level of CTCs after treatment.

4. Exploratory Efficacy: Time to Clinical or Radiographic Progression [From start of study treatment to 12 months, at every 12 weeks]

   Time to first radiologic or clinical progression is determined by one of the following: For soft tissue lesions, the determination is based on Response Evaluation Criteria in Solid Tumors 1.1. For bone disease, the determination is based on Prostate Cancer Working Cohort 2 (PCWG2) definitions, which require the appearance of at least 2 new lesions with a confirmatory bone scan at least 6 or more weeks later. For clinical progression, the investigators followed the recommendations of the PCWG25 and used their clinical judgment to determine clinical progression.

5. Progression Free Survival (PFS) End Point [From start of study treatment to 12 months, at every 12 weeks]

   PFS defined as the time from randomization (randomization referred to the date of treatment assignment) to disease progression (radiological or clinical, whichever was earlier) or death (if death occurred before progression was documented). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation.

6. Overall Survival Rate [12 months]

   The overall survival (OS) time in days was calculated as number of days since the day of first dose of study medication until the date of death.

7. Number of Subjects Who Responded to Interactive Voice Response System (IVRS) Pain [From start of study treatment until 12 months]

   The subject completed the full BPI (short form) paper questionnaire, and clinical staff completed the analgesic log. The test consists of 10 questions addressing severity, location, chronicity, and amount of relief. In question 3, subjects with pain are asked to evaluate the severity of pain at worst in the past 24 hours in a 0 to 10 scale, with 0 indicating no pain, and 10 indicating the worst pain.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed adenocarcinoma of the prostate.

• Two or more bone metastases (hot spots) confirmed by bone scintigraphy within 8 weeks prior to study entry

• Known castration-resistant disease

• Karnofsky Performance Status (KPS): ≥70% within 14 days before start of study treatment (ECOG 1)

• Life expectancy at least 6 months.

• Acceptable hematology and serum biochemistry screening values

• Eligible for use of docetaxel according to the product information (package insert or similar).

Exclusion Criteria:

• Has received an investigational therapeutic drug within the last 4 weeks prior to start of study treatment, or is scheduled to receive one during the treatment period.

• Has received external radiotherapy within the last 4 weeks prior to start of study treatment.

• Has an immediate need for radiotherapy.

• Has received prior hemibody external radiotherapy .

• Has received systemic radiotherapy (e.g. samarium, strontium etc.) for the treatment of bone metastases.

• Has received cytotoxic chemotherapy within the last 4 weeks prior to start of study treatment, or has not recovered to grade 1 or 0 from adverse events due to cytotoxic chemotherapy administered more than 4 weeks earlier.

• Has received more than ten previous infusions of docetaxel.

• Previous known experience of grade ≥ 3 docetaxel related toxicities or docetaxel toxicity related dose interruption or discontinuation.

• Previous use of G-CSF for persistent neutropenia after docetaxel treatment.

• Has received blood transfusion or erythropoietin (EPO) within the last 4 weeks prior to start of study treatment.

• Has received prior treatment with Alpharadin.

• Malignant lymphadenopathy exceeding 3 cm in short-axis diameter.

• Symptomatic nodal disease, i.e. scrotal, penile or leg edema.

• Visceral metastases from CRPC (>2 lung and/or liver metastases [size ≥2cm]), as assessed by CT scan or MRI of the chest/abdomen/pelvis within the last 8 weeks prior to start of study treatment.

• Uncontrolled loco-regional disease.

• Other primary tumor (other than CRPC) including haematological malignancy present within the last 5 years (except non-melanoma skin cancer or low-grade superficial bladder cancer).

• Has imminent or established spinal cord compression based on clinical findings and/or MRI.

• Unmanageable fecal incontinence

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		San Francisco	California	United States	94115
2		Evanston	Illinois	United States	60201
3		Baltimore	Maryland	United States	21287
4		Boston	Massachusetts	United States	02115-6013
5		New York	New York	United States	10065
6		Seattle	Washington	United States	98109
7		Villejuif Cedex		France	94805

Sponsors and Collaborators

• Bayer

Investigators

• Study Director: Bayer Study Director, Bayer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe.

Publications

None provided.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT01106352
• Other Study ID Numbers: 15469; BC1-10; 2011-000822-31
• First Posted: Apr 19, 2010
• Last Update Posted: Jan 4, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by Bayer: The target population is patients with bone metastasis from castration-resistant prostate cancer intended for treatment with docetaxel
• Additional relevant MeSH terms: Prostatic Neoplasms; Neoplasm Metastasis; Neoplasms, Second Primary; Bone Neoplasms; Bone Marrow Diseases; Docetaxel; Radium Ra 223 dichloride

Study Results

Participant Flow

Recruitment Details	Study was conducted at seven study centers in United States and one study center in France, between 23 July 2010 (first subject first visit) and 16 June 2015 (last subject last visit).
Pre-assignment Detail	A total of 70 subjects were enrolled in the study. Of these 17 were in the dose escalation cohort in three dose groups of radium-223 and docetaxel. The remaining 53 subjects were in expanded safety cohort, of them 46 were dosed; 33 received a combination of radium-223 dichloride plus docetaxel and 13 subjects received docetaxel alone.

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Period Title: Overall Study
STARTED	7	3	7	36	17
Started Dose Escalation	7	3	7	0	0
Completed Dose Escalation	6	3	5	0	0
Started Safety Cohort	0	0	0	36	17
Treated Safety Cohort	0	0	0	33	13
Completed Safety Cohort	0	0	0	23	9
COMPLETED	6	3	5	23	9
NOT COMPLETED	1	0	2	13	8

Baseline Characteristics

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort	Total
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.	Total of all reporting groups
Overall Participants	7	3	7	36	17	70
Age, Customized (participants) [Number]
<18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 28.6%	2 66.7%	3 42.9%	11 30.6%	7 41.2%	25 35.7%
>65 years	5 71.4%	1 33.3%	4 57.1%	25 69.4%	10 58.8%	45 64.3%
Gender (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Male	7 100%	3 100%	7 100%	36 100%	17 100%	70 100%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With Dose-Limiting Toxicities - Dose Escalation Part
Description	DLT was defined as - Absolute neutrophil count grade greater than or equal to (>=) 4 (Common Terminology Criteria for Adverse Events [CTCAE], Version 4.0: less than [<] 0.5 × 109 per Liter) lasting longer than 7 days without fever despite granulocyte colony-stimulating factor (G-CSF) support). Platelet count Grade >= 4 (CTCAE, v4.0: < 25× 109/L) lasting longer than 7 days. Diarrhea Grade >= 3 (CTAE, v4.0: increase of >= 7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared with baseline; limiting self-care in activities of daily living) in spite of optimal use of antidiarrheal medication. Vomiting or constipation Grade >= 4 (CTCAE, v4.0: life-threatening consequences; urgent intervention indicated). Febrile neutropenia Grade >= 3 (CTCAE, v4.0).
Time Frame	From randomization until 6 weeks post-injection in all dose cohort of dose-escalation part

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.
Measure Participants	7	3	7
Number [Participants]	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Number of Subjects With Treatment-Emergent Adverse Events (TEAE), Treatment-Emergent Serious Adverse Events (TESAE) With a CTCAE Grade of 3 or 4
Description	Treatment-emergent adverse event (TEAEs) were defined as events that occur following the first injection of study treatment, or that started prior to the first injection and worsened during treatment. An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An Serious Adverse Event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in patient hospitalization; lifethreatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events were defined as adverse events/serious adverse events that started or worsened after the study drug treatment.
Time Frame	From start of study treatment to 6 weeks after study treatment (that is maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort) and 8 weeks for serious AEs

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
TEAE CTCAE Grade 3	3 42.9%	1 33.3%	4 57.1%	6 16.7%	3 17.6%
TEAE CTCAE Grade 4	2 28.6%	1 33.3%	1 14.3%	10 27.8%	6 35.3%
TESAE	4 57.1%	0 0%	2 28.6%	7 19.4%	4 23.5%

3. Primary Outcome

Title	Change From Baseline in Serum Biochemistry (Albumin, Protein, Hemoglobin) During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only randomized participants who have this outcome measure tested were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	35	13
Albumin Baseline (n= 7,3,7,35,13)	42 (3)	43 (4)	43 (3.56)	42.7 (3.25)	42.3 (4.09)
Albumin: Change at Day 106 (n=1,0,0,27,11)	-2 (NA)	NA (NA)	NA (NA)	-1.3 (2.98)	-1.2 (2.75)
Albumin: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-2.3 (3.33)	-0.5 (2.07)
Protein: Baseline (n= 7,3,7,35,13)	70.3 (4.23)	69.7 (8.5)	70.4 (4.89)	68.7 (4.45)	69.1 (5.33)
Protein: Change at Day 106 (n=1,0,0,27,11 )	1 (NA)	NA (NA)	NA (NA)	-3.9 (3.79)	-3.8 (2.56)
Protein: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-5.3 (3.63)	-3.7 (4.18)
Hemoglobin: Baseline (n= 7,3,7,35,13)	122.43 (14.581)	120.67 (16.166)	120.43 (8.522)	122.82 (10.939)	120.23 (12.05)
Hemoglobin: Change at Day 106 (n=1,0,0,27,11 )	-10 (NA)	NA (NA)	NA (NA)	-8.81 (8.2)	-14.27 (9.067)
Hemoglobin: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	-13.65 (10.853)	-10.67 (13.794)

4. Primary Outcome

Title	Change From Baseline in Serum Biochemistry (Alkaline Phosphatase [AP], Alanine Aminotransferase [AAT], Lactate Dehydrogenase [LD]) During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	17
AP: Baseline (n= 7,3,7,33,13)	533.1 (656.36)	144 (89.2)	224.6 (115.08)	218.2 (207.63)	195.9 (110.86)
AP: Change at Day 106 (n=1,0,0,27,11)	-134 (NA)	NA (NA)	NA (NA)	-119.6 (153.1)	-78.9 (46.35)
AP: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-119.3 (112.21)	-116.8 (52.21)
AAT: Baseline (n= 7,3,7,33,13)	17.6 (5.68)	17 (6.56)	18.9 (5.9)	19.8 (9.82)	19.8 (10.78)
AAT: Change at Day 106 (n=1,0,0,27,11 )	100 (NA)	NA (NA)	NA (NA)	2.9 (13.54)	-2.2 (11.75)
AAT: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	1.1 (8.67)	-3.7 (13.81)
LD: Baseline (n= 7,3,7,33,13)	313.3 (243.9)	179 (22.52)	214.4 (38.92)	212.8 (71.07)	203.4 (61.68)
LD: Change at Day 106 (n= 1,0,0,27,11)	15 (NA)	NA (NA)	NA (NA)	10.7 (58.14)	45.1 (93.58)
LD: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	16.9 (39.74)	17.5 (100.85)

5. Primary Outcome

Title	Change From Baseline in Serum Biochemistry (Bilirubin, Creatinine) During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
Bilirubin: Baseline (n= 7,3,7,33,13)	8.9 (3.8)	6.7 (1.15)	7.1 (3.98)	7.5 (2.62)	7 (2.08)
Bilirubin: Change at Day 106 (n= 1,0,0,27,11)	2 (NA)	NA (NA)	NA (NA)	0.2 (1.84)	-0.8 (1.72)
Bilirubin: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-0.9 (1.56)	0.3 (1.51)
Creatinine: Baseline (n= 7,3,7,33,13)	92.33 (33.126)	73.67 (9.5)	70.86 (10.938)	70.07 (19.138)	75.5 (11.614)
Creatinine: Change at Day 106 (n= 1,0,0,27,11)	63.6 (NA)	NA (NA)	NA (NA)	0.74 (12.273)	-0.7 (7.232)
Creatinine: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	0.59 (11.889)	-0.17 (13.31)

6. Primary Outcome

Title	Change From Baseline in Serum Biochemistry (Calcium, Chloride, Magnesium, Potassium, Phosphate, Sodium, Urea) During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
Calcium: Baseline (n= 7,3,7,33,13)	2.231 (0.1523)	2.38 (0.0872)	2.309 (0.071)	2.357 (0.1121)	2.307 (0.1437)
Calcium: Change at Day 106 (n= 1,0,0,27,11)	0.2 (NA)	NA (NA)	NA (NA)	-0.065 (0.148)	-0.019 (0.104)
Calcium: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-0.055 (0.1225)	-0.143 (0.1536)
Chloride: Baseline (n= 7,3,7,33,13)	101.4 (3.21)	101.7 (2.52)	102 (2.77)	103.2 (2.75)	101.3 (3.99)
Chloride: Change at Day 106 (n= 1,0,0,27,11)	-1.9 (NA)	NA (NA)	NA (NA)	0 (2.72)	1.5 (2.38)
Chloride: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	0 (3.35)	2.5 (1.38)
Magnesium: Baseline (n= 7,3,7,33,13)	0.93 (0.055)	0.86 (0)	0.86 (0.088)	0.85 (0.072)	0.84 (0.073)
Magnesium: Change at Day 106 (n= 1,0,0,27,11)	-4.4 (NA)	NA (NA)	NA (NA)	-0.02 (0.058)	-0.04 (0.036)
Magnesium: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-0.01 (0.079)	-0.06 (0.045)
Potassium: Baseline (n= 7,3,7,33,13)	4.34 (0.541)	4.47 (0.306)	4.39 (0.09)	4.29 (0.277)	4.3 (0.443)
Potassium: Change at Day 106 (n= 1,0,0,27,11)	1.1 (NA)	NA (NA)	NA (NA)	0.06 (0.366)	0.11 (0.336)
Potassium: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	0.04 (0.422)	0.03 (0.501)
Phosphate: Baseline (n= 7,3,7,33,13)	1.021 (0.168)	1.167 (0.2466)	0.993 (0.369)	1.058 (0.1763)	1.145 (0.1844)
Phosphate: Change at Day 106 (n= 1,0,0,27,11)	0 (NA)	NA (NA)	NA (NA)	0.086 (0.1369)	-0.061 (0.2287)
Phosphate: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	0.128 (0.1734)	0.203 (0.1813)
Sodium: Baseline (n= 7,3,7,33,13)	136.1 (4.1)	137.7 (3.51)	137.4 (2.51)	138.5 (2.49)	137.2 (4.72)
Sodium: Change at Day 106 (n= 1,0,0,27,11)	0 (NA)	NA (NA)	NA (NA)	-0.6 (2.28)	0.8 (2.56)
Sodium: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-0.5 (2.41)	2.3 (1.37)
Urea: Baseline (n= 7,3,7,33,13)	9.14 (3.092)	7.83 (1.041)	6.79 (2.059)	7.03 (2.304)	7.78 (2.312)
Urea: Change at Day 106 (n= 1,0,0,27,11)	1.5 (NA)	NA (NA)	NA (NA)	-0.26 (1.587)	-0.26 (1.531)
Urea: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-0.15 (1.508)	0.7 (1.122)

7. Primary Outcome

Title	Change From Baseline in Serum Biochemistry (Platelets, Leukocytes, Lymphocytes, Neutrophils, Monocytes, Eosinophils, Basophils) During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
Platelets: Baseline (n= 7,3,7,33,13)	214.1 (58.05)	196.3 (51.64)	266.6 (77.43)	259.6 (69.39)	240.6 (52.17)
Platelets: Change at Day 106 (n= 1,0,0,27,11)	169 (NA)	NA (NA)	NA (NA)	-3.1 (51.39)	33 (55.17)
Platelets: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	-22 (51.04)	32.3 (68.54)
Leukocytes: Baseline (n= 7,3,7,33,13)	9.13 (4.43)	5.83 (1.858)	8.34 (2.783)	7.67 (2.871)	6.71 (2.308)
Leukocytes: Change at Day 106 (n= 1,0,0,27,11)	18.7 (NA)	NA (NA)	NA (NA)	-0.1 (2.086)	2.44 (2.263)
Leukocytes: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	-0.12 (2.603)	1.65 (1.946)
Lymphocytes: Baseline (n= 7,3,7,33,13)	1.044 (0.4687)	1.003 (0.45)	0.81 (0.4679)	1.001 (0.5902)	1.068 (0.5751)
Lymphocytes: Change at Day 106 (n= 1,0,0,27,11)	1.3 (NA)	NA (NA)	NA (NA)	-0.229 (0.5593)	-0.063 (0.5129)
Lymphocytes: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	-0.395 (0.3917)	-0.085 (0.6832)
Neutrophils: Baseline (n= 7,3,7,33,13)	7.809 (4.0998)	4.71 (1.54)	7.359 (2.7781)	6.363 (2.8618)	5.205 (2.1487)
Neutrophils: Change at Day 106 (n= 1,0,0,27,11)	517.3 (NA)	NA (NA)	NA (NA)	0.178 (2.2991)	2.622 (2.5672)
Neutrophils: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	0.341 (2.4734)	2.038 (1.8799)
Monocytes: Baseline (n= 7,3,7,33,13)	0.224 (0.2319)	0.103 (0.085)	0.153 (0.1379)	0.243 (0.2466)	0.375 (0.4203)
Monocytes: Change at Day 106 (n= 1,0,0,27,11)	0.12 (NA)	NA (NA)	NA (NA)	-0.011 (0.2959)	-0.111 (0.4164)
Monocytes: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	-0.014 (0.3185)	-0.27 (0.2964)
Eosinophils: Baseline (n= 7,3,7,33,13)	0.04 (0.0622)	0.01 (0.01)	0.014 (0.0151)	0.054 (0.0734)	0.043 (0.0407)
Eosinophils: Change at Day 106 (n= 1,0,0,27,11)	-0.12 (NA)	NA (NA)	NA (NA)	-0.043 (0.0797)	-0.008 (0.0995)
Eosinophils: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	-0.049 (0.0786)	-0.023 (0.0186)
Basophils: Baseline (n= 7,3,7,33,13)	0.013 (0.0221)	0.007 (0.0058)	0.011 (0.0107)	0.012 (0.0137)	0.018 (0.0121)
Basophils: Change at Day 106 (n= 1,0,0,27,11)	0.02 (NA)	NA (NA)	NA (NA)	0.001 (0.0169)	-0.001 (0.0197)
Basophils: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	-0.003 (0.0136)	-0.015 (0.0105)

8. Primary Outcome

Title	Change From Baseline in Serum Biochemistry (Erythrocytes) During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	Baseline, Day 106 (dose escalation period), and Day 190 (expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
Erythrocytes: Baseline (n= 7,3,7,33,13)	3.99 (0.376)	3.9 (0.361)	3.9 (0.327)	3.98 (0.378)	4.02 (0.519)
Erythrocytes: Change at Day 106 (n= 1,0,0,27,11)	-0.4 (NA)	NA (NA)	NA (NA)	-0.25 (0.233)	-0.32 (0.429)
Erythrocytes: Change at Day 190 (n= 0,0,0,23,6)	NA (NA)	NA (NA)	NA (NA)	-0.39 (0.287)	-0.15 (0.653)

9. Primary Outcome

Title	Changes From Baseline in Systolic and Diastolic Blood Pressure During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
SBP: Baseline (n= 7,3,7,33,13)	137.7 (9.11)	113 (12.12)	131.7 (13.07)	139.2 (17.01)	140.1 (10.85)
SBP: Change at Day 22 (n= 6,3,7,33,13)	-2.7 (13.52)	2.3 (5.51)	-5 (12.32)	-1.8 (19.66)	-8.5 (19.53)
SBP: Change at Day 43 (n= 6,3,7,32,13)	-8.7 (12.13)	-3 (9.54)	-0.9 (19.37)	0.6 (18.15)	-15.3 (13.91)
SBP: Change at Day 64 (n= 6,3,6,30,13)	-9.8 (16.36)	-11 (13.45)	-4.2 (13.66)	-2.5 (21.75)	-10.1 (13.32)
SBP: Change at Day 85 (n= 0,0,0,28,13)	NA (NA)	NA (NA)	NA (NA)	-3.1 (16.55)	-3.8 (17.19)
SBP: Change at Day 106 (n= 0,0,0,28,12)	NA (NA)	NA (NA)	NA (NA)	-6.7 (21.33)	-10.4 (16.33)
SBP: Change at Day 127 (n= 0,0,0,27,8)	NA (NA)	NA (NA)	NA (NA)	-4.6 (19.82)	-13.4 (22.01)
SBP: Change at Day 148 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	-3.9 (20.09)	-8.9 (18.02)
SBP: Change at Day 169 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	-3.6 (16.58)	-6.3 (17.85)
SBP: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-8.1 (18.25)	-10 (16.15)
DBP: Baseline (n= 7,3,7,33,13)	81.6 (5.68)	62 (2)	74.1 (8.86)	76.1 (10.19)	83 (11.17)
DBP: Change at Day 22 (n= 6,3,7,33,13)	-2.7 (10.67)	8 (10.39)	2.6 (7.57)	0.3 (10.88)	-6.2 (16.03)
DBP: Change at Day 43 (n= 6,3,7,32,13)	-3.7 (6.65)	2.7 (5.03)	4.1 (8.13)	-1.8 (12.17)	-11.7 (10.89)
DBP: Change at Day 64 (n= 6,3,6,30,13)	-8.7 (7.89)	-1 (1.73)	-0.2 (15.93)	-1.4 (14.66)	-8.7 (9.21)
DBP: Change at Day 85 (n= 0,0,0,28,13)	NA (NA)	NA (NA)	NA (NA)	1.1 (10.99)	-7.6 (11.2)
DBP: Change at Day 106 (n= 0,0,0,28,12)	NA (NA)	NA (NA)	NA (NA)	-0.8 (13.15)	-7.9 (14.13)
DBP: Change at Day 127 (n= 0,0,0,27,8)	NA (NA)	NA (NA)	NA (NA)	-1.4 (14.22)	-8 (9.94)
DBP: Change at Day 148 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	-2 (12.19)	-3.9 (8.36)
DBP: Change at Day 169 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	-1.2 (10.45)	-9 (8.6)
DBP: Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	-3.6 (12.8)	-12 (8.92)

10. Primary Outcome

Title	Changes From Baseline in Respiratory Rate During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
Baseline (n= 7,3,7,33,13)	19.3 (1.63)	18.7 (2.31)	19.1 (1.57)	17.1 (2.67)	17.5 (2.79)
Change at Day 22 (n= 6,3,7,33,13)	-1.7 (2.34)	-1.3 (2.31)	-0.7 (1.03)	0.3 (2.1)	-0.4 (2.14)
Change at Day 43 (n= 6,3,7,32,13)	0 (1.26)	1.3 (4.62)	-0.3 (0.82)	0 (3.08)	0.7 (3.5)
Change at Day 64 (n= 6,3,6,30,13)	-0.5 (2.81)	0 (4)	-1 (1.1)	0.4 (2.82)	0.8 (3)
Change at Day 85 (n= 0,0,0,28,13)	NA (NA)	NA (NA)	NA (NA)	0 (3.32)	-0.3 (2.39)
Change at Day 106 (n= 0,0,0,28,12)	NA (NA)	NA (NA)	NA (NA)	-0.8 (3.54)	0.5 (3.27)
Change at Day 127 (n= 0,0,0,27,8)	NA (NA)	NA (NA)	NA (NA)	0.9 (3.69)	0.4 (1.51)
Change at Day 148 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	0.7 (3.38)	-0.3 (1.51)
Change at Day 169 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	-1 (3.11)	0.4 (2.15)
Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	0 (4.79)	-0.2 (1.33)

11. Primary Outcome

Title	Changes From Baseline in Heart Rate During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
Baseline (n= 7,3,7,33,13)	88.6 (18.84)	58 (9.17)	80 (9.93)	77.9 (14.18)	73.3 (12.01)
Change at Day 22 (n= 6,3,7,33,13)	-0.2 (6.49)	9.7 (18.72)	-0.6 (7.76)	2 (11.39)	7.2 (12.17)
Change at Day 43 (n= 6,3,7,32,13)	-4.3 (9.35)	18.3 (14.57)	0.9 (10.32)	2.8 (11.13)	4.9 (11.54)
Change at Day 64 (n= 6,3,6,30,13)	0.7 (7.28)	13 (21.17)	6.5 (11.47)	3.4 (14.48)	5.1 (9.41)
Change at Day 85 (n= 0,0,0,28,13)	NA (NA)	NA (NA)	NA (NA)	2.9 (16.17)	7.2 (10.27)
Change at Day 106 (n= 0,0,0,28,12)	NA (NA)	NA (NA)	NA (NA)	0.8 (19.18)	9.2 (11.67)
Change at Day 127 (n= 0,0,0,27,8)	NA (NA)	NA (NA)	NA (NA)	2.2 (13.93)	7.5 (5.86)
Change at Day 148 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	2.2 (15.88)	15.3 (14.38)
Change at Day 169 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	3.6 (16.91)	8 (7.72)
Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	2.6 (16.01)	18 (11.31)

12. Primary Outcome

Title	Changes From Baseline in Weight During the Treatment Period
Description	In the below table, 'n' signifies those subjects who were evaluable for this measure at given time points for each group.
Time Frame	From start of study treatment to 6 weeks after study treatment (that is, maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
Baseline (n= 7,3,7,33,13)	89.3 (13.15)	81.9 (21.66)	97.1 (14.29)	87.7 (14.81)	92 (22.28)
Change at Day 22 (n= 6,3,7,33,13)	-1.8 (1.31)	-0.3 (1.55)	-1.4 (2.5)	-0.4 (1.42)	-0.2 (1.92)
Change at Day 43 (n= 6,3,7,32,13)	-1 (1.95)	0.2 (2.2)	-1 (2.99)	0 (2.2)	0.5 (1.98)
Change at Day 64 (n= 6,3,6,30,13)	0.1 (4.2)	0.3 (2.04)	-1.2 (3.08)	0.2 (2.41)	0.3 (2.48)
Change at Day 85 (n= 0,0,0,28,13)	NA (NA)	NA (NA)	NA (NA)	-0.2 (3.47)	0.4 (2.87)
Change at Day 106 (n= 0,0,0,28,12)	NA (NA)	NA (NA)	NA (NA)	-0.3 (3.53)	0.4 (3.1)
Change at Day 127 (n= 0,0,0,27,8)	NA (NA)	NA (NA)	NA (NA)	-0.1 (4.09)	2.1 (2.11)
Change at Day 148 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	-0.1 (4.45)	1.9 (2.72)
Change at Day 169 (n= 0,0,0,25,7)	NA (NA)	NA (NA)	NA (NA)	-0.1 (4.53)	1.7 (3.81)
Change at Day 190 (n= 0,0,0,24,6)	NA (NA)	NA (NA)	NA (NA)	0.1 (5)	-0.7 (3.59)

13. Primary Outcome

Title	Number of Subjects With Physical Examination During the Treatment Period
Description	Any physical examination finding that was classified by the investigator as a clinically significant change (compared with previous examination) was considered an AE, documented on the eCRF, and followed until the outcome was known. The below physical examination findings were recorded and reported. GDASC = General disorders and administration site conditions MND = Metabolism and nutrition disorders SSTD= Skin and subcutaneous tissue disorders MCTD = Musculoskeletal and connective tissue disorders IPPC = Injury, poisoning and procedural complications RTMD = Respiratory, thoracic and mediastinal disorders NBMU = Neoplasms benign, malignant and unspecified (include cysts and polyps) In the below table.
Time Frame	From start of study treatment to 6 weeks after study treatment (i.e., maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation	Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 mg/m^2 every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	7	3	7	33	13
At day 64: GDASC	0 0%	0 0%	2 28.6%	5 13.9%	2 11.8%
At day 64: MND	NA NaN	NA NaN	NA NaN	0 0%	1 5.9%
At day 64: SSTD	NA NaN	NA NaN	NA NaN	2 5.6%	6 35.3%
At day 190: GDASC	NA NaN	NA NaN	NA NaN	7 19.4%	2 11.8%
At day 190: MCTD	NA NaN	NA NaN	NA NaN	1 2.8%	0 0%
At day 190: SSTD	NA NaN	NA NaN	NA NaN	7 19.4%	2 11.8%
At day 190: Vascular disorders	NA NaN	NA NaN	NA NaN	0 0%	1 5.9%
At day 190: Gastrointestinal disorders	NA NaN	NA NaN	NA NaN	1 2.8%	1 5.9%
At day 190: IPPC	NA NaN	NA NaN	NA NaN	2 5.6%	0 0%
At day 190: RTMD	NA NaN	NA NaN	NA NaN	0 0%	1 5.9%
At day 190: NBMU	NA NaN	NA NaN	NA NaN	2 5.6%	0 0%
At day 190: Social circumstances	NA NaN	NA NaN	NA NaN	1 2.8%	0 0%

14. Primary Outcome

Title	Number of Subjects With Signs of Long-Term Radiation Toxicity
Description	Long-term radiation toxicity included incidence of potential late toxicity, such as new primary cancers and bone marrow changes (acute myelogenous leukemia, myelodysplastic syndrome, and aplastic anemia).
Time Frame	From start of study treatment upto 12 months

Outcome Measure Data

Analysis Population Description

Only participants who received treatment were assessed

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	33	13
Number [Participants]	2 28.6%	0 0%

15. Other Pre-specified Outcome

Title	Exploratory Efficacy: Weighted Mean Area Under the Curve for Bone Turnover Biomarkers
Description	Weighted mean area under the curve for the below bone turnover biomarkers were evaluated, ICTP = pyridinoline cross-linked carboxyterminal telopeptide P1NP = N-terminal peptide of procollagen type 1 uCTX-1 = urine C-telopeptide 1
Time Frame	From start of study treatment to 6 weeks after study treatment (maximum 12 weeks in dose escalation; 30 weeks in the expanded safety cohort)

Outcome Measure Data

Analysis Population Description

Subjects included in the per protocol: All subjects in the ITT population who received at least 40% of the specified number of administrations of radium-223 dichloride (in the radium-223 dichloride cohort) or of docetaxel (in the docetaxel cohort), and who did not have any major protocol violations.

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	32	13
uCTX-1	14 (16.86)	22.6 (28.2)
P1NP	42.9 (42.36)	106.5 (118.93)
ICTP	4.7 (2.43)	7 (7.08)

16. Other Pre-specified Outcome

Title	Exploratory Efficacy: Time to Prostate-specific Antigen (PSA) Progression
Description	Serum PSA progression defined as two consecutive increases in PSA over a previous reference value within 6 months of first study treatment, each measurement at least 1 week apart.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Subjects included in the per protocol: All subjects in the ITT population who received at least 40% of the specified number of administrations of radium-223 dichloride (in the radium-223 dichloride cohort) or of docetaxel (in the docetaxel cohort), and who did not have any major protocol violations.

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	32	13
Median (95% Confidence Interval) [days]	200	146

17. Other Pre-specified Outcome

Title	Exploratory Efficacy: Percent Change From Baseline in Circulating Tumor Cells at Day 85
Description	CTCs were measured to follow the evolution of the level of CTCs after treatment.
Time Frame	Baseline, Day 85, expanded safety cohort

Outcome Measure Data

Analysis Population Description

Subjects included in the per protocol: All subjects in the ITT population who received at least 40% of the specified number of administrations of radium-223 dichloride (in the radium-223 dichloride cohort) or of docetaxel (in the docetaxel cohort), and who did not have any major protocol violations.

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	32	13
Mean (Standard Deviation) [Percent Change]	-75.3 (55.29)	-68.4 (61.4)

18. Other Pre-specified Outcome

Title	Exploratory Efficacy: Time to Clinical or Radiographic Progression
Description	Time to first radiologic or clinical progression is determined by one of the following: For soft tissue lesions, the determination is based on Response Evaluation Criteria in Solid Tumors 1.1. For bone disease, the determination is based on Prostate Cancer Working Cohort 2 (PCWG2) definitions, which require the appearance of at least 2 new lesions with a confirmatory bone scan at least 6 or more weeks later. For clinical progression, the investigators followed the recommendations of the PCWG25 and used their clinical judgment to determine clinical progression.
Time Frame	From start of study treatment to 12 months, at every 12 weeks

Outcome Measure Data

Analysis Population Description

Subjects included in the per protocol: All subjects in the ITT population who received at least 40% of the specified number of administrations of radium-223 dichloride (in the radium-223 dichloride cohort) or of docetaxel (in the docetaxel cohort), and who did not have any major protocol violations.

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	32	13
Median (95% Confidence Interval) [days]	365	284

19. Other Pre-specified Outcome

Title	Progression Free Survival (PFS) End Point
Description	PFS defined as the time from randomization (randomization referred to the date of treatment assignment) to disease progression (radiological or clinical, whichever was earlier) or death (if death occurred before progression was documented). Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation.
Time Frame	From start of study treatment to 12 months, at every 12 weeks

Outcome Measure Data

Analysis Population Description

Subjects included in the per protocol: All subjects in the ITT population who received at least 40% of the specified number of administrations of radium-223 dichloride (in the radium-223 dichloride cohort) or of docetaxel (in the docetaxel cohort), and who did not have any major protocol violations.

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	32	13
Median (95% Confidence Interval) [days]	189	146

20. Other Pre-specified Outcome

Title	Overall Survival Rate
Description	The overall survival (OS) time in days was calculated as number of days since the day of first dose of study medication until the date of death.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Subjects included in the per protocol: All subjects in the ITT population who received at least 40% of the specified number of administrations of radium-223 dichloride (in the radium-223 dichloride cohort) or of docetaxel (in the docetaxel cohort), and who did not have any major protocol violations.

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	32	13
Median (95% Confidence Interval) [days]	89.1	90

21. Other Pre-specified Outcome

Title	Number of Subjects Who Responded to Interactive Voice Response System (IVRS) Pain
Description	The subject completed the full BPI (short form) paper questionnaire, and clinical staff completed the analgesic log. The test consists of 10 questions addressing severity, location, chronicity, and amount of relief. In question 3, subjects with pain are asked to evaluate the severity of pain at worst in the past 24 hours in a 0 to 10 scale, with 0 indicating no pain, and 10 indicating the worst pain.
Time Frame	From start of study treatment until 12 months

Outcome Measure Data

Analysis Population Description

Subjects included in the per protocol: All subjects in the ITT population who received at least 40% of the specified number of administrations of radium-223 dichloride (in the radium-223 dichloride cohort) or of docetaxel (in the docetaxel cohort), and who did not have any major protocol violations.

Arm/Group Title	Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort	Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.	Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks.
Measure Participants	32	13
Day 1	23 328.6%	11 366.7%
Day 22	24 342.9%	11 366.7%
Day 43	22 314.3%	10 333.3%
Day 64	21 300%	10 333.3%
Day 85	20 285.7%	11 366.7%
Day 106	20 285.7%	9 300%
Day 127	19 271.4%	6 200%
Day 148	18 257.1%	5 166.7%
Day 169	17 242.9%	5 166.7%
Day 190	17 242.9%	5 166.7%
Safety Follow-up	18 257.1%	9 300%
6-Month Follow-up	1 14.3%	2 66.7%
9-Month Follow-up	12 171.4%	7 233.3%
12-Month Follow-up	7 100%	5 166.7%

Adverse Events

Adverse Event Reporting Description	Number of participants at risk are from safety analysis set, please refer to participant flow section.
Arm/Group Title	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation		Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation		Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation		Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort		Docetaxel 75 mg/m^2 - Safety Cohort
Arm/Group Description	Subjects received two intravenous injections of Alpharadin (Radium [Ra]-223 dichloride, BAY88-8223) at a dose of 25 kBq/kg body weight based on National Institute of Standards and Technology (NIST) 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 75 milligram per square meter (mg/m^2) every three weeks; unless dose limiting toxicity (DLT) or other safety concerns limited the dose escalation		Subjects received two intravenous injections of Alpharadin at a dose of 25 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.		Subjects received two intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks; unless DLT or other safety concerns limited the dose escalation.		Subjects received five intravenous injections of Alpharadin at a dose of 50 kBq/kg body weight based on NIST 2010 standardization, separated by an interval of six weeks in combination with docetaxel at 60 mg/m^2 every three weeks.		Subjects received docetaxel at 75 mg/m^2 twice daily every three weeks
All Cause Mortality
	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation		Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation		Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation		Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort		Docetaxel 75 mg/m^2 - Safety Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation		Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation		Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation		Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort		Docetaxel 75 mg/m^2 - Safety Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/7 (57.1%)		0/3 (0%)		2/7 (28.6%)		7/33 (21.2%)		4/13 (30.8%)
Blood and lymphatic system disorders
Febrile neutropenia	2/7 (28.6%)	3	0/3 (0%)	0	2/7 (28.6%)	2	0/33 (0%)	0	2/13 (15.4%)	2
Leukopenia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Neutropenia	1/7 (14.3%)	2	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Eye disorders
Blindness unilateral	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Gastrointestinal disorders
Diarrhoea	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Ileus	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Melaena	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Stomatitis	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
General disorders
Chest pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Infections and infestations
Pneumonia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	2/13 (15.4%)	2
Skin infection	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Investigations
Biopsy lymph gland	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Bone pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Osteoporosis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	2	0/13 (0%)	0
Pain in extremity	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Spinal cord compression	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Syncope	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Psychiatric disorders
Confusional state	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Reproductive system and breast disorders
Prostatitis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Interstitial lung disease	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Pleural effusion	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Vascular disorders
Embolism	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Hypotension	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Other (Not Including Serious) Adverse Events
	Alpharadin 25 kBq/kg + Docetaxel 75 mg/m^2 - Dose Escalation		Alpharadin 25 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation		Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Dose Escalation		Alpharadin 50 kBq/kg + Docetaxel 60 mg/m^2 - Safety Cohort		Docetaxel 75 mg/m^2 - Safety Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		3/3 (100%)		7/7 (100%)		33/33 (100%)		13/13 (100%)
Blood and lymphatic system disorders
Anaemia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	3/33 (9.1%)	3	1/13 (7.7%)	1
Iron deficiency anaemia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Leukopenia	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	2/33 (6.1%)	2	2/13 (15.4%)	2
Lymphopenia	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/33 (3%)	1	0/13 (0%)	0
Neutropenia	2/7 (28.6%)	3	2/3 (66.7%)	2	5/7 (71.4%)	5	10/33 (30.3%)	28	5/13 (38.5%)	5
Cardiac disorders
Angina pectoris	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Palpitations	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Tachycardia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	1/13 (7.7%)	1
Eye disorders
Dry eye	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	2/13 (15.4%)	2
Lacrimation increased	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	4/33 (12.1%)	4	2/13 (15.4%)	3
Ocular hypertension	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Vision blurred	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Gastrointestinal disorders
Abdominal pain	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	2/33 (6.1%)	3	0/13 (0%)	0
Anorectal discomfort	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Cheilitis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Constipation	1/7 (14.3%)	1	1/3 (33.3%)	1	2/7 (28.6%)	3	11/33 (33.3%)	14	5/13 (38.5%)	6
Diarrhoea	5/7 (71.4%)	5	2/3 (66.7%)	4	5/7 (71.4%)	5	14/33 (42.4%)	36	5/13 (38.5%)	9
Dry mouth	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	2/13 (15.4%)	2
Dyspepsia	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Gastrointestinal haemorrhage	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Gastrooesophageal reflux disease	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/33 (3%)	1	4/13 (30.8%)	4
Haemorrhoids	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Melaena	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Nausea	3/7 (42.9%)	4	1/3 (33.3%)	2	2/7 (28.6%)	3	16/33 (48.5%)	33	8/13 (61.5%)	13
Oral pain	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/33 (3%)	1	0/13 (0%)	0
Rectal haemorrhage	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/33 (0%)	0	3/13 (23.1%)	3
Stomatitis	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	4/33 (12.1%)	7	2/13 (15.4%)	2
Tongue ulceration	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Toothache	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Vomiting	3/7 (42.9%)	3	0/3 (0%)	0	2/7 (28.6%)	3	5/33 (15.2%)	9	2/13 (15.4%)	3
General disorders
Asthenia	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	8/33 (24.2%)	24	2/13 (15.4%)	2
Chest discomfort	2/7 (28.6%)	2	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Chest pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	1/13 (7.7%)	1
Face oedema	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	1
Facial pain	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Fatigue	5/7 (71.4%)	5	3/3 (100%)	3	4/7 (57.1%)	4	17/33 (51.5%)	29	9/13 (69.2%)	15
Influenza like illness	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	2	1/13 (7.7%)	1
Injection site reaction	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Mucosal dryness	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	2
Mucosal inflammation	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	5/33 (15.2%)	5	2/13 (15.4%)	3
Oedema	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	4/33 (12.1%)	7	1/13 (7.7%)	2
Oedema peripheral	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	12/33 (36.4%)	16	5/13 (38.5%)	9
Pain	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	2/33 (6.1%)	2	2/13 (15.4%)	2
Pyrexia	1/7 (14.3%)	3	0/3 (0%)	0	0/7 (0%)	0	3/33 (9.1%)	3	1/13 (7.7%)	1
Swelling	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Hepatobiliary disorders
Hepatomegaly	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Immune system disorders
Drug hypersensitivity	2/7 (28.6%)	2	1/3 (33.3%)	1	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Hypersensitivity	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Seasonal allergy	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Infections and infestations
Bronchitis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Cellulitis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	1
Fungal infection	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Gastroenteritis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	1
Herpes virus infection	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Hordeolum	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Oral candidiasis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Oral infection	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Pneumonia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Rectal abscess	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Rhinitis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Sinusitis	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Tinea pedis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Upper respiratory tract infection	2/7 (28.6%)	2	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	1/13 (7.7%)	1
Urinary tract infection	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Injury, poisoning and procedural complications
Accident	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	3	1/13 (7.7%)	2
Contusion	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	5	0/13 (0%)	0
Fall	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	1/13 (7.7%)	1
Infusion related reaction	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Limb injury	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Procedural pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Radiation proctitis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Skin abrasion	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Subcutaneous haematoma	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Investigations
Blood pressure increased	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	2
Haemoglobin decreased	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Neutrophil count decreased	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	1/13 (7.7%)	2
Respiratory rate increased	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Weight decreased	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	1
White blood cell count decreased	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	3
Metabolism and nutrition disorders
Decreased appetite	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	11/33 (33.3%)	13	4/13 (30.8%)	6
Dehydration	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	2/33 (6.1%)	2	1/13 (7.7%)	1
Diabetes mellitus	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	1/13 (7.7%)	1
Hypercholesterolaemia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Hyperglycaemia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	2/13 (15.4%)	2
Hyperkalaemia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Hypoglycaemia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Hypophosphataemia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	2/13 (15.4%)	2
Insulin resistance	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/7 (0%)	0	1/3 (33.3%)	1	1/7 (14.3%)	1	7/33 (21.2%)	9	6/13 (46.2%)	10
Back pain	4/7 (57.1%)	4	1/3 (33.3%)	2	1/7 (14.3%)	1	12/33 (36.4%)	16	4/13 (30.8%)	5
Bone pain	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	3/33 (9.1%)	3	2/13 (15.4%)	2
Groin pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	2
Joint effusion	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	2
Joint swelling	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Muscle spasms	0/7 (0%)	0	1/3 (33.3%)	2	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Muscular weakness	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	1/13 (7.7%)	1
Musculoskeletal chest pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	1
Musculoskeletal pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	4/33 (12.1%)	4	1/13 (7.7%)	1
Myalgia	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	3/33 (9.1%)	3	3/13 (23.1%)	5
Neck pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Osteonecrosis of jaw	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Pain in extremity	0/7 (0%)	0	0/3 (0%)	0	3/7 (42.9%)	3	8/33 (24.2%)	9	2/13 (15.4%)	2
Spinal pain	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/33 (3%)	1	0/13 (0%)	0
Nervous system disorders
Balance disorder	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Disturbance in attention	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Dizziness	1/7 (14.3%)	1	0/3 (0%)	0	2/7 (28.6%)	2	2/33 (6.1%)	2	2/13 (15.4%)	2
Dysgeusia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	7/33 (21.2%)	10	8/13 (61.5%)	12
Headache	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	2/33 (6.1%)	2	3/13 (23.1%)	5
Hypoaesthesia	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Lethargy	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Memory impairment	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Myoclonus	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Neuropathy peripheral	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	10/33 (30.3%)	12	4/13 (30.8%)	5
Paraesthesia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Peripheral motor neuropathy	0/7 (0%)	0	0/3 (0%)	0	2/7 (28.6%)	2	2/33 (6.1%)	2	1/13 (7.7%)	1
Peripheral sensory neuropathy	1/7 (14.3%)	1	3/3 (100%)	4	0/7 (0%)	0	6/33 (18.2%)	8	2/13 (15.4%)	3
Sciatica	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Visual field defect	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Psychiatric disorders
Agitation	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Anxiety	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	0/13 (0%)	0
Confusional state	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Insomnia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	3/33 (9.1%)	4	2/13 (15.4%)	2
Renal and urinary disorders
Haematuria	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Incontinence	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	1/33 (3%)	1	0/13 (0%)	0
Nocturia	1/7 (14.3%)	2	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Pollakiuria	1/7 (14.3%)	1	1/3 (33.3%)	1	0/7 (0%)	0	5/33 (15.2%)	6	0/13 (0%)	0
Ureteric obstruction	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Urethral pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Urinary incontinence	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Reproductive system and breast disorders
Penile pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Priapism	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	4/33 (12.1%)	5	3/13 (23.1%)	3
Dysphonia	0/7 (0%)	0	1/3 (33.3%)	1	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Dyspnoea	3/7 (42.9%)	3	1/3 (33.3%)	1	3/7 (42.9%)	3	2/33 (6.1%)	2	5/13 (38.5%)	5
Dyspnoea exertional	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Epistaxis	1/7 (14.3%)	1	1/3 (33.3%)	1	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Hypoxia	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Nasal congestion	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	1/33 (3%)	1	3/13 (23.1%)	3
Nasal dryness	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Oropharyngeal pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Pneumonia aspiration	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Productive cough	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	2/13 (15.4%)	2
Pulmonary embolism	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Rhinorrhoea	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	3/13 (23.1%)	3
Wheezing	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
Acne	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Alopecia	1/7 (14.3%)	1	1/3 (33.3%)	1	3/7 (42.9%)	3	12/33 (36.4%)	12	7/13 (53.8%)	7
Dermatitis allergic	2/7 (28.6%)	2	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	0/13 (0%)	0
Dry skin	1/7 (14.3%)	1	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	3/13 (23.1%)	4
Ecchymosis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	3/33 (9.1%)	3	1/13 (7.7%)	1
Erythema	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	3/33 (9.1%)	3	1/13 (7.7%)	1
Hyperkeratosis	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Nail bed disorder	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	3/13 (23.1%)	3
Nail discolouration	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	2/33 (6.1%)	2	0/13 (0%)	0
Nail disorder	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	5/33 (15.2%)	5	2/13 (15.4%)	2
Nail dystrophy	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	5/33 (15.2%)	5	1/13 (7.7%)	2
Nail toxicity	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Night sweats	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	1/13 (7.7%)	1
Pain of skin	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	1
Palmar-plantar erythrodysaesthesia syndrome	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Petechiae	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	1/13 (7.7%)	1
Photosensitivity reaction	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Rash	1/7 (14.3%)	1	1/3 (33.3%)	2	0/7 (0%)	0	0/33 (0%)	0	2/13 (15.4%)	2
Skin atrophy	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Skin striae	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Vascular disorders
Flushing	1/7 (14.3%)	1	0/3 (0%)	0	1/7 (14.3%)	1	2/33 (6.1%)	2	0/13 (0%)	0
Hot flush	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1
Hypotension	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	1/33 (3%)	1	1/13 (7.7%)	1
Orthostatic hypotension	0/7 (0%)	0	0/3 (0%)	0	1/7 (14.3%)	1	0/33 (0%)	0	0/13 (0%)	0
Vascular pain	0/7 (0%)	0	0/3 (0%)	0	0/7 (0%)	0	0/33 (0%)	0	1/13 (7.7%)	1

Limitations/Caveats

The radium 223 dichloride treatment was calculated as 50 kBq per NIST 2010, and would be approximately 55 kBq per NIST 2015 standard. Pharmacokinetic endpoint was deleted as no PK variables were evaluated in the study.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.