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Clinical Trial Results:
A randomised phase II/III study of Docetaxel plus Prednisolone vs. Docetaxel plus Prednisolone plus Zoledronic acid vs. Docetaxel plus Prednisolone plus Strontium-89 vs. Docetaxel plus Prednisolone plus Zoledronic Acid plus Strontium-89 in Hormone Refractory Prostate Cancer metastatic to bone.

Summary
EudraCT number	2004-002295-41
Trial protocol	GB
Global end of trial date	01 Mar 2016

Results information
Results version number	v1(current)
This version publication date	29 Mar 2017
First version publication date	29 Mar 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

PR2100

ISRCTN number

ISRCTN12808747

US NCT number

NCT00554918

WHO universal trial number (UTN)

Sponsor organisation name

University of Birmingham

Sponsor organisation address

Edgbaston, Birmingham, United Kingdom, B15 2TT

Public contact

TRAPEZE Trial Office Cancer Research Clinical Trials Unit University of Birmingham, TRAPEZE Trial Office Cancer Research Clinical Trials Unit University of Birmingham, Trapeze@trials.bham.ac.uk

Scientific contact

TRAPEZE Trial Office Cancer Research Clinical Trials Unit University of Birmingham, TRAPEZE Trial Office Cancer Research Clinical Trials Unit University of Birmingham, Trapeze@trials.bham.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 Sep 2013

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 Aug 2013

Global end of trial reached?

Yes

Global end of trial date

01 Mar 2016

Was the trial ended prematurely?

Main objective of the trial

The Phase II study, concerned the feasiblity, tolerablity and safety in terms of combining docetaxel with zoledronic acid and strontium-89; the phase II data was incorporated into the phase III data for analysis. The Phase III primary endpoints were : - Clinical Progression-free survival - Cost and cost effectiveness of trial treatments All data including graphs were published with open access in 2016. Please refer to the publications listed in Online Reference section of this report for further and more detailed trial results.

Protection of trial subjects

This study was carried out in accordance with the World Medical Association (WMA) Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996) and Scotland (2000) amendments. The protocol gained ethical approval from the South West MREC. Before entering patients into the study, the Principal Investigator ensured that the protocol had approval from their local Research Ethics Committee and local Research and Development (R&D) Office. A participant’s tolerance to trial treatment and the overall tumour response was determined by the treating physician who decided whether it was in the participant’s best interest to continue with treatment or not. Participants were provided with ethically approved comprehensive information about the trial and trial treatments, and given advice on who to contact with any questions or concerns at any time. Prophylactic anti-emetic treatment(s) were advised throughout chemotherapy. Dexamethasone and a second anti-emetic, such as metoclopramide, or local standard treatment were recommended. More aggressive anti-emetic treatment, e.g. 5-HT3 antagonists, was advised for participants who experienced CTC AE (i.e. Common Terminology Criteria for Adverse Events, version 3) grade 3 or higher nausea/vomiting in a preceding cycle. If grade 3 or higher symptoms continued, the docetaxel dose was to be reduced by one dose level (i.e. standard dose 75 mg/square meters down to 60 mg/sq. meters, or 60 mg/sq. meters down to 45 mg/sq. meters). Participants with continuing grade 3 or higher nausea/vomiting were withdrawn from trial treatment. Only one docetaxel dose reduction was permitted. Expected adverse reactions to docetaxel, zoledronic acid (ZA) and Strontium-89 (Sr-89) were itemised in the protocol with guidance and recommended counter measures.

Background therapy

All supportive care medications, including: - Prednisolone - Although listed as an investigational medicinal product (IMP) this was essential NICE-recommended supportive care throughout chemotherapy regimens; - Anti-emetic medications; - Vitamin D and calcium supplements throughout ZA treatment. For participants also treated with Sr89, vitamin D/calcium supplements were halted 3 weeks prior to and recommenced 4 weeks after SR89 administration.

Evidence for comparator

Docetaxel therapy plus prednisolone for up to 10 cycles/3-weekly became the mainstay of standard therapy for metastatic, castrate (previously ‘hormone’) refractory prostate cancer (CRPC, previously referred to as HRPC) – approved by the National Institute for Health and Clinical Excellence (NICE) in 2006, following two landmark trials published in the New England Journal of Medicine in 2004 (Tannock et al. 2004; Petrylak et al, 2004). One of the commonest sites of spread, and major cause of morbidity, in metastatic CRPC is to bone. ZA and Sr89 are two of the treatments approved for the treatment of bone disease. A pre-docetaxel era trial combined chemotherapy with Sr89 in a small randomized trial and suggested a survival advantage in patients allocated to Sr89 (Tu et al, 2001). Zoledronic acid was approved on the basis of reductions in skeletal related events (SREs) demonstrated in randomised studies in mHRPC (Saad et al, 2004). Tannock IF, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12. Epub 2004/10/08. Petrylak DP, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. NEnglJ Med. 2004;351(15):1513-20. Tu SM, et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial.[erratum appears in Lancet 2001 Apr 14;357(9263):1210]. Lancet. 2001;357(9253):336-41. Saad F, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J NatlCancer Inst. 2004;96(11):879-82.

Actual start date of recruitment

04 Feb 2005

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Scientific research

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 757

Worldwide total number of subjects

757

EEA total number of subjects

757

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

194

From 65 to 84 years

563

85 years and over

Subject disposition

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Recruitment details

Patients were recruited between 04-Feb-2005 and 29-Feb-2012 at multiple centres in the United Kingdom.

Screening details

Eligible participants were male, ≥18yrs, ≥1 bone mets, ECOG 1-2 with adequate haema/renal/hepatic function Exclusions : prior chemotherapy or radionuclide therapy for CRPC, prior radiotherapy to >25% bone marrow, bisphosphonate therapy within 2 months of trial entry, other malignant disease in last 5yrs, brain mets, peripheral neuropathy

Period 1 title

Baseline

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Not applicable

Are arms mutually exclusive

Yes

Arm A

Arm description

Control – Docetaxel plus prednisolone (Standard care) Pre-treatment period

Arm type

Active comparator

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

PR1

Other name

Taxotere

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pre-treatment period.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

PR4

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pre-treatment period.

Arm B

Arm description

Docetaxel plus prednisolone plus zoledronic acid Pre-treatment period

Arm type

Experimental

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

PR1

Other name

Taxotere

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pre-treatment period.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

PR4

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pre-treatment period

Investigational medicinal product name

Zoledronic acid

Investigational medicinal product code

PR2

Other name

Zometa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pre-treatment period.

Arm C

Arm description

Docetaxel plus prednisolone plus Strontium-89 (Sr89) Pre-treatment period

Arm type

Experimental

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

PR1

Other name

Taxotere

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pre-treatment period.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

PR4

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pre-treatment period.

Investigational medicinal product name

Strontium (89Sr) chloride

Investigational medicinal product code

PR3

Other name

Metastron, Sr89

Pharmaceutical forms

Sterile concentrate

Routes of administration

Intravenous use

Dosage and administration details

Pre-treatment period.

Arm D

Arm description

Docetaxel plus prednisolone plus ZA plus Sr89 Pre-treatment period

Arm type

Experimental

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

PR1

Other name

Taxotere

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pre-treatment period.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

PR4

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pre-treatment period.

Investigational medicinal product name

Zoledronic acid

Investigational medicinal product code

PR2

Other name

Zometa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Pre-treatment period.

Investigational medicinal product name

Strontium (89Sr) chloride

Investigational medicinal product code

PR3

Other name

Metastron, Sr89

Pharmaceutical forms

Sterile concentrate

Routes of administration

Intravenous use

Dosage and administration details

Pre-treatment period.

Number of subjects in period 1	Arm A	Arm B	Arm C	Arm D
Started	191	188	190	188
Allocation	191	188	190	188
Completed	191	188	190	188

Period 2 title

Treatment and Follow Up

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Not applicable

Are arms mutually exclusive

Yes

Arm A

Arm description

Control – Docetaxel plus prednisolone (Standard care) No further docetaxel or prednisolone treatment was administered during the follow-up stage.

Arm type

Active comparator

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

PR1

Other name

Taxotere

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Post-treatment period.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

PR4

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Post-treatment period.

Arm B

Arm description

During the follow-up period 4-weekly ZA continued as clinical indicated, until disease progression or other discontinuation criteria.

Arm type

Experimental

Investigational medicinal product name

Zoledronic acid

Investigational medicinal product code

PR2

Other name

Zometa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

4 mg i.v. every 4 weeks starting one month after final chemotherapy cycle, as clinically indicated or until disease-progression or other discontinuation criteria. Patients treated with zoledronic acid also received vitamin D and calcium supplements throughout treatment.

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

PR1

Other name

Taxotere

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

As per Arm A

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

PR4

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

As per Arm A

Arm C

Arm description

No further chemotherapy, prednisolone or Sr89 was offered during the follow-up period.

Arm type

Experimental

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

PR1

Other name

Taxotere

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

As per Arm A; Cycle 7 Docetaxel given between 28 and 56 days post-Sr89 administration subject to satisfactory pre-chemotherapy assessment.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

PR4

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

As per Arm A

Investigational medicinal product name

Strontium (89Sr) chloride

Investigational medicinal product code

PR3

Other name

Metastron, Sr89

Pharmaceutical forms

Sterile concentrate

Routes of administration

Intravenous use

Dosage and administration details

Sr89 150 MBq i.v. once, 28 days after the 6th cycle of docetaxel therapy subject to acceptable pre-administration assessment.

Arm D

Arm description

As per Arm B, ZA continued on a monthly (4-weekly) basis during the follow-up period as clinically indicated, until protocol defined disease progression or othr discontinuation criteria. No further chemotherapy, prednisolone or Sr89 were given during the follow-up period.

Arm type

Experimental

Investigational medicinal product name

Zoledronic acid

Investigational medicinal product code

PR2

Other name

Zometa

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Docetaxel

Investigational medicinal product code

PR1

Other name

Taxotere

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

As per Arm A; Cycle 7 Docetaxel given between 28 and 56 days post-Sr89 administration subject to satisfactory pre-chemotherapy assessment.

Investigational medicinal product name

Prednisolone

Investigational medicinal product code

PR4

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

As per Arm A

Investigational medicinal product name

Strontium (89Sr) chloride

Investigational medicinal product code

PR3

Other name

Metastron, Sr89

Pharmaceutical forms

Sterile concentrate

Routes of administration

Intravenous use

Dosage and administration details

As per Arm C

Number of subjects in period 2	Arm A	Arm B	Arm C	Arm D
Started	191	188	190	188
Completed	188	188	189	186
Not completed	3	0	1	2
Lost to follow-up	3	-	1	2

Baseline characteristics

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Reporting group title

Arm A

Reporting group description

Control – Docetaxel plus prednisolone (Standard care) Pre-treatment period

Reporting group title

Arm B

Reporting group description

Docetaxel plus prednisolone plus zoledronic acid Pre-treatment period

Reporting group title

Arm C

Reporting group description

Docetaxel plus prednisolone plus Strontium-89 (Sr89) Pre-treatment period

Reporting group title

Arm D

Reporting group description

Docetaxel plus prednisolone plus ZA plus Sr89 Pre-treatment period

Reporting group values	Arm A	Arm B	Arm C	Arm D	Total
Number of subjects	191	188	190	188	757
Age categorical
Units: Subjects
Adults from 18-84 years	191	188	190	188	757
Age continuous
Age at randomisation
Units: years
median (inter-quartile range (Q1-Q3))	68.7 (64.3 to 73.8)	69.4 (64.4 to 73.7)	68.3 (62.9 to 72.9)	68.9 (64 to 73.1)	-
Gender categorical
All trial participants were male.
Units: Subjects
Female	0	0	0	0	0
Male	191	188	190	188	757
ECOG performance status
Units: Subjects
Score 0	76	71	70	64	281
Score 1	83	88	90	95	356
Score 2	15	15	18	14	62
Score 3	1	0	0	0	1
Not recorded	16	14	12	15	57
Diagnostic indicator
Method by which prostate cancer was diagnosed.
Units: Subjects
Adenocarcinoma	156	146	150	149	601
PSA only	35	39	37	35	146
Missing	0	3	3	4	10
Staging : T
Staging information : T value
Units: Subjects
T1	2	5	2	1	10
T1b	1	0	1	0	2
T1c	0	1	2	1	4
T2	19	16	11	17	63
T2a	2	2	0	0	4
T2b	4	1	1	2	8
T3	54	53	49	63	219
T3a	4	3	5	4	16
T3b	12	10	10	9	41
T4	28	22	20	25	95
TX	16	18	20	18	72
T2c	1	0	0	1	2
Missing	48	57	69	47	221
Staging : M
Staging scores : M values
Units: Subjects
M0	44	41	33	40	158
M1a	20	20	22	21	83
M1b	8	7	3	2	20
M1c	4	10	6	5	25
MX	26	14	17	26	83
M1	41	39	40	47	167
Missing	48	57	69	47	221
Staging : N
Staging : N values
Units: Subjects
N0	59	57	46	58	220
N1	42	28	32	39	141
NX	42	46	43	44	175
Missing	48	57	69	47	221
Gleason score
Units: Subjects
03	0	0	0	1	1
04	2	0	1	0	3
05	2	3	2	3	10
06	9	12	12	6	39
07	43	48	39	41	171
08	30	24	35	25	114
09	57	55	41	54	207
10	1	1	8	4	14
Missing	47	45	52	54	198
Prior radiotherapy received
Number of participants who received radiotherapy prior to randomisation
Units: Subjects
No	114	107	95	98	414
Yes	77	80	92	88	337
Missing	0	1	3	2	6
Method of castration
Units: Subjects
Surgery	5	4	3	2	14
Ongoing LHRH agonists	186	184	187	186	743
Participants receiving anti-androgen
Units: Subjects
No	10	19	17	14	60
Yes	181	168	170	171	690
Missing	0	1	3	3	7
Participants receiving flutamide, nilutamide or cyprooterone acetate
Units: Subjects
Not received	151	141	142	133	567
Received	29	27	27	38	121
Missing	11	20	21	17	69
Participants who received bicalutamide
Units: Subjects
Not received	11	14	8	15	48
Received	170	154	162	156	642
Missing	10	20	20	17	67
Method used to determine progression at trial entry
Units: Subjects
All methods	26	27	27	27	107
Elevated PSA	42	48	42	44	176
New lesion	15	16	21	19	71
Objective	5	1	1	1	8
Objective + new lesion	3	4	7	5	19
PSA + new lesion	94	85	82	88	349
PSA + objective	5	4	8	2	19
Missing	1	3	2	2	8

Subject analysis set title

Subject analysis set type

Intention-to-treat

Subject analysis set description

Factorial analysis 1 : ZA with no ZA, stratified by Sr89. Thus, Arms B and D (ZA) were compared with arms A and C (No ZA)

Subject analysis set title

Sr89

Subject analysis set type

Intention-to-treat

Subject analysis set description

Factorial analsyis 2 : Sr89 with no Sr89, stratified by ZA. Thus, Arms C and D (Sr89) were compared with arms A and B (No Sr89).

Subject analysis set title

No ZA

Subject analysis set type

Intention-to-treat

Subject analysis set description

Factorial analysis 1 : ZA with no ZA, stratified by Sr89. Thus, Arms A and C (No ZA)were compared with Arms B and D (ZA)

Subject analysis set title

No Sr89

Subject analysis set type

Intention-to-treat

Subject analysis set description

Factorial analsyis 2 : Sr89 with no Sr89, stratified by ZA. Thus, Arms A and B (No Sr89) were compared with Arms C and D (Sr89).

Subject analysis sets values	ZA	Sr89	No ZA	No Sr89
Number of subjects	376	378	381	379
Age categorical
Units: Subjects
Adults from 18-84 years	376	378
Age continuous
Age at randomisation
Units: years
median (inter-quartile range (Q1-Q3))	68.9 (64.1 to 73.4)	68.6 (63.2 to 73.1)	68.6 (63.6 to 73.5)	68.9 (64.3 to 73.8)
Gender categorical
All trial participants were male.
Units: Subjects
Female	0	0	0	0
Male	376	378	381	379
ECOG performance status
Units: Subjects
Score 0	135	134	146	147
Score 1	183	185	173	171
Score 2	29	32	33	30
Score 3	0	0	1	1
Not recorded	26	23	26	29
Diagnostic indicator
Method by which prostate cancer was diagnosed.
Units: Subjects
Adenocarcinoma	295	299	306	302
PSA only	74	72	72	74
Missing	4	3	1	2
Staging : T
Staging information : T value
Units: Subjects
T1	6	3	4	7
T1b	0	1	2	1
T1c	2	3	2	1
T2	33	28	30	35
T2a	2	0	2	4
T2b	3	3	5	5
T3	116	112	103	107
T3a	7	9	9	7
T3b	19	19	22	22
T4	47	45	48	50
TX	36	38	36	34
T2c	1	1	1	1
Missing	101	112	115	104
Staging : M
Staging scores : M values
Units: Subjects
M0	81	73	77	85
M1a	41	43	42	40
M1b	9	5	11	15
M1c	15	11	10	14
MX	40	43	43	40
M1	86	87	81	80
Missing	101	112	115	104
Staging : N
Staging : N values
Units: Subjects
N0	115	104	105	116
N1	67	71	74	70
NX	90	87	85	88
Missing	101	112	115	104
Gleason score
Units: Subjects
03	1	1	0	0
04	0	1	3	2
05	6	5	4	5
06	18	18	21	21
07	89	80	82	91
08	49	60	65	54
09	109	95	98	112
10	5	12	9	2
Missing	96	102	97	91
Prior radiotherapy received
Number of participants who received radiotherapy prior to randomisation
Units: Subjects
No	205	193	209	221
Yes	168	180	169	157
Missing	0	1	1	0
Method of castration
Units: Subjects
Surgery	6	5	8	9
Ongoing LHRH agonists	367	369	371	369
Participants receiving anti-androgen
Units: Subjects
No	33	31	27	29
Yes	339	341	351	349
Missing	0	2	0	0
Participants receiving flutamide, nilutamide or cyprooterone acetate
Units: Subjects
Not received	274	275	293	292
Received	65	65	56	56
Missing	37	38	32	31
Participants who received bicalutamide
Units: Subjects
Not received	29	23	19	25
Received	310	318	332	324
Missing	34	33	28	29
Method used to determine progression at trial entry
Units: Subjects
All methods	54	54	53	53
Elevated PSA	92	86	84	90
New lesion	35	40	36	31
Objective	2	2	6	6
Objective + new lesion	9	12	10	7
PSA + new lesion	173	170	176	179
PSA + objective	6	10	13	9
Missing	2	0	1	3

End points

Top of page

Reporting group title

Arm A

Reporting group description

Control – Docetaxel plus prednisolone (Standard care) Pre-treatment period

Reporting group title

Arm B

Reporting group description

Docetaxel plus prednisolone plus zoledronic acid Pre-treatment period

Reporting group title

Arm C

Reporting group description

Docetaxel plus prednisolone plus Strontium-89 (Sr89) Pre-treatment period

Reporting group title

Arm D

Reporting group description

Docetaxel plus prednisolone plus ZA plus Sr89 Pre-treatment period

Reporting group title

Arm A

Reporting group description

Control – Docetaxel plus prednisolone (Standard care) No further docetaxel or prednisolone treatment was administered during the follow-up stage.

Reporting group title

Arm B

Reporting group description

During the follow-up period 4-weekly ZA continued as clinical indicated, until disease progression or other discontinuation criteria.

Reporting group title

Arm C

Reporting group description

No further chemotherapy, prednisolone or Sr89 was offered during the follow-up period.

Reporting group title

Arm D

Reporting group description

Subject analysis set title

Subject analysis set type

Intention-to-treat

Subject analysis set description

Factorial analysis 1 : ZA with no ZA, stratified by Sr89. Thus, Arms B and D (ZA) were compared with arms A and C (No ZA)

Subject analysis set title

Sr89

Subject analysis set type

Intention-to-treat

Subject analysis set description

Factorial analsyis 2 : Sr89 with no Sr89, stratified by ZA. Thus, Arms C and D (Sr89) were compared with arms A and B (No Sr89).

Subject analysis set title

No ZA

Subject analysis set type

Intention-to-treat

Subject analysis set description

Factorial analysis 1 : ZA with no ZA, stratified by Sr89. Thus, Arms A and C (No ZA)were compared with Arms B and D (ZA)

Subject analysis set title

No Sr89

Subject analysis set type

Intention-to-treat

Subject analysis set description

Factorial analsyis 2 : Sr89 with no Sr89, stratified by ZA. Thus, Arms A and B (No Sr89) were compared with Arms C and D (Sr89).

Primary: Clinical Progression-Free Survival (CPFS) - ZA comparison

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End point title

Clinical Progression-Free Survival (CPFS) - ZA comparison

End point description

The primary Phase III analysis compared ZA versus no ZA (stratified for Sr-89 use) and Sr-89 versus no Sr-89 (stratified for ZA use) in terms of CPFS. CPFS was defined as the number of whole days from the date of randomisation to the first occurrence of SRE, pain progression or death. Patients not experiencing clinical progression were censored at the date last known to be progression free.

End point type

Primary

End point timeframe

Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.

End point values	ZA	No ZA
Number of subjects analysed	376	381
Units: Days
Death	122	87
Skeletal-related event (SRE)	56	73
Pain	132	132
Death SRE	1	0
SRE pain	41	52

Unadjusted log rank

Statistical analysis description

The first analysis of the primary outcome was an unadjusted stratified log-rank test comparing ZA with no ZA, stratified by Sr-89.

Comparison groups

ZA v No ZA

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7553 ^[1]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.13

Notes
[1] - In total, there were 696 events: 352 (51%) in the ZA group and 344 (49%) in the no ZA. A stratified log-rank test was performed comparing ZA and no ZA. No statistical difference in CPFS between the two groups was observed (χ2 = 0.10; p = 0.7553)

Adjusted Cox regression model

Statistical analysis description

Second analysis of CPFS: adjusted Cox regression model, including both treatment comparisons and stratification factors (ECOG and randomising centre). Using stratification factors within the design leads to correlation between the treatment groups which, when not adjusted for, can lead to upwards biased standard error rates for treatment effects, CIs which are too wide, type 1 error rates which are too low and a reduction in power. Owning to this conclusions are based on adjusted analysis.

Comparison groups

ZA v No ZA

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.808

Method

Regression, Cox

Parameter type

Hazard ratio (HR)

Point estimate

0.982

Confidence interval

level

95%

sides

2-sided

lower limit

0.845

upper limit

1.141

Notes
[2] - The use of both log-rank and cox regression models was pre-specified in the protocol.

Primary: Clinical Progression-Free Survival (CPFS) - Sr89 comparison

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End point title

Clinical Progression-Free Survival (CPFS) - Sr89 comparison

End point description

The primary Phase III analysis compared Sr-89 versus no Sr-89 (stratified for ZA use) and ZA versus no ZA (stratified for Sr-89 use) in terms of CPFS. CPFS was defined as the number of whole days from the date of randomisation to the first occurrence of SRE, pain progression or death. Patients not experiencing clinical progression were censored at the date last known to be progression free.

End point type

Primary

End point timeframe

Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.

End point values	Sr89	No Sr89
Number of subjects analysed	378	379
Units: Days
Death	103	106
SRE	68	61
Pain	120	144
Death SRE	0	1
SRE pain	58	35

Unadjusted, stratified log rank

Comparison groups

No Sr89 v Sr89

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.123 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.03

Notes
[3] - In total, there were 696 events: 349 (50%) in the Sr-89 group and 347 (50%) in the no Sr-89 group. A stratified log-rank test comparing Sr-89 and no Sr-89 revealed no difference in CPFS between the two groups (χ2 = 2.38; p = 0.1230).

Adjusted Cox proportional hazards model

Comparison groups

No Sr89 v Sr89

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.031

Method

Regression, Cox

Parameter type

Cox proportional hazard

Point estimate

0.847

Confidence interval

level

95%

sides

2-sided

lower limit

0.729

upper limit

0.985

Primary: Cost-effectiveness ICER per additional QALY - ZA & Sr89

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End point title

Cost-effectiveness ICER per additional QALY - ZA & Sr89 ^[4]

End point description

A total NHS cost and number of QALYs were calculated for each of the 707 patients for whom information on costs and preference-based quality of life (EQ-5D) was available. The mean total cost and mean total QALYs across all patients under a given treatment were calculated. As the distribution of costs and QALYs are typically skewed, 95% confidence intervals around mean values were obtained on the basis of 1000 replications using the bias corrected and accelerated (BCa) bootstrap method. Incremental analysis was carried out to determine the difference in mean total costs and QALYs. These differences were summarised in an incremental cost-effectiveness ratio (ICER), a measure that reflects the extra cost associated with a gain of one additional QALY. Full details of the cost effectiveness analysis can be found in the National Institute for Health Research (UK) Health Technology Assessment Program (vol20(53) July 2016) and a separate BJUI 2016 paper by Andronis et al.

End point type

Primary

End point timeframe

Analysed once all patients had complete follow-up.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Full cost effectiveness analysis was conducted and results were published in the end of trial report published by the NIHR HTA and in a separate journal article in 2016, both listed in the Further information section of this report.

End point values	ZA	Sr89
Number of subjects analysed	707	707
Units: Pounds Sterling
number (not applicable)	8005	16590

No statistical analyses for this end point

Secondary: Skeletal-related event-free interval(SREFI) - ZA

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End point title

Skeletal-related event-free interval(SREFI) - ZA

End point description

Skeletal-related event-free interval (SREFI) was defined as the time in whole days from the date of randomisation to the date of the first occurrence of a SRE. A SRE was defined as any one of the following: - symptomatic pathological bone fracture - spinal cord or nerve root compression likely to be related to cancer or treatment - cancer related surgery to bone - radiation therapy to bone (including use of radioisotopes) - change of antineoplastic therapy to treat bone pain due to prostate cancer - hypercalcaemia Patients who did not experience a SRE were censored at death or the date last known to be alive.

End point type

Secondary

End point timeframe

Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.

End point values	ZA	No ZA
Number of subjects analysed	376	381
Units: Months
median (confidence interval 95%)	13.6 (11.76 to 16.62)	11.17 (9.76 to 13.01)

Stratified log-rank

Statistical analysis description

An unadjusted log rank test comparing ZA with no ZA stratified by Sr89 use.

Comparison groups

ZA v No ZA

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011 ^[5]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.65

upper limit

0.95

Notes
[5] - In total, there were 437 events: 234 (54%) in the no ZA group and 203 (46%) in the ZA group. Stratified log-rank test showed a statistically significant difference in SREFIs between the two groups (χ2 = 6.49, p = 0.011).

Secondary: Skeletal-related event-free interval(SREFI) - Sr89

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End point title

Skeletal-related event-free interval(SREFI) - Sr89

End point description

As per Skeletal-related event-free survival (SREFS) - ZA

End point type

Secondary

End point timeframe

Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.

End point values	Sr89	No Sr89
Number of subjects analysed	378	379
Units: Months
median (confidence interval 95%)	13.04 (11.14 to 14.69)	11.7 (10.58 to 13.6)

Stratified log-rank

Statistical analysis description

Unadjusted log rank test comparing Sr89 with no Sr89 stratified by ZA use.

Comparison groups

Sr89 v No Sr89

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.169 ^[6]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

0.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

1.06

Notes
[6] - There were 437 events: 222 (51%) in the no Sr-89 group and 215 (49%) in the Sr-89 group. Stratified log-rank test showed no difference in SREFI between the two groups (χ2 = 1.89; p = 0.169).

Secondary: Pain progression-free interval- ZA

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End point title

Pain progression-free interval- ZA

End point description

Pain progression-free interval (PPFI) was defined as the time in whole days from the date of randomisation to the date of clinician-determined pain progression. Patients not experiencing pain progression were censored at the date of death or the date last known to be alive.

End point type

Secondary

End point timeframe

Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.

End point values	ZA	No ZA
Number of subjects analysed	376	381
Units: Months
median (confidence interval 95%)	12.19 (10.78 to 15.38)	11.76 (10.55 to 13.37)

Stratified log-rank

Statistical analysis description

A stratified log-rank test comparing ZA with no ZA, stratified by Sr-89.

Comparison groups

ZA v No ZA

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3127 ^[7]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

0.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.1

Notes
[7] - There were 432 events: 225 (52%) in the no ZA group and 207 (48%) in the ZA group. A stratified log-rank test was performed comparing ZA with no ZA. No difference in PPFI between the two groups was observed (χ2 = 1.02; p = 0.3127).

Secondary: Pain progression-free interval- Sr89

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End point title

Pain progression-free interval- Sr89

End point description

As per ZA comparison group.

End point type

Secondary

End point timeframe

Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.

End point values	Sr89	No Sr89
Number of subjects analysed	378	379
Units: Months
median (confidence interval 95%)	12.22 (10.94 to 14.09)	11.76 (10.32 to 13.54)

Stratified log-rank

Statistical analysis description

A stratified log-rank test comparing Sr-89 with no Sr-89, stratified by ZA. Conclusions were based on a two-sided 5% significance level. No adjustments for multiple testing were made.

Comparison groups

Sr89 v No Sr89

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3991 ^[8]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

1.11

Notes
[8] - There were 432 events: 215 (50%) in the no Sr-89 group and 217 (50%) in the Sr-89 group. A stratified log-rank test was performed comparing Sr-89 with no Sr-89. No difference in PPFI between the two groups was observed (χ2 = 0.40; p = 0.3991).

Secondary: Overall survival (OS) -- ZA

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End point title

Overall survival (OS) -- ZA

End point description

Overall survival was defined as the number of whole days from the date of randomisation to the date of death from any cause. Patients alive at the date of analysis were censored at the date last known to be alive.

End point type

Secondary

End point timeframe

Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.

End point values	ZA	No ZA
Number of subjects analysed	376	381
Units: Months
median (confidence interval 95%)	16.99 (16.07 to 19.23)	17.61 (16.1 to 18.96)

Stratified log-rank

Statistical analysis description

A stratified log-rank comparing ZA with no ZA, stratified by Sr-89, with no adjustments made for multiple testing.

Comparison groups

No ZA v ZA

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.909 ^[9]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.84

upper limit

1.16

Notes
[9] - There were 618 events: 309 (50%) occurred in each group. Stratified log-rank test comparing ZA with no ZA demonstrated no difference in OS between the two groups (χ2 = 0.01; p = 0.909).

Secondary: Overall survival (OS) -- Sr89

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End point title

Overall survival (OS) -- Sr89

End point description

As per Overall survival (OS) -- ZA

End point type

Secondary

End point timeframe

Outcome was assessed once all patients had completed a minimum of 12 months' follow-up from randomisation.

End point values	Sr89	No Sr89
Number of subjects analysed	378	379
Units: Months
median (confidence interval 95%)	18.17 (16.66 to 19.12)	16.59 (15.61 to 18.27)

Stratified log-rank

Statistical analysis description

A stratified log rank test comparing Sr89 with No Sr89 stratified by ZA use.

Comparison groups

Sr89 v No Sr89

Number of subjects included in analysis

757

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3359 ^[10]

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.08

Notes
[10] - There were 618 events: 310 (50%) in the no Sr-89 group and 308 in the Sr-89 (50%) group. Stratified log-rank test comparing Sr-89 with no Sr-89 demonstrated no difference in OS between the two groups (χ2 = 0.93; p = 0.3359).

Secondary: Quality-Adjusted Survival - ZA

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End point title

Quality-Adjusted Survival - ZA

End point description

The integrated quality adjusted survival product is the product of the survival and EQ-5D quality of life measure over the 2 year period of interest. The methodology of integrating QoL and survival was carried out at the group level. The area under the curve at 2 years gave the mean QALY for each group. Standard errors were calculated and 95% confidence intervals constructed using bootstrapping techniques with 1000 replications. Full descriptive quality of life data has been published in the Trial report published by the National Institute for Health Research (UK) Health Technology Assessment Program (Vol 20(53) July 2016; ISSN 1366-5278; DOI 10.3310/hta20530)

End point type

Secondary

End point timeframe

Group based quality adjusted survival analysis conducted to assess the balance between Quality of Life and Survival. As the median survival in the trial was 1.4 years, 2 years was deemed the appropriate cut-off point for the quality adjusted survival.

End point values	ZA	No ZA
Number of subjects analysed
Units: Years
median (confidence interval 95%)	1.04 (0.98 to 1.1)	1 (0.93 to 1.1)

No statistical analyses for this end point

Secondary: Quality Adjusted Survival - Sr89

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End point title

Quality Adjusted Survival - Sr89

End point description

End point type

Secondary

End point timeframe

End point values	Sr89	No Sr89
Number of subjects analysed	350	357
Units: Years
median (confidence interval 95%)	1.05 (0.99 to 1.12)	0.97 (0.91 to 1.03)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Enter the time point(s) or time period for adverse events assessment.

Adverse event reporting additional description

Enter information about the adverse event collection and provide details about the method of assessment and monitoring (e.g. daily questionnaire).

Assessment type

Systematic

Dictionary name

NCI CTCAE

Dictionary version

3.0

Reporting group title

Arm A

Reporting group description

Standard care (Docetaxel and prednisolone)

Reporting group title

Arm B

Reporting group description

Docetaxel, prednisolone and ZA

Reporting group title

Arm C

Reporting group description

Docetaxel, prednisolone and Sr89

Reporting group title

Arm D

Reporting group description

Docetaxel, prednisolone, ZA and Sr89

Serious adverse events	Arm A	Arm B	Arm C	Arm D
Total subjects affected by serious adverse events
subjects affected / exposed	84 / 191 (43.98%)	106 / 188 (56.38%)	97 / 190 (51.05%)	86 / 188 (45.74%)
number of deaths (all causes)	154	156	155	153
number of deaths resulting from adverse events	6	4	3	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy
Additional description: Possibly related to cancer treatment
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Phlebitis (including superficial thrombosis)
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis/embolism (Vascular access-related)
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	1 / 190 (0.53%)	3 / 188 (1.60%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Thrombosis/thrombus/embolism
subjects affected / exposed	3 / 191 (1.57%)	3 / 188 (1.60%)	2 / 190 (1.05%)	3 / 188 (1.60%)
occurrences causally related to treatment / all	1 / 3	2 / 3	1 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Vessel injury-artery
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Surgical and medical procedures
Intra-operative Injury, Unspecified
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Consitutional symptoms - unspecified
subjects affected / exposed	3 / 191 (1.57%)	0 / 188 (0.00%)	1 / 190 (0.53%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	2 / 3	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death not associated with CTCAE term
subjects affected / exposed	1 / 191 (0.52%)	6 / 188 (3.19%)	6 / 190 (3.16%)	5 / 188 (2.66%)
occurrences causally related to treatment / all	0 / 1	0 / 6	1 / 6	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 6	1 / 6	0 / 5
Lethargy
subjects affected / exposed	3 / 191 (1.57%)	2 / 188 (1.06%)	1 / 190 (0.53%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	2 / 4	1 / 2	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
Pain
subjects affected / exposed	10 / 191 (5.24%)	12 / 188 (6.38%)	14 / 190 (7.37%)	10 / 188 (5.32%)
occurrences causally related to treatment / all	0 / 12	1 / 13	2 / 17	4 / 10
deaths causally related to treatment / all	0 / 1	1 / 2	0 / 2	1 / 1
Pain, Unspecified
subjects affected / exposed	1 / 191 (0.52%)	1 / 188 (0.53%)	1 / 190 (0.53%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Rigors/chills
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	9 / 191 (4.71%)	7 / 188 (3.72%)	5 / 190 (2.63%)	5 / 188 (2.66%)
occurrences causally related to treatment / all	6 / 11	5 / 8	2 / 5	3 / 7
deaths causally related to treatment / all	1 / 1	1 / 2	1 / 2	0 / 0
Pneumonitis/pulmonary infiltrates
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Pulmonary/Upper Respiratory, Unspecified
subjects affected / exposed	3 / 191 (1.57%)	0 / 188 (0.00%)	0 / 190 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Pleural effusion (non-malignant)
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac - General unspecified
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Infarction
subjects affected / exposed	0 / 191 (0.00%)	2 / 188 (1.06%)	1 / 190 (0.53%)	3 / 188 (1.60%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	2 / 3
Hypotension
subjects affected / exposed	2 / 191 (1.05%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Left ventricular systolic dysfunction
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular and nodal arrhythmia
subjects affected / exposed	2 / 191 (1.05%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vasovagal episode
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular arrhythmia
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
CNS cerebrovascular ischemia
subjects affected / exposed	2 / 191 (1.05%)	3 / 188 (1.60%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
Cognitive disorder
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusion
subjects affected / exposed	0 / 191 (0.00%)	2 / 188 (1.06%)	1 / 190 (0.53%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	1 / 190 (0.53%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Memory impairment
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mood altered
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Neurology, Unspecified
subjects affected / exposed	4 / 191 (2.09%)	3 / 188 (1.60%)	0 / 190 (0.00%)	4 / 188 (2.13%)
occurrences causally related to treatment / all	0 / 4	1 / 3	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathy, motor
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathy, sensory
subjects affected / exposed	2 / 191 (1.05%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Speech impairment
Additional description: e.g. dysphasia or aphasia
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Bone Marrow - unspecified event
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Disseminated intravascular coagulation
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema - limb
subjects affected / exposed	0 / 191 (0.00%)	2 / 188 (1.06%)	1 / 190 (0.53%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Haematoma
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Haemoglobin
subjects affected / exposed	2 / 191 (1.05%)	3 / 188 (1.60%)	1 / 190 (0.53%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	1 / 2	2 / 5	1 / 1	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage, GI
subjects affected / exposed	1 / 191 (0.52%)	4 / 188 (2.13%)	6 / 190 (3.16%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 1	2 / 4	3 / 6	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Haemorrhage, GU
subjects affected / exposed	0 / 191 (0.00%)	3 / 188 (1.60%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemorrhage, pulmonary/upper respiratory
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophils/granulocytes (ANC/AGC)
subjects affected / exposed	6 / 191 (3.14%)	7 / 188 (3.72%)	8 / 190 (4.21%)	8 / 188 (4.26%)
occurrences causally related to treatment / all	6 / 6	7 / 7	9 / 9	9 / 9
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Platelets
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemolysis
Additional description: e.g. immune hemolytic anemia, drug-related hemolysis
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Haemorrhage, Unspecified
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Ocular/Visual, Unspecified
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blurred vision
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 191 (0.52%)	1 / 188 (0.53%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	5 / 191 (2.62%)	3 / 188 (1.60%)	6 / 190 (3.16%)	5 / 188 (2.66%)
occurrences causally related to treatment / all	5 / 5	2 / 3	5 / 6	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Fever
Additional description: In the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L
subjects affected / exposed	11 / 191 (5.76%)	7 / 188 (3.72%)	13 / 190 (6.84%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	9 / 14	7 / 10	9 / 14	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal - unspecified event
subjects affected / exposed	2 / 191 (1.05%)	1 / 188 (0.53%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 191 (1.05%)	3 / 188 (1.60%)	1 / 190 (0.53%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	1 / 2	2 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ulcer
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 191 (1.05%)	2 / 188 (1.06%)	4 / 190 (2.11%)	3 / 188 (1.60%)
occurrences causally related to treatment / all	1 / 2	2 / 2	3 / 4	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mucositis/stomatitis (clinical exam)
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstruction
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatology/Skin - Unspecified event
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injection site reaction/extravasation changes
subjects affected / exposed	1 / 191 (0.52%)	1 / 188 (0.53%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound complication, non-infectious
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Fistula, GU
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstruction, GU
subjects affected / exposed	0 / 191 (0.00%)	2 / 188 (1.06%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 191 (0.52%)	5 / 188 (2.66%)	0 / 190 (0.00%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 1	1 / 5	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 2
Renal/Genitourinary, Unspecified
subjects affected / exposed	2 / 191 (1.05%)	3 / 188 (1.60%)	2 / 190 (1.05%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	2 / 3	0 / 3	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stenosis, GU
Additional description: including anastomotic
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention (including neurogenic bladder)
subjects affected / exposed	0 / 191 (0.00%)	6 / 188 (3.19%)	1 / 190 (0.53%)	4 / 188 (2.13%)
occurrences causally related to treatment / all	0 / 0	1 / 6	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Urine colour change
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Extremity-lower (Gait/Walking)
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fracture
subjects affected / exposed	2 / 191 (1.05%)	4 / 188 (2.13%)	5 / 190 (2.63%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	1 / 2	0 / 5	0 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Muscle weakness, generalized or specific area
Additional description: Not due to neuropathy
subjects affected / exposed	5 / 191 (2.62%)	4 / 188 (2.13%)	2 / 190 (1.05%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	1 / 5	0 / 6	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
Musculoskeletal/Soft Tissue, Unspecified
subjects affected / exposed	2 / 191 (1.05%)	1 / 188 (0.53%)	3 / 190 (1.58%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
Additional description: Inflammation/damage of muscle
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis (avascular necrosis)
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	0 / 190 (0.00%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Febrile neutropenia
Additional description: Fever of unknown origin without clinically or microbiologically documented infection (ANC <1.0 x 10e9/L, fever >=38.5 degrees C)
subjects affected / exposed	10 / 191 (5.24%)	9 / 188 (4.79%)	14 / 190 (7.37%)	9 / 188 (4.79%)
occurrences causally related to treatment / all	10 / 10	9 / 9	14 / 14	9 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils
Additional description: (ANC <1.0 x 10e9/L)
subjects affected / exposed	10 / 191 (5.24%)	7 / 188 (3.72%)	2 / 190 (1.05%)	4 / 188 (2.13%)
occurrences causally related to treatment / all	9 / 10	7 / 7	2 / 2	2 / 4
deaths causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
Infection, Unspecified
subjects affected / exposed	0 / 191 (0.00%)	6 / 188 (3.19%)	5 / 190 (2.63%)	2 / 188 (1.06%)
occurrences causally related to treatment / all	0 / 0	4 / 6	4 / 5	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Infection with normal ANC or Grade 1 or 2 neutrophils
subjects affected / exposed	5 / 191 (2.62%)	6 / 188 (3.19%)	5 / 190 (2.63%)	6 / 188 (3.19%)
occurrences causally related to treatment / all	3 / 5	3 / 6	5 / 6	4 / 7
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 1	1 / 1
Infection with unknown ANC
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	1 / 190 (0.53%)	3 / 188 (1.60%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Metabolism and nutrition disorders
Hypercalcaemia
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	0 / 190 (0.00%)	5 / 188 (2.66%)
occurrences causally related to treatment / all	0 / 0	2 / 3	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Creatinine blood test abnormality
subjects affected / exposed	0 / 191 (0.00%)	1 / 188 (0.53%)	1 / 190 (0.53%)	1 / 188 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic/Laboratory, Unspecified
subjects affected / exposed	0 / 191 (0.00%)	0 / 188 (0.00%)	1 / 190 (0.53%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 191 (0.52%)	0 / 188 (0.00%)	0 / 190 (0.00%)	0 / 188 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 2%

Non-serious adverse events	Arm A	Arm B	Arm C	Arm D
Total subjects affected by non serious adverse events
subjects affected / exposed	81 / 191 (42.41%)	72 / 188 (38.30%)	76 / 190 (40.00%)	73 / 188 (38.83%)
Nervous system disorders
Sensory neuropathy
subjects affected / exposed	3 / 191 (1.57%)	1 / 188 (0.53%)	5 / 190 (2.63%)	3 / 188 (1.60%)
occurrences all number	3	1	7	3
Blood and lymphatic system disorders
Oedema peripheral
subjects affected / exposed	5 / 191 (2.62%)	4 / 188 (2.13%)	5 / 190 (2.63%)	4 / 188 (2.13%)
occurrences all number	7	4	5	10
Haemoglobin
subjects affected / exposed	5 / 191 (2.62%)	9 / 188 (4.79%)	7 / 190 (3.68%)	8 / 188 (4.26%)
occurrences all number	6	15	11	16
Neutrophils/granulocytes (ANC/AGC)
subjects affected / exposed	8 / 191 (4.19%)	7 / 188 (3.72%)	10 / 190 (5.26%)	8 / 188 (4.26%)
occurrences all number	12	7	12	8
General disorders and administration site conditions
Fatigue
subjects affected / exposed	11 / 191 (5.76%)	13 / 188 (6.91%)	17 / 190 (8.95%)	10 / 188 (5.32%)
occurrences all number	14	14	23	12
Pain
subjects affected / exposed	23 / 191 (12.04%)	13 / 188 (6.91%)	22 / 190 (11.58%)	16 / 188 (8.51%)
occurrences all number	35	23	31	25
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	7 / 191 (3.66%)	4 / 188 (2.13%)	7 / 190 (3.68%)	5 / 188 (2.66%)
occurrences all number	7	4	7	6
Nausea
subjects affected / exposed	7 / 191 (3.66%)	4 / 188 (2.13%)	2 / 190 (1.05%)	4 / 188 (2.13%)
occurrences all number	10	5	2	4
Vomiting
subjects affected / exposed	6 / 191 (3.14%)	4 / 188 (2.13%)	1 / 190 (0.53%)	3 / 188 (1.60%)
occurrences all number	6	4	1	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	7 / 191 (3.66%)	3 / 188 (1.60%)	2 / 190 (1.05%)	0 / 188 (0.00%)
occurrences all number	8	3	2	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	4 / 191 (2.09%)	4 / 188 (2.13%)	4 / 190 (2.11%)	2 / 188 (1.06%)
occurrences all number	4	7	6	2
Renal and urinary disorders
Urinary frequency/urgency
subjects affected / exposed	0 / 191 (0.00%)	3 / 188 (1.60%)	1 / 190 (0.53%)	4 / 188 (2.13%)
occurrences all number	0	4	1	4
Infections and infestations
Febrile neutropenia
subjects affected / exposed	10 / 191 (5.24%)	6 / 188 (3.19%)	7 / 190 (3.68%)	6 / 188 (3.19%)
occurrences all number	15	8	8	6
Infection
Additional description: Unknown ANC
subjects affected / exposed	4 / 191 (2.09%)	5 / 188 (2.66%)	7 / 190 (3.68%)	4 / 188 (2.13%)
occurrences all number	5	5	7	5
Metabolism and nutrition disorders
Alkaline phosphatase
subjects affected / exposed	3 / 191 (1.57%)	4 / 188 (2.13%)	6 / 190 (3.16%)	3 / 188 (1.60%)
occurrences all number	4	8	9	5

More information

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Were there any global substantial amendments to the protocol? Yes

23 Mar 2005

PHASE II PROTOCOL • Change to the eligibility criteria to enable patients to enter the study without the need for a confirmation prostate biopsy if they have confirmed bone disease with a PSA value > 100ng/ml. • Change to wording of baseline and post chemotherapy assessment requirements will allow centres to take part in the study without the need to perform clinical procedures if local facilities are not available.

07 Jun 2005

• Safety amendment to clarification of zoledronic acid dose procedures to comply with SmPC.

04 May 2007

• Changes to the inclusion criteria clarified patient eligibility regarding abnormal ALT and AST levels. • The requirement for a confirmed Serum Testosterone blood test was removed from the screening procedures. • A new entry criteria question was added to ensure that at time of study entry all patients were fit enough to receive any of the trial treatments, in the opinion of the investigator. • Clarification of administration sequence of trial treatments.

24 Sep 2008

PHASE III PROTOCOL • The majority of the changes related to the transition from a phase II to a phase III clinical trial, covering trial infrastructure, data collection procedures and statistical considerations. These changes had no direct impact on patient participation or safety, but did increase the maximum number of chemotherapy cycles from 6 to10, according to NICE guidelines for docetaxel chemotherapy.

12 Apr 2011

• This amendment concerns a statistical redesign of the phase III trial from a 4 arm comparison to a 2 by 2 factorial design to assess treatment efficacy. • Reduction of target recruitment from 1240 (as per version 8 amendment) to 618 evaluable patients. The trial will close to recruitment at the end of February 2012.

25 May 2011

• This amendment concerns a correction in section 12.2.3 on timing of analysis. We intend to conduct initial analysis once all patients have at least 1 year’s follow-up not 2 years as previously stated.

17 Feb 2012

Substantial amendments : • Changing the requirement for both ALT and AST to be tested – only one of them needs to have been performed. • Change of definition for skeletal related event-free interval and pain progression-free interval, and removal of the event of death as a skeletal related event and element of pain progression criteria. Non-substantial amendments : • Clarification of prophylactic anti-emetic for nausea/vomiting due to chemotherapy, and permission to use local protocols that coincide with off-study practice. • Additional safety information for zoledronic acid administration. • Updating of Deputy Clinical Co-ordinators details.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Describe any significant limitations of the trial (e.g. early termination leading to a small number of subjects analysed; technical problems with measurement leading to unreliable, or uninterpretable data).

http://www.ncbi.nlm.nih.gov/pubmed/27434595
http://www.ncbi.nlm.nih.gov/pubmed/26794729
http://www.ncbi.nlm.nih.gov/pubmed/27256016

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Baseline characteristics

Baseline characteristics

End points

End points

Primary: Clinical Progression-Free Survival (CPFS) - ZA comparison

Primary: Clinical Progression-Free Survival (CPFS) - ZA comparison

Primary: Clinical Progression-Free Survival (CPFS) - Sr89 comparison

Primary: Clinical Progression-Free Survival (CPFS) - Sr89 comparison

Primary: Cost-effectiveness ICER per additional QALY - ZA & Sr89

Primary: Cost-effectiveness ICER per additional QALY - ZA & Sr89

Secondary: Skeletal-related event-free interval(SREFI) - ZA

Secondary: Skeletal-related event-free interval(SREFI) - ZA

Secondary: Skeletal-related event-free interval(SREFI) - Sr89

Secondary: Skeletal-related event-free interval(SREFI) - Sr89

Secondary: Pain progression-free interval- ZA

Secondary: Pain progression-free interval- ZA

Secondary: Pain progression-free interval- Sr89

Secondary: Pain progression-free interval- Sr89

Secondary: Overall survival (OS) -- ZA

Secondary: Overall survival (OS) -- ZA

Secondary: Overall survival (OS) -- Sr89

Secondary: Overall survival (OS) -- Sr89

Secondary: Quality-Adjusted Survival - ZA

Secondary: Quality-Adjusted Survival - ZA

Secondary: Quality Adjusted Survival - Sr89

Secondary: Quality Adjusted Survival - Sr89

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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