ENTHUSE M1: A Phase III Trial of ZD4054 (Zibotentan) (Endothelin A Antagonist) in Hormone Resistant Prostate Cancer With Bone Metastases

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00554229
• Collaborator: (none)
• Enrollment: 896
• Locations: 199
• Arms: 2
• Duration (Months): 45
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Enthuse M1 is a large phase III clinical trial studying the safety and efficacy of ZD4054 (Zibotentan) in patients with hormone resistant prostate cancer and bone metastases.

• This clinical trial will test if the Endothelin A Receptor Antagonist ZD4054 (Zibotentan) can improve survival compared with placebo.

• ZD4054(Zibotentan) is a new type of agent, which is thought to slow tumour growth and spread by blocking Endothelin A receptor activity. This trial will look at the effects of ZD4054 (Zibotentan) in hormone resistant prostate cancer patients with bone metastases.

• All patients participating in this clinical trial will receive existing standard prostate cancer treatments in addition to trial therapy.

• Half the patients will receive ZD4054 (Zibotentan), and half the patients will receive placebo in addition to standard prostate cancer therapy. By participating in this trial there is a 50% chance that patients will receive an agent that may slow the progression of the tumour.

• No patients will be deprived of standard prostate cancer therapy.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: ZD4054; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 896 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III Trial to Test the Efficacy of ZD4054(Zibotentan), an Endothelin A Receptor Antagonist, Versus Placebo in Patients With Hormone Resistant Prostate Cancer (HRPC) and Bone Metastasis Who Are Pain Free and Mildly Symptomatic.
• Study Start Date: Nov 1, 2007
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ZD4054 ZD4054 10 mg oral tablet once daily	Drug: ZD4054; ZD4054 10 mg oral tablet once daily; Other Names: Zibotentan
Placebo Comparator: Placebo Matching Placebo, oral tablets once daily	Drug: Placebo; Matching placebo oral tablet once daily

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From date of randomization until date of death, assessed up to 32 months]

   Median time (in months) from randomisation until death using the Kaplan-Meier method

Secondary Outcome Measures

1. Progression Free Survival [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 31 months]

   Median time (in months) from randomisation until clinical progression of disease, where progression is defined, using RECIST, as a measurable increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline, using the Kaplan-Meier method

2. Time to Use of Opiates [From date of randomization until use of opiates for disease-related symptoms for a duration ≥1 week, assessed up to 31 months]

   Median time (in months) from randomisation until use of opiates for disease-related symptoms for a duration ≥1 week using the Kaplan-Meier method

3. Incidence of Skeletal Related Events [From date of randomization until occurrence of a skeletal related event, assessed up to 31 months]

   Median time (in months) from randomisation until occurrence of a skeletal related event, where skeletal related event is defined as the first occurrence of a pathological fracture, a vertebral compression fracture not related to trauma, prophylactic surgery or radiation for impending fracture or spinal cord compression, or a spinal cord compression, using the Kaplan-Meier method.

4. Bone Metastases Formation [Patients were assessed every 12 weeks]

   Median time (in months) from randomisation to appearance of ≥4 new bone lesions using the Kaplan-Meier method

5. Health Related Quality of Life [Patients were assessed at every visit]

   Median time (in months) from randomisation until deterioration of Health related Quality of Life using the Kaplan-Meier method, where deterioration is defined as a change from baseline of less than or equal to -6 points in Total FACT-P score maintained for 2 consecutive visits.

6. Time to Prostate-specific Antigen (PSA) Progression [Patients were assessed every 12 weeks]

   Median time (in months) from randomisation to first PSA value >50% higher than baseline of at least 5ng/ml seen in at least 2 consecutive PSA values at least 2 weeks apart using the Kaplan-Meier method.

7. Time to Pain Progression [Patients were assessed every 12 weeks]

   Median time (in months) from randomisation to first assessment of an increased pain event, where increased pain event is defined as the first of a patient requiring opiate medication for duration of ≥1 week for pain due to prostate cancer metastasis, pain due to metastasis that has an increase in the worst pain item of the Brief Pain Inventory (BPI) from baseline to a minimum score of 5 with no decrease in analgesic use, or pain due to metastasis requiring radionuclide therapy, radiation therapy or surgery.

8. Time to Initiation of Chemotherapy [Patients were assessed every 12 weeks]

   Median time (in months) from randomisation to first administration of any chemotherapy using the Kaplan-Meier method

9. Pharmacokinetic Characteristics of ZD4054 [PK samples were performed at randomisation, Week 4, Week 8 and Week 12]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Patients who answer TRUE to the following criteria may be eligible to participate in this trial.

1. Confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate) that has spread to the bone (bone metastases)

2. Increasing Prostate Specific Antigen (PSA) over a one month period

3. No pain, or mild pain from prostate cancer

4. Currently receiving treatment with surgical or medical castration

Exclusion Criteria:

Patients who answer TRUE to the following may NOT eligible to participate in this trial.

1. Currently using opiates based pain killers)

2. Previous treatment with chemotherapy (paclitaxel, docetaxel, and mitoxantrone)

3. Suffering from heart failure or had a myocardial infarction within last 6 months

4. A history of epilepsy or seizures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Tucson	Arizona	United States
2	Research Site	Greenbrae	California	United States
3	Research Site	Los Angeles	California	United States
4	Research Site	Palm Springs	California	United States
5	Research Site	San Mateo	California	United States
6	Research Site	Norwich	Connecticut	United States
7	Research Site	Washington	District of Columbia	United States
8	Research Site	Gainsville	Florida	United States
9	Research Site	Port St.Lucie	Florida	United States
10	Research Site	Des Moines	Iowa	United States
11	Research Site	Canton	Ohio	United States
12	Research Site	Pittsburgh	Pennsylvania	United States
13	Research Site	Nashville	Tennessee	United States
14	Research Site	Salt Lake City	Utah	United States
15	Research Site	Burlington	Vermont	United States
16	Research Site	Norfolk	Virginia	United States
17	Research Site	Seattle	Washington	United States
18	Research Site	Wheeling	West Virginia	United States
19	Research Site	Milwaukee	Wisconsin	United States
20	Research Site	Buenos Aires	Buenos Aires Province	Argentina
21	Research Site	Santa Fe	Santa Fe Province	Argentina
22	Research Site	Hornsby	New South Wales	Australia
23	Research Site	St Leonards	New South Wales	Australia
24	Research Site	Redcliffe	Queensland	Australia
25	Research Site	Ashford	South Australia	Australia
26	Research Site	Subiaco	Western Australia	Australia
27	Research Site	Graz		Austria
28	Research Site	Wels		Austria
29	Research Site	Brussels		Belgium
30	Research Site	Gent		Belgium
31	Research Site	Kortrijk		Belgium
32	Research Site	Leuven		Belgium
33	Research Site	Fortaleza	Ceara	Brazil
34	Research Site	Goiania	Goias	Brazil
35	Research Site	Belo Horizonte	Minas Gerais	Brazil
36	Research Site	Curitiba	Parana	Brazil
37	Research Site	Porto Alegre	Rio Grande do Sul	Brazil
38	Research Site	Ribeirao Preto	Sao Paulo	Brazil
39	Research Site	Santo Andre	Sao Paulo	Brazil
40	Research Site	Sao Paulo		Brazil
41	Research Site	Calgary	Alberta	Canada
42	Research Site	Edmonton	Alberta	Canada
43	Research Site	Vancouver	British Columbia	Canada
44	Research Site	Kentville	Nova Scotia	Canada
45	Research Site	Barrie	Ontario	Canada
46	Research Site	Burlington	Ontario	Canada
47	Research Site	Hamilton	Ontario	Canada
48	Research Site	Kitchener	Ontario	Canada
49	Research Site	London	Ontario	Canada
50	Research Site	Mississauga	Ontario	Canada
51	Research Site	North York	Ontario	Canada
52	Research Site	Oakville	Ontario	Canada
53	Research Site	Ottawa	Ontario	Canada
54	Research Site	Toronto	Ontario	Canada
55	Research Site	Granby	Quebec	Canada
56	Research Site	Laval	Quebec	Canada
57	Research Site	Montreal	Quebec	Canada
58	Research Site	Point-Claire	Quebec	Canada
59	Research Site	Quebec City	Quebec	Canada
60	Research Site	Quebec		Canada
61	Research Site	Haidian District	Beijing	China
62	Research Site	Xi Cheng District	Beijing	China
63	Research Site	Xicheng District	Beijing	China
64	Research Site	Wuhan	Hubei	China
65	Research Site	Nanjing	Jiangsu	China
66	Research Site	Pudong New Area	Shanghai	China
67	Research Site	Shanghai	Shanghai	China
68	Research Site	Xuhui District	Shanghai	China
69	Research Site	Xi'an	Shanxi	China
70	Research Site	Prague 4	Prague	Czech Republic
71	Research Site	Prague 6	Prague	Czech Republic
72	Research Site	Brno		Czech Republic
73	Research Site	Olomouc		Czech Republic
74	Research Site	Usti nad Labem		Czech Republic
75	Research Site	Aalborg		Denmark
76	Research Site	Aarhus		Denmark
77	Research Site	Herlev		Denmark
78	Research Site	Kobenhavn		Denmark
79	Research Site	Joensuu		Finland
80	Research Site	Kajaanintie		Finland
81	Research Site	Tampere		Finland
82	Research Site	Montpellier		France
83	Research Site	Paris		France
84	Research Site	Poitiers Cedex		France
85	Research Site	Suresnes		France
86	Research Site	Toulouse		France
87	Research Site	Villejuif		France
88	Research Site	Planegg	Muenchen	Germany
89	Research Site	Kirchheim	Teck	Germany
90	Research Site	Augsburg		Germany
91	Research Site	Bad Gegeberg		Germany
92	Research Site	Berlin		Germany
93	Research Site	Emmendingen		Germany
94	Research Site	Leipzig		Germany
95	Research Site	Luebeck		Germany
96	Research Site	Mannheim		Germany
97	Research Site	Muenchen		Germany
98	Research Site	Reutlingen		Germany
99	Research Site	Hong Kong		Hong Kong
100	Research Site	Shatin		Hong Kong
101	Research Site	Tuen Mun		Hong Kong
102	Research Site	Budapest		Hungary
103	Research Site	Debrecen		Hungary
104	Research Site	Miskolc		Hungary
105	Research Site	Nyiregyhaza		Hungary
106	Research Site	Szeged		Hungary
107	Research Site	Rohini	Delhi	India
108	Research Site	Trivandrum	Kerala	India
109	Research Site	Bhopal	Madhya Pradesh	India
110	Research Site	Mumbai	Maharashtra	India
111	Research Site	Chandigarh	Punjab	India
112	Research Site	Ludhiana	Punjab	India
113	Research Site	Bikaner	Rajasthan	India
114	Research Site	Jaipur	Rajasthan	India
115	Research Site	Kolkota	West Bengal	India
116	Research Site	Gujarat		India
117	Research Site	New Delhi		India
118	Research Site	Milan		Italy
119	Research Site	Rome		Italy
120	Research Site	Asahi-City	Chiba	Japan
121	Research Site	Chiba-City	Chiba	Japan
122	Research Site	Narashino-city	Chiba	Japan
123	Research Site	Matsuyama-City	Ehime	Japan
124	Research Site	Fukuoka-City	Fukuoka	Japan
125	Research Site	Maebashi-City	Gunma	Japan
126	Research Site	Otake-City	Hiroshima	Japan
127	Research Site	Sapporo-City	Hokkaido	Japan
128	Research Site	Kobe-City	Hyogo	Japan
129	Research Site	Tsukuba-City	Ibaraki	Japan
130	Research Site	Kita-gun	Kagawa	Japan
131	Research Site	Sagamihara-City	Kanagawa	Japan
132	Research Site	Kyoto-City	Kyoto	Japan
133	Research Site	Sendai-City	Miyagi	Japan
134	Research Site	Oita-City	Oita	Japan
135	Research Site	Osaka-City	Osaka	Japan
136	Research Site	Osaka-Sayama-City	Osaka	Japan
137	Research Site	Suita-City	Osaka	Japan
138	Research Site	Wako-City	Saitama	Japan
139	Research Site	Hamamatsu-city	Shizuoka	Japan
140	Research Site	Sunto-gun	Shizuoka	Japan
141	Research Site	Bunkyo-ku	Tokyo	Japan
142	Research Site	Fuchu_city	Tokyo	Japan
143	Research Site	Itabashi-Ku	Tokyo	Japan
144	Research Site	Meguro-ku	Tokyo	Japan
145	Research Site	Mitaka-City	Tokyo	Japan
146	Research Site	Shinjuku-ku	Tokyo	Japan
147	Research Site	Nagasaki		Japan
148	Research Site	Heungduk-gu Cheongju	Chungbuk	Korea, Republic of
149	Research Site	Seongnam-si	Gyeonggi-do	Korea, Republic of
150	Research Site	Seo-gu	Pusan	Korea, Republic of
151	Research Site	Gangnam-gu	Seoul	Korea, Republic of
152	Research Site	Songpa-gu	Seoul	Korea, Republic of
153	Research Site	Metepec	Estado de Mexico	Mexico
154	Research Site	Distrito Federal Ciudad		Mexico
155	Research Site	Mexico City		Mexico
156	Research Site	Amsterdam		Netherlands
157	Research Site	Eindhoven		Netherlands
158	Research Site	Groningen		Netherlands
159	Research Site	Nijmegen		Netherlands
160	Research Site	Bialystok		Poland
161	Research Site	Koscierzyna		Poland
162	Research Site	Krakow		Poland
163	Research Site	Rzeszow		Poland
164	Research Site	Warszawa		Poland
165	Research Site	Wroclaw		Poland
166	Research Site	Coimbra		Portugal
167	Research Site	Lisboa		Portugal
168	Research Site	Porto		Portugal
169	Research Site	Stary Oskol	Belgorodskaya region	Russian Federation
170	Research Site	Barnaul		Russian Federation
171	Research Site	Izhevsk		Russian Federation
172	Research Site	Kursk		Russian Federation
173	Research Site	Moscow		Russian Federation
174	Research Site	Sochi		Russian Federation
175	Research Site	St. Petersgurg		Russian Federation
176	Research Site	Voronezh		Russian Federation
177	Research Site	Belgrade		Serbia
178	Research Site	Nis		Serbia
179	Research Site	Novi Sad		Serbia
180	Research Site	Singapore		Singapore
181	Research Site	Tygerberg	Cape Town	South Africa
182	Research Site	Bloemfontein		South Africa
183	Research Site	Pietermaritzburg		South Africa
184	Research Site	Port Elizabeth		South Africa
185	Research Site	Goteborg		Sweden
186	Research Site	Gothenburg		Sweden
187	Research Site	Stockholm		Sweden
188	Research Site	Basel		Switzerland
189	Research Site	Bern		Switzerland
190	Research Site	Locarno		Switzerland
191	Research Site	Sursee		Switzerland
192	Research Site	Kaohsiung		Taiwan
193	Research Site	Taipei		Taiwan
194	Research Site	Taoyuan		Taiwan
195	Research Site	Reading	Berkshire	United Kingdom
196	Research Site	Cambridge	Cambridgeshire	United Kingdom
197	Research Site	Maidstone	Kent	United Kingdom
198	Research Site	Huddersfield	Yorkshire	United Kingdom
199	Research Site	London		United Kingdom

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Martin Gleave, MD, FRCSC, FACS, The Prostate Centre at Vancouver General Hospital
• Principal Investigator: Joel B Nelson, MD, University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00554229
• Other Study ID Numbers: D4320C00014; 2007-003227-20; NCT00707395
• First Posted: Nov 6, 2007
• Last Update Posted: Feb 8, 2016
• Last Verified: Apr 1, 2012

• Keywords provided by AstraZeneca: Hormone Resistant Prostate Cancer; Endothelin A Receptor Antagonist; Endothelin A; Endothelin A antagonist
• Additional relevant MeSH terms: Prostatic Neoplasms

Study Results

Participant Flow

Recruitment Details	896 patients with hormone-resistant prostate cancer patients and bone metastasis were recruited between 20th November 2007 and 13th February 2009.
Pre-assignment Detail	302 of the 896 enrolled patients were not randomised to treatments groups as they failed screening.

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Period Title: Overall Study
STARTED	299	295
Patients Who Received Treatment	298	295
COMPLETED	73	70
NOT COMPLETED	226	225

Baseline Characteristics

Arm/Group Title	ZD4054	Placebo	Total
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily	Total of all reporting groups
Overall Participants	299	295	594
Age (Years) [Mean (Standard Deviation) ]
Overall	70.2 (7.8)	70.9 (8.6)	70.5 (8.2)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	299 100%	295 100%	594 100%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Median time (in months) from randomisation until death using the Kaplan-Meier method
Time Frame	From date of randomization until date of death, assessed up to 32 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Full Range) [months]	24.5	22.5

2. Secondary Outcome

Title	Progression Free Survival
Description	Median time (in months) from randomisation until clinical progression of disease, where progression is defined, using RECIST, as a measurable increase in the smallest dimension of any target or non-target lesion, or the appearance of new lesions, since baseline, using the Kaplan-Meier method
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 31 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Inter-Quartile Range) [Months]	6.2	6.5

3. Secondary Outcome

Title	Time to Use of Opiates
Description	Median time (in months) from randomisation until use of opiates for disease-related symptoms for a duration ≥1 week using the Kaplan-Meier method
Time Frame	From date of randomization until use of opiates for disease-related symptoms for a duration ≥1 week, assessed up to 31 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Inter-Quartile Range) [Months]	16.7	14.8

4. Secondary Outcome

Title	Incidence of Skeletal Related Events
Description	Median time (in months) from randomisation until occurrence of a skeletal related event, where skeletal related event is defined as the first occurrence of a pathological fracture, a vertebral compression fracture not related to trauma, prophylactic surgery or radiation for impending fracture or spinal cord compression, or a spinal cord compression, using the Kaplan-Meier method.
Time Frame	From date of randomization until occurrence of a skeletal related event, assessed up to 31 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Inter-Quartile Range) [Months]	18.4	17.1

5. Secondary Outcome

Title	Bone Metastases Formation
Description	Median time (in months) from randomisation to appearance of ≥4 new bone lesions using the Kaplan-Meier method
Time Frame	Patients were assessed every 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Inter-Quartile Range) [Months]	15.1	11.9

6. Secondary Outcome

Title	Health Related Quality of Life
Description	Median time (in months) from randomisation until deterioration of Health related Quality of Life using the Kaplan-Meier method, where deterioration is defined as a change from baseline of less than or equal to -6 points in Total FACT-P score maintained for 2 consecutive visits.
Time Frame	Patients were assessed at every visit

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Inter-Quartile Range) [Months]	5.5	5.5

7. Secondary Outcome

Title	Time to Prostate-specific Antigen (PSA) Progression
Description	Median time (in months) from randomisation to first PSA value >50% higher than baseline of at least 5ng/ml seen in at least 2 consecutive PSA values at least 2 weeks apart using the Kaplan-Meier method.
Time Frame	Patients were assessed every 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Inter-Quartile Range) [Months]	5.6	5.6

8. Secondary Outcome

Title	Time to Pain Progression
Description	Median time (in months) from randomisation to first assessment of an increased pain event, where increased pain event is defined as the first of a patient requiring opiate medication for duration of ≥1 week for pain due to prostate cancer metastasis, pain due to metastasis that has an increase in the worst pain item of the Brief Pain Inventory (BPI) from baseline to a minimum score of 5 with no decrease in analgesic use, or pain due to metastasis requiring radionuclide therapy, radiation therapy or surgery.
Time Frame	Patients were assessed every 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Inter-Quartile Range) [Months]	9.0	8.4

9. Secondary Outcome

Title	Time to Initiation of Chemotherapy
Description	Median time (in months) from randomisation to first administration of any chemotherapy using the Kaplan-Meier method
Time Frame	Patients were assessed every 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ZD4054	Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily	Placebo oral tablet once daily
Measure Participants	299	295
Median (Inter-Quartile Range) [Months]	11.4	10.6

10. Secondary Outcome

Title	Pharmacokinetic Characteristics of ZD4054
Time Frame	PK samples were performed at randomisation, Week 4, Week 8 and Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	ZD4054		Placebo
Arm/Group Description	ZD4054 10 mg oral tablet once daily		Placebo oral tablet once daily
All Cause Mortality
	ZD4054		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	ZD4054		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	98/298 (32.9%)		105/295 (35.6%)
Blood and lymphatic system disorders
Anaemia	6/298 (2%)		1/295 (0.3%)
Febrile Neutropenia	2/298 (0.7%)		3/295 (1%)
Neutropenia	2/298 (0.7%)		3/295 (1%)
Bone Marrow Failure	0/298 (0%)		1/295 (0.3%)
Disseminated Intravascular Coagulation	0/298 (0%)		1/295 (0.3%)
Leukopenia	0/298 (0%)		1/295 (0.3%)
Thrombocytopenia	1/298 (0.3%)		1/295 (0.3%)
Cardiac disorders
Cardiac Failure	6/298 (2%)		0/295 (0%)
Myocardial Infarction	3/298 (1%)		2/295 (0.7%)
Acute Myocardial Infarction	2/298 (0.7%)		0/295 (0%)
Left Ventricular Failure	0/298 (0%)		1/295 (0.3%)
Angina Unstable	1/298 (0.3%)		0/295 (0%)
Atrial Fibrillation	1/298 (0.3%)		1/295 (0.3%)
Atrial Flutter	1/298 (0.3%)		1/295 (0.3%)
Atrioventricular Block	1/298 (0.3%)		0/295 (0%)
Atrioventricular Block Complete	0/298 (0%)		1/295 (0.3%)
Cardiac Failure Acute	0/298 (0%)		1/295 (0.3%)
Cardiac Failure Congestive	1/298 (0.3%)		0/295 (0%)
Cardio-Respiratory Arrest	1/298 (0.3%)		0/295 (0%)
Coronary Artery Stenosis	0/298 (0%)		1/295 (0.3%)
Myocardial Ischaemia	0/298 (0%)		1/295 (0.3%)
Prinzmetal Angina	1/298 (0.3%)		0/295 (0%)
Right Ventricular Failure	1/298 (0.3%)		0/295 (0%)
Sick Sinus Syndrome	0/298 (0%)		1/295 (0.3%)
Supraventricular Tachycardia	1/298 (0.3%)		0/295 (0%)
Ventricular Tachycardia	1/298 (0.3%)		0/295 (0%)
Ear and labyrinth disorders
Sudden Hearing Loss	1/298 (0.3%)		0/295 (0%)
Eye disorders
Cataract	1/298 (0.3%)		0/295 (0%)
Retinal Detachment	1/298 (0.3%)		0/295 (0%)
Gastrointestinal disorders
Constipation	3/298 (1%)		1/295 (0.3%)
Diarrhoea	0/298 (0%)		2/295 (0.7%)
Abdominal Hernia	0/298 (0%)		1/295 (0.3%)
Abdominal Pain	0/298 (0%)		1/295 (0.3%)
Ascites	1/298 (0.3%)		0/295 (0%)
Colitis Ulcerative	0/298 (0%)		1/295 (0.3%)
Colonic Polyp	1/298 (0.3%)		0/295 (0%)
Duodenal Ulcer Perforation	1/298 (0.3%)		0/295 (0%)
Erosive Oesophagitis	0/298 (0%)		1/295 (0.3%)
Gastric Haemorrhage	1/298 (0.3%)		0/295 (0%)
Gastric Ulcer	0/298 (0%)		1/295 (0.3%)
Gastric Ulcer Haemorrhage	1/298 (0.3%)		0/295 (0%)
Gastritis Haemorrhagic	0/298 (0%)		1/295 (0.3%)
Gastrointestinal Haemorrhage	0/298 (0%)		1/295 (0.3%)
Haematemesis	0/298 (0%)		1/295 (0.3%)
Melaena	0/298 (0%)		1/295 (0.3%)
Nausea	1/298 (0.3%)		0/295 (0%)
Pancreatitis	1/298 (0.3%)		0/295 (0%)
Pancreatitis Acute	0/298 (0%)		1/295 (0.3%)
Peptic Ulcer Perforation	0/298 (0%)		1/295 (0.3%)
Retroperitoneal Haemorrhage	1/298 (0.3%)		0/295 (0%)
Vomiting	1/298 (0.3%)		1/295 (0.3%)
General disorders
Death	2/298 (0.7%)		7/295 (2.4%)
Pyrexia	3/298 (1%)		2/295 (0.7%)
Disease Progression	1/298 (0.3%)		2/295 (0.7%)
Oedema Peripheral	2/298 (0.7%)		0/295 (0%)
Asthenia	0/298 (0%)		1/295 (0.3%)
Chest Discomfort	0/298 (0%)		1/295 (0.3%)
Chest Pain	1/298 (0.3%)		0/295 (0%)
Fatigue	0/298 (0%)		1/295 (0.3%)
General Physical Health Deterioration	1/298 (0.3%)		0/295 (0%)
Malaise	1/298 (0.3%)		0/295 (0%)
Multi-Organ Failure	1/298 (0.3%)		0/295 (0%)
Non-Cardiac Chest Pain	1/298 (0.3%)		1/295 (0.3%)
Hepatobiliary disorders
Cholecystitis	0/298 (0%)		2/295 (0.7%)
Bile Duct Obstruction	0/298 (0%)		1/295 (0.3%)
Bile Duct Stone	1/298 (0.3%)		0/295 (0%)
Cholangitis	1/298 (0.3%)		0/295 (0%)
Infections and infestations
Pneumonia	6/298 (2%)		1/295 (0.3%)
Sepsis	3/298 (1%)		3/295 (1%)
Bronchopneumonia	2/298 (0.7%)		0/295 (0%)
Respiratory Tract Infection	0/298 (0%)		2/295 (0.7%)
Septic Shock	0/298 (0%)		2/295 (0.7%)
Abscess Jaw	0/298 (0%)		1/295 (0.3%)
Appendicitis	1/298 (0.3%)		0/295 (0%)
Bronchitis	1/298 (0.3%)		0/295 (0%)
Cellulitis	1/298 (0.3%)		0/295 (0%)
Gastroenteritis	0/298 (0%)		1/295 (0.3%)
Infected Cyst	1/298 (0.3%)		0/295 (0%)
Lower Respiratory Tract Infection	0/298 (0%)		1/295 (0.3%)
Lung Infection	0/298 (0%)		1/295 (0.3%)
Meningitis	1/298 (0.3%)		1/295 (0.3%)
Necrotising Fasciitis	1/298 (0.3%)		0/295 (0%)
Oesophageal Candidiasis	0/298 (0%)		1/295 (0.3%)
Post Procedural Infection	0/298 (0%)		1/295 (0.3%)
Staphylococcal Infection	0/298 (0%)		1/295 (0.3%)
Urinary Tract Infection	1/298 (0.3%)		1/295 (0.3%)
Urosepsis	1/298 (0.3%)		0/295 (0%)
Viral Pericarditis	0/298 (0%)		1/295 (0.3%)
Injury, poisoning and procedural complications
Hip Fracture	0/298 (0%)		2/295 (0.7%)
Subdural Haematoma	2/298 (0.7%)		1/295 (0.3%)
Cerebral Haemorrhage Traumatic	0/298 (0%)		1/295 (0.3%)
Cervical Vertebral Fracture	1/298 (0.3%)		1/295 (0.3%)
Cystitis Radiation	0/298 (0%)		1/295 (0.3%)
Femoral Neck Fracture	0/298 (0%)		1/295 (0.3%)
Fibula Fracture	0/298 (0%)		1/295 (0.3%)
Splenic Rupture	1/298 (0.3%)		0/295 (0%)
Subcutaneous Haematoma	0/298 (0%)		1/295 (0.3%)
Therapeutic Agent Toxicity	1/298 (0.3%)		0/295 (0%)
Metabolism and nutrition disorders
Hyponatraemia	0/298 (0%)		2/295 (0.7%)
Decreased Appetite	1/298 (0.3%)		1/295 (0.3%)
Dehydration	1/298 (0.3%)		1/295 (0.3%)
Diabetes Mellitus	0/298 (0%)		1/295 (0.3%)
Gout	1/298 (0.3%)		0/295 (0%)
Musculoskeletal and connective tissue disorders
Muscular Weakness	0/298 (0%)		2/295 (0.7%)
Back Pain	0/298 (0%)		1/295 (0.3%)
Intervertebral Disc Protrusion	0/298 (0%)		1/295 (0.3%)
Osteonecrosis Of Jaw	1/298 (0.3%)		0/295 (0%)
Pain In Extremity	0/298 (0%)		1/295 (0.3%)
Pathological Fracture	1/298 (0.3%)		0/295 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Myeloid Leukaemia	1/298 (0.3%)		1/295 (0.3%)
Bladder Transitional Cell Carcinoma	1/298 (0.3%)		0/295 (0%)
Colon Cancer	1/298 (0.3%)		0/295 (0%)
Gastric Cancer	0/298 (0%)		1/295 (0.3%)
Lung Neoplasm Malignant	0/298 (0%)		1/295 (0.3%)
Metastases To Spine	0/298 (0%)		1/295 (0.3%)
Neoplasm Progression	1/298 (0.3%)		0/295 (0%)
Oesophageal Carcinoma	1/298 (0.3%)		0/295 (0%)
Oesophageal Neoplasm	1/298 (0.3%)		0/295 (0%)
Nervous system disorders
Cerebrovascular Accident	3/298 (1%)		2/295 (0.7%)
Transient Ischaemic Attack	0/298 (0%)		2/295 (0.7%)
Cerebral Haemorrhage	1/298 (0.3%)		0/295 (0%)
Cerebral Infarction	0/298 (0%)		1/295 (0.3%)
Cerebral Ischaemia	0/298 (0%)		1/295 (0.3%)
Cerebral Thrombosis	1/298 (0.3%)		0/295 (0%)
Cerebrovascular Disorder	1/298 (0.3%)		0/295 (0%)
Convulsion	0/298 (0%)		1/295 (0.3%)
Headache	1/298 (0.3%)		0/295 (0%)
Lethargy	0/298 (0%)		1/295 (0.3%)
Loss Of Consciousness	1/298 (0.3%)		0/295 (0%)
Neuropathy Peripheral	1/298 (0.3%)		0/295 (0%)
Paraesthesia	0/298 (0%)		1/295 (0.3%)
Spinal Cord Compression	1/298 (0.3%)		1/295 (0.3%)
Trigeminal Neuralgia	0/298 (0%)		1/295 (0.3%)
Vith Nerve Paralysis	0/298 (0%)		1/295 (0.3%)
Psychiatric disorders
Completed Suicide	0/298 (0%)		1/295 (0.3%)
Delirium	0/298 (0%)		1/295 (0.3%)
Suicide Attempt	0/298 (0%)		1/295 (0.3%)
Renal and urinary disorders
Renal Failure Acute	1/298 (0.3%)		4/295 (1.4%)
Urinary Retention	3/298 (1%)		0/295 (0%)
Renal Failure	1/298 (0.3%)		2/295 (0.7%)
Anuria	0/298 (0%)		1/295 (0.3%)
Haematuria	0/298 (0%)		1/295 (0.3%)
Haemorrhage Urinary Tract	0/298 (0%)		1/295 (0.3%)
Hydronephrosis	1/298 (0.3%)		1/295 (0.3%)
Urethral Stenosis	0/298 (0%)		1/295 (0.3%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia	1/298 (0.3%)		0/295 (0%)
Priapism	0/298 (0%)		1/295 (0.3%)
Prostatic Haemorrhage	1/298 (0.3%)		0/295 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	5/298 (1.7%)		2/295 (0.7%)
Pleural Effusion	4/298 (1.3%)		0/295 (0%)
Chronic Obstructive Pulmonary Disease	0/298 (0%)		3/295 (1%)
Pneumonia Aspiration	0/298 (0%)		3/295 (1%)
Asthma	1/298 (0.3%)		0/295 (0%)
Dyspnoea	2/298 (0.7%)		2/295 (0.7%)
Pulmonary Oedema	2/298 (0.7%)		1/295 (0.3%)
Epistaxis	1/298 (0.3%)		0/295 (0%)
Hydrothorax	1/298 (0.3%)		0/295 (0%)
Interstitial Lung Disease	0/298 (0%)		1/295 (0.3%)
Obstructive Airways Disorder	0/298 (0%)		1/295 (0.3%)
Pulmonary Hypertension	1/298 (0.3%)		0/295 (0%)
Respiratory Failure	1/298 (0.3%)		1/295 (0.3%)
Upper Respiratory Tract Inflammation	1/298 (0.3%)		0/295 (0%)
Skin and subcutaneous tissue disorders
Decubitus Ulcer	0/298 (0%)		1/295 (0.3%)
Vascular disorders
Deep Vein Thrombosis	1/298 (0.3%)		2/295 (0.7%)
Aortic Dissection	0/298 (0%)		1/295 (0.3%)
Arteriosclerosis	0/298 (0%)		1/295 (0.3%)
Haematoma	1/298 (0.3%)		1/295 (0.3%)
Iliac Artery Occlusion	0/298 (0%)		1/295 (0.3%)
Lymphoedema	1/298 (0.3%)		0/295 (0%)
Phlebitis	0/298 (0%)		1/295 (0.3%)
Venous Thrombosis Limb	0/298 (0%)		1/295 (0.3%)
Other (Not Including Serious) Adverse Events
	ZD4054		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	257/298 (86.2%)		221/295 (74.9%)
Blood and lymphatic system disorders
Anaemia	46/298 (15.4%)		33/295 (11.2%)
Neutropenia	11/298 (3.7%)		16/295 (5.4%)
Gastrointestinal disorders
Nausea	62/298 (20.8%)		44/295 (14.9%)
Constipation	61/298 (20.5%)		51/295 (17.3%)
Diarrhoea	28/298 (9.4%)		46/295 (15.6%)
Vomiting	34/298 (11.4%)		23/295 (7.8%)
General disorders
Oedema Peripheral	132/298 (44.3%)		56/295 (19%)
Fatigue	58/298 (19.5%)		52/295 (17.6%)
Pyrexia	30/298 (10.1%)		22/295 (7.5%)
Asthenia	18/298 (6%)		22/295 (7.5%)
Infections and infestations
Rhinitis	35/298 (11.7%)		13/295 (4.4%)
Nasopharyngitis	28/298 (9.4%)		25/295 (8.5%)
Urinary Tract Infection	19/298 (6.4%)		24/295 (8.1%)
Weight Decreased	15/298 (5%)		13/295 (4.4%)
Metabolism and nutrition disorders
Decreased Appetite	44/298 (14.8%)		37/295 (12.5%)
Musculoskeletal and connective tissue disorders
Back Pain	35/298 (11.7%)		37/295 (12.5%)
Arthralgia	31/298 (10.4%)		32/295 (10.8%)
Pain In Extremity	22/298 (7.4%)		23/295 (7.8%)
Musculoskeletal Pain	15/298 (5%)		19/295 (6.4%)
Myalgia	12/298 (4%)		16/295 (5.4%)
Nervous system disorders
Headache	92/298 (30.9%)		37/295 (12.5%)
Hypoaesthesia	17/298 (5.7%)		8/295 (2.7%)
Dizziness	14/298 (4.7%)		16/295 (5.4%)
Dysgeusia	11/298 (3.7%)		17/295 (5.8%)
Psychiatric disorders
Insomnia	24/298 (8.1%)		19/295 (6.4%)
Renal and urinary disorders
Haematuria	20/298 (6.7%)		19/295 (6.4%)
Respiratory, thoracic and mediastinal disorders
Nasal Congestion	48/298 (16.1%)		9/295 (3.1%)
Dyspnoea	32/298 (10.7%)		20/295 (6.8%)
Cough	17/298 (5.7%)		17/295 (5.8%)
Skin and subcutaneous tissue disorders
Alopecia	24/298 (8.1%)		19/295 (6.4%)
Vascular disorders
Hypertension	11/298 (3.7%)		19/295 (6.4%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

AstraZeneca can review results communications prior to public release and may within 60 days of receipt require amendments to be made. AstraZeneca can also require that submission or disclosure be delayed to allow for the filing of a patent application.