A Phase I/II Study of Cediranib (AZD2171) in Japanese Metastatic Colorectal Cancer Patients in Combination With FOLFOX

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00494221
• Collaborator: (none)
• Enrollment: 172
• Locations: 2
• Arms: 3
• Duration (Months): 62
• Patients Per Site: 86
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This Study is in two parts, the first part is to make sure that combining a potential new treatment, cediranib (AZD2171), with a standard treatment (FOLFOX) for metastatic colorectal cancer is safe. Once this part is complete and it is decided that it is safe to continue the Study will the go on to look at the efficacy of the two drugs together. This will be done by studying two treatment options. One will be the standard treatment alone (FOLFOX) + dummy cediranib (AZD2171) tablets and the other will be the standard treatment (FOLFOX) + real cediranib (AZD2171) tablets. Using dummy tablets means the study is 'blinded' and that non-one can tell the difference between the two treatment groups. This kind of study design is done to try to avoid the chance that the results might be biased in some way. The overall aim of the second part of the study is to see if adding cediranib (AZD2171) to a standard treatment for Metastatic Colorectal Cancer (mCRC), in this case FOLFOX, gives better results. That is, it's better than giving standard treatment alone in helping to prevent progression of mCRC.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: AZD2171; Drug: FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin); Drug: Placebo Cediranib	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 172 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Two Part Study in Japanese Patients With mCRC, Consisting of an Open-label Phase I Part to Assess the Safety and Tolerability of Cediranib (AZD2171) in Combination With FOLFOX Followed by a Phase II, Randomised, Double-blind, Parallel Group Study to Assess the Efficacy of Cediranib (AZD2171) in Combination With FOLFOX
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Aug 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: FOLFOX + Cediranib 20 mg FOLFOX + Cediranib 20 mg	Drug: AZD2171; oral tablet; Other Names: cediranib RECENTIN™ ; Drug: FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin); intravenous infusion; Other Names: Eloxatin® 5-FU Leucovorin
Active Comparator: FOLFOX + Cediranib 30 mg FOLFOX + Cediranib 30 mg	Drug: AZD2171; oral tablet; Other Names: cediranib RECENTIN™ ; Drug: FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin); intravenous infusion; Other Names: Eloxatin® 5-FU Leucovorin
Placebo Comparator: FOLFOX + Placebo Cediranib FOLFOX + Placebo Cediranib	Drug: FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin); intravenous infusion; Other Names: Eloxatin® 5-FU Leucovorin ; Drug: Placebo Cediranib; oral tablet

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival [RECIST at Baseline, Weeks 6, 12, 18, 24 and then every 12 weeks until progression through to a cut-off date of 13th Oct 2009 (based on approx 105 progression events observed across the 3 groups)]

   Number of months from randomisation until progressive disease based on RECIST (progression of target lesions, clear progression of existing non-target lesions or the appearance of one or more new lesions) or death in the absence of progression.

Secondary Outcome Measures

1. Objective Tumour Response Rate [RECIST at Baseline, Weeks 6, 12, 18, 24 and then every 12 weeks until progression through to a cut-off date of 13th Oct 2009 (based on approx 105 progression events observed across the 3 groups)]

   Number of patients with complete (CR) /partial response (PR) (based on RECIST). CR is defined as Disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of Longest Diameter (LD) of target lesions taking as reference the baseline sum LD.

2. Best Percentage Change in Tumour Size [Randomisation until cut-off date 13OCT2009 (based on approximately 105 progression events observed across the 3 groups)]

   Best percentage change in tumour size from baseline, based on the sum of the longest diameters of the target lesions

3. Duration of Response [RECIST at Baseline, Weeks 6, 12, 18, 24 and then every 12 weeks until progression through to a cut-off date of 13th Oct 2009 (based on approx 105 progression events observed across the 3 groups)]

   Number of months from Complete/Partial response until progression up to cut-off date 13OCT2009 (based on approximately 105 progression events observed across the 3 groups).

4. Overall Survival [Randomisation until cut-off date 13OCT2009 (based on approximately 105 progression events observed across the 3 groups)]

   Number of months until death (censored if still alive at date cut-off). Median non-estimable if >50% of subjects within a group are censored.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Metastatic colorectal cancer

• WHO performance status 0-1

• Life expectancy is 12 weeks or longer

Exclusion Criteria:

• Patient with uncontrolled brain metastases

• Patient with inappropriate laboratory tests values

• Patient with poorly controlled hypertension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Osaka		Japan
2	Research Site	Saitama		Japan

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Jane Robertson, AstraZeneca
• Principal Investigator: Hideyuki Mishima, M.D., PhD, National Hospital Organization Osaka National Hospital
• Study Chair: Xiaojin Shi, MD, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• CSR-D8480C00039.pdf

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00494221
• Other Study ID Numbers: D8480C00039
• First Posted: Jun 29, 2007
• Last Update Posted: Mar 27, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by AstraZeneca: Colorectal cancer; Recentin; Metastatic Cancer; FOLFOX
• Additional relevant MeSH terms: Colorectal Neoplasms; Leucovorin; Fluorouracil; Oxaliplatin; Cediranib; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	Randomised=ITT=Safety: Cediranib 20mg=58, Cediranib 30mg=56, Placebo=58
Pre-assignment Detail	PFS & OS: median based on Kaplan Meier analysis (i.e. adjusted for censored observations) but full range based on raw data (i.e. not adjusted for censored observations). OS: median non-estimable due to censored observations

Arm/Group Title	Cediranib 20 mg	Cediranib 30 mg	Placebo
Arm/Group Description	FOLFOX + Cediranib 20 mg	FOLFOX + Cediranib 30 mg	FOLFOX + Placebo
Period Title: Overall Study
STARTED	58	56	58
COMPLETED	42	45	44
NOT COMPLETED	16	11	14

Baseline Characteristics

Arm/Group Title	Cediranib 20 mg	Cediranib 30 mg	Placebo	Total
Arm/Group Description	FOLFOX + Cediranib 20 mg	FOLFOX + Cediranib 30 mg	FOLFOX + Placebo	Total of all reporting groups
Overall Participants	58	56	58	172
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.4 (9.3)	62.1 (9.9)	62.2 (9.6)	62.2 (9.5)
Sex: Female, Male (Count of Participants)
Female	20 34.5%	26 46.4%	19 32.8%	65 37.8%
Male	38 65.5%	30 53.6%	39 67.2%	107 62.2%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival
Description	Number of months from randomisation until progressive disease based on RECIST (progression of target lesions, clear progression of existing non-target lesions or the appearance of one or more new lesions) or death in the absence of progression.
Time Frame	RECIST at Baseline, Weeks 6, 12, 18, 24 and then every 12 weeks until progression through to a cut-off date of 13th Oct 2009 (based on approx 105 progression events observed across the 3 groups)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cediranib 20 mg	Cediranib 30 mg	Placebo
Arm/Group Description	FOLFOX + Cediranib 20 mg	FOLFOX + Cediranib 30 mg	FOLFOX + Placebo
Measure Participants	58	56	58
Median (Full Range) [Months]	10.23	8.85	8.32

2. Secondary Outcome

Title	Objective Tumour Response Rate
Description	Number of patients with complete (CR) /partial response (PR) (based on RECIST). CR is defined as Disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of Longest Diameter (LD) of target lesions taking as reference the baseline sum LD.
Time Frame	RECIST at Baseline, Weeks 6, 12, 18, 24 and then every 12 weeks until progression through to a cut-off date of 13th Oct 2009 (based on approx 105 progression events observed across the 3 groups)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cediranib 20 mg	Cediranib 30 mg	Placebo
Arm/Group Description	FOLFOX + Cediranib 20 mg	FOLFOX + Cediranib 30 mg	FOLFOX + Placebo
Measure Participants	58	56	58
Number [Participants]	31 53.4%	39 69.6%	31 53.4%

3. Secondary Outcome

Title	Best Percentage Change in Tumour Size
Description	Best percentage change in tumour size from baseline, based on the sum of the longest diameters of the target lesions
Time Frame	Randomisation until cut-off date 13OCT2009 (based on approximately 105 progression events observed across the 3 groups)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cediranib 20 mg	Cediranib 30 mg	Placebo
Arm/Group Description	FOLFOX + Cediranib 20 mg	FOLFOX + Cediranib 30 mg	FOLFOX + Placebo
Measure Participants	58	54	57
Mean (Standard Deviation) [Percentage]	-36.56 (24.52)	-43.99 (22.62)	-40.22 (35.84)

4. Secondary Outcome

Title	Duration of Response
Description	Number of months from Complete/Partial response until progression up to cut-off date 13OCT2009 (based on approximately 105 progression events observed across the 3 groups).
Time Frame	RECIST at Baseline, Weeks 6, 12, 18, 24 and then every 12 weeks until progression through to a cut-off date of 13th Oct 2009 (based on approx 105 progression events observed across the 3 groups)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cediranib 20 mg	Cediranib 30 mg	Placebo
Arm/Group Description	FOLFOX + Cediranib 20 mg	FOLFOX + Cediranib 30 mg	FOLFOX + Placebo
Measure Participants	31	39	31
Mean (Standard Deviation) [Months]	13.26 (16.81)	8.12 (6.18)	10.42 (10.97)

5. Secondary Outcome

Title	Overall Survival
Description	Number of months until death (censored if still alive at date cut-off). Median non-estimable if >50% of subjects within a group are censored.
Time Frame	Randomisation until cut-off date 13OCT2009 (based on approximately 105 progression events observed across the 3 groups)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cediranib 20 mg	Cediranib 30 mg	Placebo
Arm/Group Description	FOLFOX + Cediranib 20 mg	FOLFOX + Cediranib 30 mg	FOLFOX + Placebo
Measure Participants	58	56	58
Median (Full Range) [Months]	NA	20.07	19.51

Adverse Events

Arm/Group Title	Cediranib 20 mg		Cediranib 30 mg		Placebo
Arm/Group Description	Cediranib 20 mg		Cediranib 30 mg		Placebo
All Cause Mortality
	Cediranib 20 mg		Cediranib 30 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cediranib 20 mg		Cediranib 30 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/58 (39.7%)		22/56 (39.3%)		11/58 (19%)
Blood and lymphatic system disorders
Anaemia	0/58 (0%)		0/56 (0%)		1/58 (1.7%)
Febrile Neutropenia	1/58 (1.7%)		0/56 (0%)		1/58 (1.7%)
Cardiac disorders
Cardiac Failure	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Prinzmetal Angina	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Gastrointestinal disorders
Ileus	2/58 (3.4%)		0/56 (0%)		4/58 (6.9%)
Nausea	4/58 (6.9%)		2/56 (3.6%)		1/58 (1.7%)
Vomiting	2/58 (3.4%)		3/56 (5.4%)		1/58 (1.7%)
Diarrhoea	2/58 (3.4%)		2/56 (3.6%)		0/58 (0%)
Abdominal Pain	1/58 (1.7%)		1/56 (1.8%)		0/58 (0%)
Anal Haemorrhage	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Constipation	0/58 (0%)		0/56 (0%)		1/58 (1.7%)
Duodenal Perforation	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Gastritis	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Large Intestine Perforation	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Mesenteric Artery Thrombosis	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Peritonitis	0/58 (0%)		0/56 (0%)		1/58 (1.7%)
Stomatitis	1/58 (1.7%)		1/56 (1.8%)		0/58 (0%)
Subileus	0/58 (0%)		0/56 (0%)		1/58 (1.7%)
General disorders
Pyrexia	3/58 (5.2%)		0/56 (0%)		0/58 (0%)
Fatigue	2/58 (3.4%)		2/56 (3.6%)		0/58 (0%)
Malaise	0/58 (0%)		0/56 (0%)		2/58 (3.4%)
Hepatobiliary disorders
Cholecystitis	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Hepatic Function Abnormal	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Immune system disorders
Anaphylactic Shock	0/58 (0%)		0/56 (0%)		1/58 (1.7%)
Infections and infestations
Pneumonia	2/58 (3.4%)		1/56 (1.8%)		0/58 (0%)
Abdominal Abscess	0/58 (0%)		0/56 (0%)		1/58 (1.7%)
Catheter Site Infection	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Wound Infection	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Injury, poisoning and procedural complications
Postoperative Ileus	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Investigations
Weight Decreased	2/58 (3.4%)		0/56 (0%)		0/58 (0%)
Blood Creatinine Increased	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Metabolism and nutrition disorders
Decreased Appetite	10/58 (17.2%)		5/56 (8.9%)		2/58 (3.4%)
Dehydration	2/58 (3.4%)		0/56 (0%)		0/58 (0%)
Hyperglycaemia	0/58 (0%)		0/56 (0%)		1/58 (1.7%)
Musculoskeletal and connective tissue disorders
Back Pain	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile Duct Cancer	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Nervous system disorders
Altered State Of Consciousness	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Brain Stem Infarction	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Cerebral Haemorrhage	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Dizziness	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Peripheral Sensory Neuropathy	0/58 (0%)		0/56 (0%)		1/58 (1.7%)
Reversible Posterior Leukoencephalopathy Syndrome	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Psychiatric disorders
Disorientation	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Renal and urinary disorders
Renal Failure Acute	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Respiratory, thoracic and mediastinal disorders
Chylothorax	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Dyspnoea Exertional	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Interstitial Lung Disease	1/58 (1.7%)		1/56 (1.8%)		0/58 (0%)
Pneumonia Aspiration	1/58 (1.7%)		0/56 (0%)		0/58 (0%)
Pneumonitis	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Vascular disorders
Hypertension	0/58 (0%)		1/56 (1.8%)		0/58 (0%)
Other (Not Including Serious) Adverse Events
	Cediranib 20 mg		Cediranib 30 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/58 (100%)		56/56 (100%)		58/58 (100%)
Blood and lymphatic system disorders
Anaemia	6/58 (10.3%)		7/56 (12.5%)		3/58 (5.2%)
Neutropenia	6/58 (10.3%)		3/56 (5.4%)		1/58 (1.7%)
Endocrine disorders
Hypothyroidism	5/58 (8.6%)		6/56 (10.7%)		1/58 (1.7%)
Gastrointestinal disorders
Diarrhoea	52/58 (89.7%)		48/56 (85.7%)		22/58 (37.9%)
Nausea	37/58 (63.8%)		36/56 (64.3%)		37/58 (63.8%)
Stomatitis	32/58 (55.2%)		29/56 (51.8%)		25/58 (43.1%)
Vomiting	23/58 (39.7%)		27/56 (48.2%)		14/58 (24.1%)
Constipation	21/58 (36.2%)		14/56 (25%)		15/58 (25.9%)
Abdominal Pain Upper	3/58 (5.2%)		4/56 (7.1%)		8/58 (13.8%)
Haemorrhoids	6/58 (10.3%)		0/56 (0%)		1/58 (1.7%)
Abdominal Pain	3/58 (5.2%)		5/56 (8.9%)		4/58 (6.9%)
Cheilitis	5/58 (8.6%)		3/56 (5.4%)		4/58 (6.9%)
Gingivitis	5/58 (8.6%)		5/56 (8.9%)		1/58 (1.7%)
Dental Caries	4/58 (6.9%)		0/56 (0%)		1/58 (1.7%)
Dyspepsia	0/58 (0%)		3/56 (5.4%)		4/58 (6.9%)
Periodontitis	4/58 (6.9%)		1/56 (1.8%)		0/58 (0%)
Abdominal Distension	1/58 (1.7%)		3/56 (5.4%)		0/58 (0%)
Anal Haemorrhage	2/58 (3.4%)		3/56 (5.4%)		1/58 (1.7%)
Ascites	3/58 (5.2%)		1/56 (1.8%)		0/58 (0%)
Glossitis	3/58 (5.2%)		1/56 (1.8%)		1/58 (1.7%)
Toothache	3/58 (5.2%)		1/56 (1.8%)		2/58 (3.4%)
General disorders
Fatigue	38/58 (65.5%)		40/56 (71.4%)		36/58 (62.1%)
Pyrexia	8/58 (13.8%)		12/56 (21.4%)		11/58 (19%)
Oedema Peripheral	5/58 (8.6%)		7/56 (12.5%)		2/58 (3.4%)
Influenza Like Illness	4/58 (6.9%)		3/56 (5.4%)		5/58 (8.6%)
Mucosal Inflammation	3/58 (5.2%)		1/56 (1.8%)		1/58 (1.7%)
Hepatobiliary disorders
Hepatic Function Abnormal	3/58 (5.2%)		3/56 (5.4%)		0/58 (0%)
Immune system disorders
Drug Hypersensitivity	6/58 (10.3%)		9/56 (16.1%)		12/58 (20.7%)
Infections and infestations
Nasopharyngitis	14/58 (24.1%)		10/56 (17.9%)		6/58 (10.3%)
Oral Candidiasis	4/58 (6.9%)		1/56 (1.8%)		0/58 (0%)
Cystitis	3/58 (5.2%)		0/56 (0%)		1/58 (1.7%)
Metabolism and nutrition disorders
Decreased Appetite	38/58 (65.5%)		42/56 (75%)		38/58 (65.5%)
Dehydration	3/58 (5.2%)		2/56 (3.6%)		0/58 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	11/58 (19%)		5/56 (8.9%)		5/58 (8.6%)
Musculoskeletal Pain	3/58 (5.2%)		4/56 (7.1%)		1/58 (1.7%)
Nervous system disorders
Neuropathy Peripheral	42/58 (72.4%)		35/56 (62.5%)		38/58 (65.5%)
Dysgeusia	18/58 (31%)		17/56 (30.4%)		18/58 (31%)
Peripheral Sensory Neuropathy	7/58 (12.1%)		15/56 (26.8%)		11/58 (19%)
Headache	6/58 (10.3%)		6/56 (10.7%)		6/58 (10.3%)
Psychiatric disorders
Insomnia	4/58 (6.9%)		2/56 (3.6%)		3/58 (5.2%)
Respiratory, thoracic and mediastinal disorders
Dysphonia	24/58 (41.4%)		16/56 (28.6%)		2/58 (3.4%)
Epistaxis	15/58 (25.9%)		19/56 (33.9%)		9/58 (15.5%)
Hiccups	7/58 (12.1%)		4/56 (7.1%)		6/58 (10.3%)
Upper Respiratory Tract Inflammation	0/58 (0%)		5/56 (8.9%)		2/58 (3.4%)
Cough	4/58 (6.9%)		3/56 (5.4%)		2/58 (3.4%)
Dyspnoea	1/58 (1.7%)		3/56 (5.4%)		0/58 (0%)
Oropharyngeal Pain	3/58 (5.2%)		2/56 (3.6%)		3/58 (5.2%)
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysaesthesia Syndrome	31/58 (53.4%)		34/56 (60.7%)		8/58 (13.8%)
Alopecia	12/58 (20.7%)		17/56 (30.4%)		15/58 (25.9%)
Rash	12/58 (20.7%)		12/56 (21.4%)		8/58 (13.8%)
Pigmentation Disorder	8/58 (13.8%)		5/56 (8.9%)		7/58 (12.1%)
Pruritus	4/58 (6.9%)		3/56 (5.4%)		7/58 (12.1%)
Skin Hyperpigmentation	4/58 (6.9%)		7/56 (12.5%)		4/58 (6.9%)
Dermatitis	5/58 (8.6%)		2/56 (3.6%)		2/58 (3.4%)
Urticaria	5/58 (8.6%)		0/56 (0%)		1/58 (1.7%)
Dermatitis Contact	4/58 (6.9%)		4/56 (7.1%)		1/58 (1.7%)
Haemorrhage Subcutaneous	4/58 (6.9%)		2/56 (3.6%)		0/58 (0%)
Vascular disorders
Hypertension	47/58 (81%)		47/56 (83.9%)		18/58 (31%)
Hypotension	3/58 (5.2%)		0/56 (0%)		0/58 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If a Study Site, or an investigator, requests permission to publish data from this study, any such publication (including oral presentations) is to be agreed with AstraZeneca prior to publication.