Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer (VENICE)

• ClinicalTrials.gov Identifier: NCT00519285
• Recruitment Status: Completed
• First Posted: August 22, 2007
• Results First Posted: October 10, 2013
• Last Update Posted: July 22, 2016
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Conditions: Prostatic Neoplasms; Neoplasm Metastasis
• Interventions: Drug: Aflibercept; Drug: Placebo (for aflibercept); Drug: Docetaxel; Drug: Prednisone or Prednisolone
• Enrollment: 1224

Participant Flow

Recruitment Details	Between August 2007 and February 2010, a total of 1548 patients gave informed consent for this study.
Pre-assignment Details	Amongst these patients, a total of 324 were screening failures (primarily due to non-compliance with exclusion criteria) and did not get randomized.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Period Title: Overall Study
Started	612 [1]	612 [1]
TREATED	604 [2]	605 [3]
Still Treated at Cut-off Date	1 [4]	2
Completed	0 [5]	0
Not Completed	612	612
Reason Not Completed
Adverse Event	127	266
Disease progression	334	186
Physician Decision	75	47
Participant's request	53	84
Consent withdrawn	4	5
Poor compliance to protocol	5	7
Reason unspecified	5	8
Not treated	8	7
Treatment ongoing	1	2
[1] Randomized; [2] Received at least part of one dose of placebo; [3] Received at least part of one dose of aflibercept; [4] The cut-off date for analysis was defined as 07 February 2012, date at which 873 deaths has occurred; [5] Participants were treated until progressive disease, unacceptable toxicity, or refusal of treatment

Baseline Characteristics

Arm/Group Title		Placebo	Aflibercept	Total
Arm/Group Description		Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Total of all reporting groups
Overall Number of Baseline Participants		612	612	1224
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	612 participants	612 participants	1224 participants
		67.6 (8.0)	67.9 (7.8)	67.8 (7.9)
Age, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	612 participants	612 participants	1224 participants
<65 years		225	195	420
65-74 years		259	283	542
≥75 years		128	134	262
Sex/Gender, Customized; Measure Type: Number; Unit of measure: Participants
Male	Number Analyzed	612 participants	612 participants	1224 participants
		612	612	1224
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	612 participants	612 participants	1224 participants
Caucasian/White		552	560	1112
Black		17	15	32
Asian/Oriental		36	32	68
Other		7	5	12
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	612 participants	612 participants	1224 participants
Western Europe		219	227	446
Eastern Europe		131	132	263
North America		81	95	176
South America		88	71	159
Other region		93	87	180
Body Surface Area (BSA); Mean (Standard Deviation); Unit of measure: M²
	Number Analyzed	612 participants	612 participants	1224 participants
		2.0 (0.2)	2.0 (0.2)	2.0 (0.2)
Eastern Co-operative Group (ECOG) performance status [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	612 participants	612 participants	1224 participants
ECOG 0		285	283	568
ECOG 1		299	303	602
ECOG 2		28	26	54
		[1] Measure Description: ECOG performance status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 = Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours

Outcome Measures

1. Primary Outcome

Title	Overall Survival Time
Description	Overall survival (OS) time was measured as the time from date of randomization to the date of death due to any cause. The median OS time and its 95.6% confidence interval were estimated using the Kaplan-Meier method. In the absence of confirmation of death, the participant was censored at the last date he/she was known to be alive or the study cut-off date (when 873 deaths have occurred), whichever was earlier.
Time Frame	From randomization up to the cut-off date (median follow-up of 35.4 months)

Outcome Measure Data

Analysis Population Description

The analysis was performed on the Intent-to-treat (ITT) population (i.e all randomized participants according to the treatment assigned regardless of the drug actually received).

At the cut-off date, 873 deaths had occurred, 445 in the Placebo group and 428 in the Aflibercept group.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	612	612
Median (95% Confidence Interval); Unit of Measure: months
	21.22; (19.614 to 23.754)	22.14; (20.304 to 24.082)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Aflibercept
	Comments	Null hypothesis: No difference between aflibercept and placebo The study was designed to provide 90% power to detect a 1.25-fold increase in median survival with aflibercept compared to placebo at a overall one-sided significance level of 0.025 with 873 deaths.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3802
	Comments	A priori threshold for statistical significance was set to 0.044 using the O'Brien-Fleming alpha spending function to account for two interim analyses.
	Method	Log Rank
	Comments	Log rank test stratified on ECOG Performance Status
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.942
	Confidence Interval	(2-Sided) 95.6%; 0.822 to 1.08
	Estimation Comments	Hazard ratio (HR) aflibercept versus placebo estimated from a Cox proportional hazard model stratified on ECOG Performance Status

2. Secondary Outcome

Title	Prostate Specific Antigen Response Rate
Description	Prostate specific antigen (PSA) response was defined as ≥50% decrease from baseline in serum PSA levels, confirmed at least 3 weeks later. Increases of any magnitude during the first 12 weeks were ignored in determining PSA response.
Time Frame	Before randomization (baseline) then every 3 weeks up to PSA progression (≥25% increase) or the cut-off date, whichever occurred first

Outcome Measure Data

Analysis Population Description

The analysis was performed on the ITT population evaluable for PSA response (i.e. with a baseline PSA ≥10 ng/mL).

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	559	560
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	63.5; (59.5 to 67.5)	68.6; (64.7 to 72.4)

3. Secondary Outcome

Title	Time to Skeletal Related Events
Description	Skeletal Related Events (SRE) included pathological fractures and/or spinal cord compression, need for bone irradiation, including radioisotopes or bone surgery, change in antineoplastic therapy to treat bone pain. Time to SRE was defined as the time from the date of randomization to the date of occurence of the first event defining a SRE or death due to any cause, whichever occurred first. The median time to SRE and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of SRE, the participant was censored at the last date he/she was known to be alive or the study cut-off date, whichever was earlier.
Time Frame	From randomization up to the cut-off date (median follow-up of 35.4 months)

Outcome Measure Data

Analysis Population Description

The analysis was performed on the ITT population.

At the cut-off date, SRE or death had occurred in 1013 participants, 516 in the Placebo group and 497 in the Aflibercept group.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	612	612
Median (95% Confidence Interval); Unit of Measure: months
	14.98; (13.733 to 16.427)	15.31; (14.127 to 16.657)

4. Secondary Outcome

Title	Progression Free Survival Time
Description	Disease progression was defined as a composite of: Radiological tumor progression (≥20% increase in target lesions, or appearance of at least 2 new bone lesions); PSA progression (≥25% increase in PSA level confirmed 3 weeks later); Pain progression (increase in pain intensity or in analgesic consumption for cancer related pain confirmed 3 weeks later); Radiotherapy for cancer related symptoms; Occurence of Skeletal related events (SRE). Progression Free survival (PFS) time was measured as the time from the date of randomization up to the date of occurrence of the first event defining a disease progression or death due to any cause, whichever occurred first. The median PFS time and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of disease progression, the participant was censored at the the date of last assessment without evidence of progression or the study cut-off date, whichever was earlier.
Time Frame	From randomization up to the cut-off date (median follow-up of 35.4 months)

Outcome Measure Data

Analysis Population Description

The analysis was performed on the ITT population.

At the cut-off date, disease progression or death had occurred in 1184 participants, 592 in each treatment group.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	612	612
Median (95% Confidence Interval); Unit of Measure: months
	6.24; (5.585 to 6.899)	6.90; (6.209 to 7.359)

5. Secondary Outcome

Title	Tumor Response Rate in Participants With Measurable Disease
Description	Tumor response was defined as either a Complete Response (disappearance of all target lesions) or a Partial Response (≥30% decrease from baseline in target lesions) as assessed by Response Evaluation Criteria In Solid Tumors (RECIST)version 1.0.
Time Frame	Before randomization (baseline) then every 3 months up to tumor progression (≥25% increase) or the cut-off date, whichever occurred first

Outcome Measure Data

Analysis Population Description

The analysis was performed on the ITT population evaluable for tumor response (i.e. received at least one dose of study drugs (aflibercept/placebo or docetaxel), had no important deviations to protocol and was evaluable for response as per RECIST version 1.0).

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	320	323
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	28.1; (23.2 to 33.1)	38.7; (33.4 to 44.0)

6. Secondary Outcome

Title	Prostate Specific Antigen Progression-free Survival Time
Description	Prostate specific antigen (PSA) progression was defined as ≥25% increase in PSA level confirmed 3 weeks later, above the nadir in participants who had achieved a PSA response, or above the baseline in participants who hadn't achieved a PSA response. PSA progression-free survival (PFS) time was defined as the time from the date of randomization up to the date of the first documented PSA progression or death due to any cause, whichever occurred first. The median PSA-PFS time and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of PSA progression or death, the participant was censored at the the date of last assessment without evidence of progression or the study cut-off date, whichever was earlier.
Time Frame	From randomization up to the cut-off date (median follow-up of 35.4 months)

Outcome Measure Data

Analysis Population Description

The analysis was performed in the ITT population evaluable for PSA progression (i.e. with an evaluable baseline PSA).

At the cut-off date, PSA progression or death had occurred in 1138 participants, 571 in the Placebo group and 567 in the Aflibercept group.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	606	608
Median (95% Confidence Interval); Unit of Measure: months
	8.11; (7.622 to 8.575)	8.25; (7.819 to 8.772)

7. Secondary Outcome

Title	Pain Progression-free Survival Time
Description	Pain progression was defined as either ≥1-point increase in Present Pain Intensity (PPI) score or ≥25% increase in Analgesics Score (AS) confirmed at least 3 weeks later, or requirement for palliative radiotherapy. PPI scale is a self-report 0-5 scale to assess pain intensity - a score 0 reflects no pain, a score 5 reflects excruciating pain. AS is a scoring method to assess analgesics consumption. Each analgesic is scored 1 or 4 depending on the analgesic type and dose. AS is the sum of the analgesic scores. Pain progression-free survival (PFS) time was measured as the time from the date of randomization up to the date of first pain progression or death due to any cause, whichever occurred first. The median pain-PFS and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of event, the participant was censored at the the date of last assessment without evidence of pain progression or the study cut-off date, whichever was earlier.
Time Frame	From randomization up to the cut-off date (median follow-up of 35.4 months)

Outcome Measure Data

Analysis Population Description

The analysis was performed on the ITT population evaluable for pain progression (i.e. with no pain or with stable pain at baseline).

At the cut-off date, pain progression or death had occurred in 507 participants, 263 in the Placebo group and 244 in the Aflibercept group.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	301	287
Median (95% Confidence Interval); Unit of Measure: months
	9.72; (8.509 to 11.499)	9.20; (8.181 to 10.448)

8. Secondary Outcome

Title	Pain Response Rate
Description	Pain response was defined as either a ≥2-point decrease from baseline in Present Pain Intensity (PPI) score without increase in Analgesics Score (AS), or a ≥50% decrease from baseline in AS without increase in the PPI score confirmed at least 3 weeks later. Increases in PPI or AS during the first 12 weeks were ignored in determining pain response.
Time Frame	Before randomization (baseline) then every 3 weeks up to pain progression or the cut-off date, whichever occurred first

Outcome Measure Data

Analysis Population Description

The analysis was performed in the ITT population evaluable for pain response (i.e. stable analgesia at baseline and, baseline PPI ≥2 and/or baseline AS ≥10 points).

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	67	67
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	46.3; (34.3 to 58.2)	35.8; (24.3 to 47.3)

9. Secondary Outcome

Title	Change From Baseline in Functional Assessment of Cancer Therapy-Prostate Total Score as a Measure of Health Related Quality of Life
Description	Functional Assessment of Cancer Therapy-Prostate (FACT-P) is a 39-item participant questionnaire that measures the concerns of patients with prostate cancer. It consists of 5 subscales assessing physical well-being, social/family well-being, emotional well-being, functional well-being, and prostate-specific concerns. FACT-P total score is the sum of the 5 subscores. It ranges from 0 to 156 with higher score indicating better quality of life.
Time Frame	Before randomization (baseline) then every 3 weeks until disease progression or administration of further antitumor therapy, whichever came first

Outcome Measure Data

Analysis Population Description

The analysis was performed on the ITT population evaluable for Health related quality of life (i.e. with baseline and at least one post-baseline evaluable FACT-P questionnaire).

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	574	568
Mean (Standard Deviation); Unit of Measure: units on a scale
Change from baseline at cycle 1 (n =493, 461)	5.08 (12.73)	1.30 (15.70)
Change from baseline at cycle 2 (n =467, 437)	6.22 (14.50)	-0.03 (17.99)
Change from baseline at cycle 6 (n =293, 224)	5.50 (16.38)	-1.00 (16.85)
Change from baseline at cycle 10 (n =158, 117)	6.61 (16.35)	-1.60 (15.41)

10. Secondary Outcome

Title	Number of Participants With Adverse Events as a Measure of Safety
Description	Adverse Events (AE) are any unfavorable and unintended sign, symptom, syndrome or illness observed by the investigator or reported by the participant during the study. AE were collected at regular intervals throughout the study then graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.3.0).
Time Frame	From first dose of study treatment (aflibercept/placebo or docetaxel whichever came first) to last dose of study treatment (aflibercept/placebo or docetaxel whichever came last) + 30 days

Outcome Measure Data

Analysis Population Description

The analysis was performed on the safety population (i.e. all randomized and treated participants according to the treatment actually received). Six participants in the Placebo group who received at least one dose of aflibercept in error were considered in the Aflibercept group.

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	598	611
Measure Type: Number; Unit of Measure: participants
Any Adverse Event	585	607
- Grade 3-4 AE	290	470
- Serious AE	184	331
- AE leading to death	23	46
--- Related AE leading to death	8	19
- AE leading to permanent discontinuation	125	268
- AE leading to premature discontinuation	73	116

11. Secondary Outcome

Title	Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept
Description	Serum for detection of anti-drug antibodies (ADA) was collected in patients treated in selected centers only. Samples were analyzed using a titer-based, bridging immunoassay developed and validated to detect ADAs in human serum. Samples with positive antibody levels were further analyzed using a validated, non-quantitative ligand binding assay to detect neutralizing antibodies Ab). A participant was considered to have positive antibody levels if antibodies were detected above the quantification limits.
Time Frame	Pre-dose of cycle 1 (baseline), pre-dose of each every other cycle, then 30 and 90 days after the last administration of the study drug

Outcome Measure Data

Analysis Population Description

The analysis was performed on the safety population evaluable for immunogenicity (i.e. exposed to aflibercept with serum samples evaluable for immunogenicity).

Arm/Group Title	Placebo	Aflibercept
Arm/Group Description:	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Number of Participants Analyzed	149	179
Measure Type: Number; Unit of Measure: participants
At baseline	0	2
At any time post-baseline	4	9
- Neutralizing Ab	0	2
- Not neutralizing Ab	2	5
- Neutralizing potential not evaluated	2	2

Adverse Events

Time Frame	Adverse Events (AE) were collected from signature of the informed consent form up to the last visit in the study.
Adverse Event Reporting Description	The analysis was performed on the safety population as described for Outcome measure 10 (i.e. according to the treatment actually received) and included all AE that developed or worsened from first dose of aflibercept/placebo or docetaxel whichever came first, to 30 days after last dose of aflibercept/placebo or docetaxel whichever came last.
Arm/Group Title	Placebo	Aflibercept
Arm/Group Description	Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
All-Cause Mortality
	Placebo	Aflibercept
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	Placebo	Aflibercept
	Affected / at Risk (%)	Affected / at Risk (%)
Total	184/598 (30.77%)	331/611 (54.17%)
Blood and lymphatic system disorders
Febrile neutropenia * 1	21/598 (3.51%)	48/611 (7.86%)
Neutropenia * 1	8/598 (1.34%)	30/611 (4.91%)
Anaemia * 1	3/598 (0.50%)	2/611 (0.33%)
Thrombocytopenia * 1	0/598 (0.00%)	1/611 (0.16%)
Thrombotic microangiopathy * 1	0/598 (0.00%)	2/611 (0.33%)
Leukopenia * 1	1/598 (0.17%)	1/611 (0.16%)
Normochromic normocytic anaemia * 1	1/598 (0.17%)	0/611 (0.00%)
Pancytopenia * 1	0/598 (0.00%)	1/611 (0.16%)
Cardiac disorders
Atrial fibrillation * 1	3/598 (0.50%)	7/611 (1.15%)
Palpitations * 1	0/598 (0.00%)	1/611 (0.16%)
Sinus tachycardia * 1	0/598 (0.00%)	1/611 (0.16%)
Angina pectoris * 1	0/598 (0.00%)	1/611 (0.16%)
Acute myocardial infarction * 1	5/598 (0.84%)	0/611 (0.00%)
Supraventricular tachycardia * 1	0/598 (0.00%)	1/611 (0.16%)
Myocardial infarction * 1	2/598 (0.33%)	1/611 (0.16%)
Left ventricular dysfunction * 1	1/598 (0.17%)	0/611 (0.00%)
Myocardial ischaemia * 1	2/598 (0.33%)	0/611 (0.00%)
Ventricular extrasystoles * 1	0/598 (0.00%)	1/611 (0.16%)
Angina unstable * 1	0/598 (0.00%)	1/611 (0.16%)
Atrioventricular block complete * 1	1/598 (0.17%)	0/611 (0.00%)
Cardiac arrest * 1	1/598 (0.17%)	0/611 (0.00%)
Coronary artery stenosis * 1	1/598 (0.17%)	0/611 (0.00%)
Left ventricular failure * 1	0/598 (0.00%)	1/611 (0.16%)
Mitral valve incompetence * 1	0/598 (0.00%)	1/611 (0.16%)
Restrictive cardiomyopathy * 1	0/598 (0.00%)	1/611 (0.16%)
Tachycardia paroxysmal * 1	1/598 (0.17%)	0/611 (0.00%)
Ventricular fibrillation * 1	0/598 (0.00%)	1/611 (0.16%)
Endocrine disorders
Hyperthyroidism * 1	0/598 (0.00%)	1/611 (0.16%)
Eye disorders
Corneal erosion * 1	0/598 (0.00%)	1/611 (0.16%)
Pigmentary glaucoma * 1	0/598 (0.00%)	1/611 (0.16%)
Gastrointestinal disorders
Diarrhoea * 1	11/598 (1.84%)	17/611 (2.78%)
Stomatitis * 1	1/598 (0.17%)	14/611 (2.29%)
Nausea * 1	1/598 (0.17%)	1/611 (0.16%)
Constipation * 1	3/598 (0.50%)	3/611 (0.49%)
Vomiting * 1	3/598 (0.50%)	5/611 (0.82%)
Abdominal pain * 1	1/598 (0.17%)	2/611 (0.33%)
Abdominal pain upper * 1	0/598 (0.00%)	1/611 (0.16%)
Rectal haemorrhage * 1	0/598 (0.00%)	4/611 (0.65%)
Dysphagia * 1	0/598 (0.00%)	1/611 (0.16%)
Anal fistula * 1	0/598 (0.00%)	5/611 (0.82%)
Haematochezia * 1	1/598 (0.17%)	0/611 (0.00%)
Oesophagitis * 1	0/598 (0.00%)	1/611 (0.16%)
Anal fissure * 1	0/598 (0.00%)	3/611 (0.49%)
Gastritis * 1	0/598 (0.00%)	1/611 (0.16%)
Gastric ulcer * 1	0/598 (0.00%)	2/611 (0.33%)
Gastrointestinal haemorrhage * 1	3/598 (0.50%)	3/611 (0.49%)
Intestinal perforation * 1	0/598 (0.00%)	7/611 (1.15%)
Anal inflammation * 1	1/598 (0.17%)	0/611 (0.00%)
Diverticular perforation * 1	0/598 (0.00%)	5/611 (0.82%)
Lower gastrointestinal haemorrhage * 1	1/598 (0.17%)	3/611 (0.49%)
Ileus * 1	0/598 (0.00%)	2/611 (0.33%)
Rectal ulcer * 1	1/598 (0.17%)	3/611 (0.49%)
Colitis * 1	0/598 (0.00%)	1/611 (0.16%)
Duodenal ulcer * 1	0/598 (0.00%)	2/611 (0.33%)
Gastrointestinal inflammation * 1	0/598 (0.00%)	2/611 (0.33%)
Oesophageal ulcer * 1	0/598 (0.00%)	3/611 (0.49%)
Peptic ulcer * 1	0/598 (0.00%)	2/611 (0.33%)
Upper gastrointestinal haemorrhage * 1	1/598 (0.17%)	2/611 (0.33%)
Colitis ischaemic * 1	0/598 (0.00%)	2/611 (0.33%)
Diverticulum intestinal * 1	0/598 (0.00%)	1/611 (0.16%)
Duodenal ulcer perforation * 1	1/598 (0.17%)	1/611 (0.16%)
Enteritis * 1	0/598 (0.00%)	1/611 (0.16%)
Enterovesical fistula * 1	0/598 (0.00%)	2/611 (0.33%)
Gastritis erosive * 1	0/598 (0.00%)	1/611 (0.16%)
Duodenal ulcer haemorrhage * 1	0/598 (0.00%)	1/611 (0.16%)
Faecalith * 1	0/598 (0.00%)	1/611 (0.16%)
Gastric haemorrhage * 1	0/598 (0.00%)	1/611 (0.16%)
Gastric ulcer haemorrhage * 1	0/598 (0.00%)	1/611 (0.16%)
Gastrointestinal tract mucosal discolouration * 1	0/598 (0.00%)	1/611 (0.16%)
Ileus paralytic * 1	1/598 (0.17%)	0/611 (0.00%)
Intestinal obstruction * 1	0/598 (0.00%)	1/611 (0.16%)
Intestinal prolapse * 1	0/598 (0.00%)	1/611 (0.16%)
Large intestine perforation * 1	0/598 (0.00%)	1/611 (0.16%)
Mallory-weiss syndrome * 1	0/598 (0.00%)	1/611 (0.16%)
Necrotising colitis * 1	0/598 (0.00%)	1/611 (0.16%)
Neutropenic colitis * 1	0/598 (0.00%)	1/611 (0.16%)
Omental infarction * 1	0/598 (0.00%)	1/611 (0.16%)
Peptic ulcer perforation * 1	0/598 (0.00%)	1/611 (0.16%)
Periproctitis * 1	1/598 (0.17%)	0/611 (0.00%)
Pharyngoesophageal diverticulum * 1	0/598 (0.00%)	1/611 (0.16%)
Pneumoperitoneum * 1	0/598 (0.00%)	1/611 (0.16%)
Rectal ulcer haemorrhage * 1	0/598 (0.00%)	1/611 (0.16%)
Small intestinal haemorrhage * 1	0/598 (0.00%)	1/611 (0.16%)
General disorders
Fatigue * 1	0/598 (0.00%)	5/611 (0.82%)
Asthenia * 1	3/598 (0.50%)	6/611 (0.98%)
Oedema peripheral * 1	1/598 (0.17%)	1/611 (0.16%)
Pyrexia * 1	6/598 (1.00%)	8/611 (1.31%)
Pain * 1	0/598 (0.00%)	1/611 (0.16%)
Disease progression * 1	3/598 (0.50%)	10/611 (1.64%)
Non-cardiac chest pain * 1	1/598 (0.17%)	1/611 (0.16%)
Infusion site extravasation * 1	0/598 (0.00%)	1/611 (0.16%)
Performance status decreased * 1	0/598 (0.00%)	1/611 (0.16%)
General physical health deterioration * 1	0/598 (0.00%)	1/611 (0.16%)
Impaired healing * 1	0/598 (0.00%)	1/611 (0.16%)
Death * 1	1/598 (0.17%)	2/611 (0.33%)
Injection site reaction * 1	1/598 (0.17%)	0/611 (0.00%)
Multi-organ failure * 1	1/598 (0.17%)	1/611 (0.16%)
Sudden death * 1	0/598 (0.00%)	2/611 (0.33%)
Sudden cardiac death * 1	0/598 (0.00%)	1/611 (0.16%)
Hepatobiliary disorders
Bile duct obstruction * 1	0/598 (0.00%)	1/611 (0.16%)
Hepatitis * 1	1/598 (0.17%)	0/611 (0.00%)
Immune system disorders
Hypersensitivity * 1	1/598 (0.17%)	3/611 (0.49%)
Drug hypersensitivity * 1	1/598 (0.17%)	3/611 (0.49%)
Anaphylactic reaction * 1	1/598 (0.17%)	0/611 (0.00%)
Infections and infestations
Urinary tract infection * 1	4/598 (0.67%)	10/611 (1.64%)
Upper respiratory tract infection * 1	2/598 (0.33%)	1/611 (0.16%)
Pneumonia * 1	11/598 (1.84%)	21/611 (3.44%)
Neutropenic infection * 1	12/598 (2.01%)	22/611 (3.60%)
Bronchitis * 1	1/598 (0.17%)	2/611 (0.33%)
Oral candidiasis * 1	0/598 (0.00%)	1/611 (0.16%)
Pharyngitis * 1	0/598 (0.00%)	1/611 (0.16%)
Anal abscess * 1	0/598 (0.00%)	13/611 (2.13%)
Herpes zoster * 1	0/598 (0.00%)	1/611 (0.16%)
Lower respiratory tract infection * 1	2/598 (0.33%)	0/611 (0.00%)
Respiratory tract infection * 1	1/598 (0.17%)	1/611 (0.16%)
Cystitis * 1	1/598 (0.17%)	0/611 (0.00%)
Cellulitis * 1	1/598 (0.17%)	1/611 (0.16%)
Localised infection * 1	0/598 (0.00%)	1/611 (0.16%)
Neutropenic sepsis * 1	3/598 (0.50%)	7/611 (1.15%)
Sepsis * 1	2/598 (0.33%)	4/611 (0.65%)
Gastroenteritis * 1	0/598 (0.00%)	1/611 (0.16%)
Diverticulitis * 1	0/598 (0.00%)	4/611 (0.65%)
Skin infection * 1	1/598 (0.17%)	1/611 (0.16%)
Bronchopneumonia * 1	1/598 (0.17%)	3/611 (0.49%)
Device related infection * 1	0/598 (0.00%)	1/611 (0.16%)
Escherichia urinary tract infection * 1	1/598 (0.17%)	0/611 (0.00%)
Infection * 1	1/598 (0.17%)	2/611 (0.33%)
Peridiverticular abscess * 1	0/598 (0.00%)	3/611 (0.49%)
Rectal abscess * 1	0/598 (0.00%)	3/611 (0.49%)
Abscess intestinal * 1	0/598 (0.00%)	2/611 (0.33%)
Abscess limb * 1	1/598 (0.17%)	0/611 (0.00%)
Anal infection * 1	0/598 (0.00%)	1/611 (0.16%)
Erysipelas * 1	0/598 (0.00%)	2/611 (0.33%)
Escherichia sepsis * 1	1/598 (0.17%)	1/611 (0.16%)
Osteomyelitis * 1	1/598 (0.17%)	0/611 (0.00%)
Pneumonia staphylococcal * 1	1/598 (0.17%)	1/611 (0.16%)
Septic shock * 1	1/598 (0.17%)	2/611 (0.33%)
Abdominal abscess * 1	1/598 (0.17%)	1/611 (0.16%)
Bacteraemia * 1	1/598 (0.17%)	0/611 (0.00%)
Gastroenteritis viral * 1	0/598 (0.00%)	1/611 (0.16%)
Gastrointestinal infection * 1	1/598 (0.17%)	0/611 (0.00%)
Lobar pneumonia * 1	1/598 (0.17%)	1/611 (0.16%)
Lung infection * 1	1/598 (0.17%)	0/611 (0.00%)
Nasal abscess * 1	1/598 (0.17%)	0/611 (0.00%)
Necrotising fasciitis * 1	0/598 (0.00%)	2/611 (0.33%)
Pulmonary tuberculosis * 1	0/598 (0.00%)	1/611 (0.16%)
Pyonephrosis * 1	1/598 (0.17%)	1/611 (0.16%)
Tracheobronchitis * 1	0/598 (0.00%)	1/611 (0.16%)
Abdominal infection * 1	0/598 (0.00%)	1/611 (0.16%)
Appendicitis * 1	1/598 (0.17%)	0/611 (0.00%)
Aspergillosis * 1	0/598 (0.00%)	1/611 (0.16%)
Bronchiolitis * 1	0/598 (0.00%)	1/611 (0.16%)
Catheter site cellulitis * 1	1/598 (0.17%)	0/611 (0.00%)
Cystitis bacterial * 1	1/598 (0.17%)	0/611 (0.00%)
Cytomegalovirus hepatitis * 1	1/598 (0.17%)	0/611 (0.00%)
Herpes oesophagitis * 1	0/598 (0.00%)	1/611 (0.16%)
Infected bites * 1	0/598 (0.00%)	1/611 (0.16%)
Infectious peritonitis * 1	0/598 (0.00%)	1/611 (0.16%)
Listeria sepsis * 1	1/598 (0.17%)	0/611 (0.00%)
Lung abscess * 1	1/598 (0.17%)	0/611 (0.00%)
Perineal abscess * 1	1/598 (0.17%)	0/611 (0.00%)
Perirectal abscess * 1	1/598 (0.17%)	0/611 (0.00%)
Pneumonia bacterial * 1	0/598 (0.00%)	1/611 (0.16%)
Pneumonia necrotising * 1	0/598 (0.00%)	1/611 (0.16%)
Post procedural infection * 1	0/598 (0.00%)	1/611 (0.16%)
Pulmonary sepsis * 1	1/598 (0.17%)	0/611 (0.00%)
Pyelonephritis acute * 1	0/598 (0.00%)	1/611 (0.16%)
Staphylococcal bacteraemia * 1	0/598 (0.00%)	1/611 (0.16%)
Staphylococcal infection * 1	1/598 (0.17%)	0/611 (0.00%)
Urosepsis * 1	1/598 (0.17%)	0/611 (0.00%)
West nile viral infection * 1	1/598 (0.17%)	0/611 (0.00%)
Injury, poisoning and procedural complications
Fall * 1	0/598 (0.00%)	1/611 (0.16%)
Traumatic fracture * 1	1/598 (0.17%)	2/611 (0.33%)
Gastroenteritis radiation * 1	0/598 (0.00%)	1/611 (0.16%)
Abdominal wound dehiscence * 1	0/598 (0.00%)	2/611 (0.33%)
Joint dislocation * 1	0/598 (0.00%)	1/611 (0.16%)
Post procedural haemorrhage * 1	1/598 (0.17%)	0/611 (0.00%)
Pelvic fracture * 1	1/598 (0.17%)	0/611 (0.00%)
Pneumothorax traumatic * 1	0/598 (0.00%)	1/611 (0.16%)
Procedural complication * 1	1/598 (0.17%)	0/611 (0.00%)
Skull fracture * 1	1/598 (0.17%)	0/611 (0.00%)
Upper limb fracture * 1	1/598 (0.17%)	0/611 (0.00%)
Urinary bladder rupture * 1	0/598 (0.00%)	1/611 (0.16%)
Investigations
Haemoglobin decreased * 1	0/598 (0.00%)	2/611 (0.33%)
Electrocardiogram t wave inversion * 1	0/598 (0.00%)	1/611 (0.16%)
International normalised ratio increased * 1	0/598 (0.00%)	1/611 (0.16%)
Electrocardiogram st-t segment abnormal * 1	0/598 (0.00%)	1/611 (0.16%)
Metabolism and nutrition disorders
Decreased appetite * 1	0/598 (0.00%)	1/611 (0.16%)
Dehydration * 1	2/598 (0.33%)	19/611 (3.11%)
Hyperglycaemia * 1	2/598 (0.33%)	1/611 (0.16%)
Hypoglycaemia * 1	1/598 (0.17%)	2/611 (0.33%)
Diabetes mellitus inadequate control * 1	1/598 (0.17%)	0/611 (0.00%)
Failure to thrive * 1	0/598 (0.00%)	2/611 (0.33%)
Hypocalcaemia * 1	0/598 (0.00%)	2/611 (0.33%)
Hyponatraemia * 1	0/598 (0.00%)	2/611 (0.33%)
Hypernatraemia * 1	0/598 (0.00%)	1/611 (0.16%)
Musculoskeletal and connective tissue disorders
Back pain * 1	6/598 (1.00%)	0/611 (0.00%)
Arthralgia * 1	1/598 (0.17%)	1/611 (0.16%)
Bone pain * 1	1/598 (0.17%)	0/611 (0.00%)
Muscular weakness * 1	2/598 (0.33%)	0/611 (0.00%)
Pathological fracture * 1	3/598 (0.50%)	2/611 (0.33%)
Osteonecrosis of jaw * 1	1/598 (0.17%)	1/611 (0.16%)
Neck pain * 1	1/598 (0.17%)	0/611 (0.00%)
Spinal osteoarthritis * 1	0/598 (0.00%)	1/611 (0.16%)
Intervertebral disc protrusion * 1	1/598 (0.17%)	0/611 (0.00%)
Osteoporotic fracture * 1	0/598 (0.00%)	1/611 (0.16%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic pain * 1	3/598 (0.50%)	0/611 (0.00%)
Tumour pain * 1	1/598 (0.17%)	0/611 (0.00%)
Colon cancer * 1	1/598 (0.17%)	2/611 (0.33%)
Cardiac myxoma * 1	1/598 (0.17%)	0/611 (0.00%)
Colorectal cancer * 1	0/598 (0.00%)	1/611 (0.16%)
Lung neoplasm malignant * 1	1/598 (0.17%)	0/611 (0.00%)
Meningioma * 1	0/598 (0.00%)	1/611 (0.16%)
Metastases to bone * 1	1/598 (0.17%)	0/611 (0.00%)
Pituitary tumour benign * 1	1/598 (0.17%)	0/611 (0.00%)
Nervous system disorders
Peripheral sensory neuropathy * 1	0/598 (0.00%)	1/611 (0.16%)
Syncope * 1	4/598 (0.67%)	8/611 (1.31%)
Hypoaesthesia * 1	0/598 (0.00%)	1/611 (0.16%)
Peripheral motor neuropathy * 1	1/598 (0.17%)	2/611 (0.33%)
Spinal cord compression * 1	8/598 (1.34%)	2/611 (0.33%)
Loss of consciousness * 1	0/598 (0.00%)	1/611 (0.16%)
Presyncope * 1	0/598 (0.00%)	3/611 (0.49%)
Cerebral ischaemia * 1	2/598 (0.33%)	0/611 (0.00%)
Convulsion * 1	1/598 (0.17%)	1/611 (0.16%)
Ataxia * 1	1/598 (0.17%)	0/611 (0.00%)
Hypotonia * 1	0/598 (0.00%)	1/611 (0.16%)
Ischaemic stroke * 1	2/598 (0.33%)	0/611 (0.00%)
Transient ischaemic attack * 1	1/598 (0.17%)	1/611 (0.16%)
Cerebral infarction * 1	0/598 (0.00%)	1/611 (0.16%)
Grand mal convulsion * 1	0/598 (0.00%)	1/611 (0.16%)
Haemorrhagic stroke * 1	1/598 (0.17%)	0/611 (0.00%)
Leukoencephalopathy * 1	0/598 (0.00%)	1/611 (0.16%)
Posterior reversible encephalopathy syndrome * 1	0/598 (0.00%)	1/611 (0.16%)
Vocal cord paralysis * 1	0/598 (0.00%)	1/611 (0.16%)
Psychiatric disorders
Anxiety * 1	0/598 (0.00%)	1/611 (0.16%)
Depression * 1	1/598 (0.17%)	0/611 (0.00%)
Confusional state * 1	0/598 (0.00%)	1/611 (0.16%)
Mental status changes * 1	1/598 (0.17%)	0/611 (0.00%)
Renal and urinary disorders
Haematuria * 1	4/598 (0.67%)	5/611 (0.82%)
Proteinuria * 1	0/598 (0.00%)	1/611 (0.16%)
Urinary retention * 1	3/598 (0.50%)	2/611 (0.33%)
Hydronephrosis * 1	1/598 (0.17%)	1/611 (0.16%)
Urethral stenosis * 1	1/598 (0.17%)	1/611 (0.16%)
Renal colic * 1	1/598 (0.17%)	0/611 (0.00%)
Nephrotic syndrome * 1	0/598 (0.00%)	1/611 (0.16%)
Renal failure * 1	1/598 (0.17%)	1/611 (0.16%)
Urinary tract obstruction * 1	1/598 (0.17%)	0/611 (0.00%)
Bladder neck obstruction * 1	1/598 (0.17%)	0/611 (0.00%)
Renal failure acute * 1	0/598 (0.00%)	1/611 (0.16%)
Ureteric haemorrhage * 1	0/598 (0.00%)	1/611 (0.16%)
Urethral meatus stenosis * 1	1/598 (0.17%)	0/611 (0.00%)
Reproductive system and breast disorders
Genital ulceration * 1	0/598 (0.00%)	1/611 (0.16%)
Respiratory, thoracic and mediastinal disorders
Epistaxis * 1	1/598 (0.17%)	20/611 (3.27%)
Dyspnoea * 1	3/598 (0.50%)	2/611 (0.33%)
Oropharyngeal pain * 1	0/598 (0.00%)	2/611 (0.33%)
Pulmonary embolism * 1	17/598 (2.84%)	13/611 (2.13%)
Dyspnoea exertional * 1	0/598 (0.00%)	1/611 (0.16%)
Haemoptysis * 1	1/598 (0.17%)	1/611 (0.16%)
Hypoxia * 1	0/598 (0.00%)	2/611 (0.33%)
Pleural effusion * 1	0/598 (0.00%)	1/611 (0.16%)
Bronchospasm * 1	0/598 (0.00%)	1/611 (0.16%)
Pneumonitis * 1	0/598 (0.00%)	1/611 (0.16%)
Respiratory failure * 1	0/598 (0.00%)	2/611 (0.33%)
Acute respiratory failure * 1	0/598 (0.00%)	2/611 (0.33%)
Interstitial lung disease * 1	1/598 (0.17%)	1/611 (0.16%)
Acute respiratory distress syndrome * 1	0/598 (0.00%)	1/611 (0.16%)
Pneumothorax * 1	0/598 (0.00%)	1/611 (0.16%)
Vascular disorders
Hypertension * 1	1/598 (0.17%)	5/611 (0.82%)
Hypotension * 1	3/598 (0.50%)	4/611 (0.65%)
Deep vein thrombosis * 1	6/598 (1.00%)	4/611 (0.65%)
Phlebitis superficial * 1	1/598 (0.17%)	0/611 (0.00%)
Orthostatic hypotension * 1	1/598 (0.17%)	2/611 (0.33%)
Hypertensive crisis * 1	0/598 (0.00%)	1/611 (0.16%)
Subclavian artery stenosis * 1	1/598 (0.17%)	0/611 (0.00%)
Venous thrombosis limb * 1	0/598 (0.00%)	1/611 (0.16%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 14.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Aflibercept
	Affected / at Risk (%)	Affected / at Risk (%)
Total	551/598 (92.14%)	573/611 (93.78%)
Eye disorders
Lacrimation increased * 1	71/598 (11.87%)	119/611 (19.48%)
Gastrointestinal disorders
Diarrhoea * 1	209/598 (34.95%)	268/611 (43.86%)
Stomatitis * 1	123/598 (20.57%)	340/611 (55.65%)
Nausea * 1	166/598 (27.76%)	165/611 (27.00%)
Constipation * 1	131/598 (21.91%)	133/611 (21.77%)
Vomiting * 1	84/598 (14.05%)	90/611 (14.73%)
Abdominal pain * 1	45/598 (7.53%)	47/611 (7.69%)
Dyspepsia * 1	29/598 (4.85%)	31/611 (5.07%)
Haemorrhoids * 1	14/598 (2.34%)	31/611 (5.07%)
Dysphagia * 1	1/598 (0.17%)	31/611 (5.07%)
General disorders
Fatigue * 1	241/598 (40.30%)	243/611 (39.77%)
Asthenia * 1	123/598 (20.57%)	144/611 (23.57%)
Oedema peripheral * 1	157/598 (26.25%)	57/611 (9.33%)
Pyrexia * 1	54/598 (9.03%)	61/611 (9.98%)
Infections and infestations
Urinary tract infection * 1	38/598 (6.35%)	39/611 (6.38%)
Nasopharyngitis * 1	36/598 (6.02%)	23/611 (3.76%)
Investigations
Weight decreased * 1	51/598 (8.53%)	201/611 (32.90%)
Metabolism and nutrition disorders
Decreased appetite * 1	110/598 (18.39%)	190/611 (31.10%)
Musculoskeletal and connective tissue disorders
Back pain * 1	83/598 (13.88%)	55/611 (9.00%)
Arthralgia * 1	66/598 (11.04%)	42/611 (6.87%)
Pain in extremity * 1	62/598 (10.37%)	42/611 (6.87%)
Myalgia * 1	58/598 (9.70%)	41/611 (6.71%)
Bone pain * 1	44/598 (7.36%)	35/611 (5.73%)
Musculoskeletal pain * 1	33/598 (5.52%)	21/611 (3.44%)
Muscle spasms * 1	31/598 (5.18%)	17/611 (2.78%)
Nervous system disorders
Dysgeusia * 1	107/598 (17.89%)	108/611 (17.68%)
Headache * 1	45/598 (7.53%)	95/611 (15.55%)
Neuropathy peripheral * 1	76/598 (12.71%)	56/611 (9.17%)
Peripheral sensory neuropathy * 1	75/598 (12.54%)	51/611 (8.35%)
Paraesthesia * 1	49/598 (8.19%)	38/611 (6.22%)
Dizziness * 1	50/598 (8.36%)	29/611 (4.75%)
Psychiatric disorders
Insomnia * 1	44/598 (7.36%)	45/611 (7.36%)
Renal and urinary disorders
Proteinuria * 1	6/598 (1.00%)	31/611 (5.07%)
Respiratory, thoracic and mediastinal disorders
Dysphonia * 1	36/598 (6.02%)	230/611 (37.64%)
Epistaxis * 1	55/598 (9.20%)	199/611 (32.57%)
Cough * 1	77/598 (12.88%)	111/611 (18.17%)
Dyspnoea * 1	62/598 (10.37%)	89/611 (14.57%)
Oropharyngeal pain * 1	23/598 (3.85%)	69/611 (11.29%)
Rhinorrhoea * 1	17/598 (2.84%)	38/611 (6.22%)
Skin and subcutaneous tissue disorders
Alopecia * 1	268/598 (44.82%)	224/611 (36.66%)
Nail disorder * 1	97/598 (16.22%)	94/611 (15.38%)
Rash * 1	33/598 (5.52%)	49/611 (8.02%)
Palmar-plantar erythrodysaesthesia syndrome * 1	5/598 (0.84%)	51/611 (8.35%)
Vascular disorders
Hypertension * 1	66/598 (11.04%)	207/611 (33.88%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 14.0

Limitations and Caveats

Pain response initially defined as a key secondary endpoint together with PSA response, time to occurence of SRE and PFS was finally considered as an exploratory endpoint in final statistical analysis plan.

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The investigator shall have the right to independently publish study results from his site after a multicenter publication, or 12 months after the completion of the study by all sites. He must provide the sponsor a copy of any such publication derived from the study for review and comment at least 45 days (20 days for abstracts) in advance of any submission to a journal, and delay publication till the approval of the publication is given in writing by the Sponsor (not to exceed ninety days).

Results Point of Contact

• Name/Title: Trial Transparency Team
• Organization: Sanofi
• EMail: Contact-Us@sanofi.com

Publications of Results:

Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Flechon A, Skoneczna I, Orlandi F, Gravis G, Matveev V, Bavbek S, Gil T, Viana L, Aren O, Karyakin O, Elliott T, Birtle A, Magherini E, Hatteville L, Petrylak D, Tombal B, Rosenthal M; VENICE investigators. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013 Jul;14(8):760-8. doi: 10.1016/S1470-2045(13)70184-0. Epub 2013 Jun 4.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

van Soest RJ, Templeton AJ, Vera-Badillo FE, Mercier F, Sonpavde G, Amir E, Tombal B, Rosenthal M, Eisenberger MA, Tannock IF, de Wit R. Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials. Ann Oncol. 2015 Apr;26(4):743-749. doi: 10.1093/annonc/mdu569. Epub 2014 Dec 15.

de Liano AG, Reig O, Mellado B, Martin C, Rull EU, Maroto JP. Prognostic and predictive value of plasma testosterone levels in patients receiving first-line chemotherapy for metastatic castrate-resistant prostate cancer. Br J Cancer. 2014 Apr 29;110(9):2201-8. doi: 10.1038/bjc.2014.189. Epub 2014 Apr 10.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00519285
• Other Study ID Numbers: EFC6546; 2006-004756-20 ( EudraCT Number )
• First Submitted: August 21, 2007
• First Posted: August 22, 2007
• Results First Submitted: April 25, 2013
• Results First Posted: October 10, 2013
• Last Update Posted: July 22, 2016