VENICE: Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer
Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT00519285
Collaborator
Regeneron Pharmaceuticals (Industry)
1,224
31
2
56
39.5
0.7
Study Details
Study Description
Brief Summary
Primary objective was to demonstrate overall survival improvement with aflibercept compared to placebo in patients receiving docetaxel / prednisone for metastatic androgen-independent prostate cancer (MAIPC).
The secondary objectives were:
-
To assess the efficacy of aflibercept compared to placebo on other parameters such prostate-specific antigen (PSA) level, cancer related pain, progression free survival (PFS), tumor-based and skeletal events and health-related quality of life (HRQL);
-
To assess the overall safety in both treatment arms;
-
To determine the pharmacokinetics of intravenous (IV) aflibercept in this population;
-
to determine immunogenicity of IV aflibercept.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
The study consisted in 3-week treatment cycles until progressive disease, unacceptable toxicity, or participant's refusal of further study treatment. After disease progression, participants were to be followed every 3 months until death or the study cutoff date, whichever came first.
The study cut-off date was event-driven and was defined as the date when 873 deaths had occurred.
Study Design
Study Type:
Interventional
Actual Enrollment
:
1224 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Randomized, Double Blind Study Comparing the Efficacy and Safety of Aflibercept Versus Placebo Administered Every 3 Weeks in Patients Treated With Docetaxel/ Prednisone for Metastatic Androgen-independent Prostate Cancer
Study Start Date
:
Aug 1, 2007
Actual Primary Completion Date
:
Apr 1, 2012
Actual Study Completion Date
:
Apr 1, 2012
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo Placebo added to standard chemotherapy with docetaxel plus prednisone or prednisolone |
Drug: Placebo (for aflibercept)
Sterile aqueous buffered solution identical to aflibercept
1-hour IV on Day 1 of each 3-Week cycle
Drug: Docetaxel
Marketed formulation
75 mg/m², 1 hour IV on Day 1 of each 3-week cycle (immediately after Aflibercept or placebo)
Other Names:
Drug: Prednisone or Prednisolone
Marketed formulation
5 mg twice daily PO from day 1 continuously
|
| Experimental: Aflibercept Aflibercept added to standard chemotherapy with docetaxel plus prednisone or prednisolone |
Drug: Aflibercept
25 mg/ml solution
6 mg/kg, 1-hour IV on Day 1 of each 3-Week cycle
Other Names:
Drug: Docetaxel
Marketed formulation
75 mg/m², 1 hour IV on Day 1 of each 3-week cycle (immediately after Aflibercept or placebo)
Other Names:
Drug: Prednisone or Prednisolone
Marketed formulation
5 mg twice daily PO from day 1 continuously
|
Outcome Measures
Primary Outcome Measures
- Overall Survival Time [From randomization up to the cut-off date (median follow-up of 35.4 months)]
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.
Secondary Outcome Measures
- Prostate Specific Antigen Response Rate [Before randomization (baseline) then every 3 weeks up to PSA progression (≥25% increase) or the cut-off date, whichever occurred first]
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 to Skeletal Related Events [From randomization up to the cut-off date (median follow-up of 35.4 months)]
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.
- Progression Free Survival Time [From randomization up to the cut-off date (median follow-up of 35.4 months)]
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.
- Tumor Response Rate in Participants With Measurable Disease [Before randomization (baseline) then every 3 months up to tumor progression (≥25% increase) or the cut-off date, whichever occurred first]
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.
- Prostate Specific Antigen Progression-free Survival Time [From randomization up to the cut-off date (median follow-up of 35.4 months)]
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.
- Pain Progression-free Survival Time [From randomization up to the cut-off date (median follow-up of 35.4 months)]
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.
- Pain Response Rate [Before randomization (baseline) then every 3 weeks up to pain progression or the cut-off date, whichever occurred first]
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.
- Change From Baseline in Functional Assessment of Cancer Therapy-Prostate Total Score as a Measure of Health Related Quality of Life [Before randomization (baseline) then every 3 weeks until disease progression or administration of further antitumor therapy, whichever came first]
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.
- Number of Participants With Adverse Events as a Measure of Safety [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]
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).
- Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept [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]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
Male
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Histologically- or cytologically-confirmed prostate adenocarcinoma;
-
Metastatic disease;
-
Progressive disease while receiving hormonal therapy or after surgical castration;
-
Effective castration.
Exclusion Criteria:
-
Prior cytotoxic chemotherapy for prostate cancer, except estramustine and except adjuvant/neoadjuvant treatment completed >3 years ago;
-
Prior treatment with Vascular Endothelial Growth Factor (VEGF) inhibitors or VEGF receptor inhibitors;
-
Eastern Cooperative Oncology Group (ECOG) performance status >2.
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Sanofi-Aventis Administrative Office | Bridgewater | New Jersey | United States | 08807 |
| 2 | Sanofi-Aventis Administrative Office | Buenos Aires | Argentina | ||
| 3 | Sanofi-Aventis Administrative Office | Macquarie Park | Australia | ||
| 4 | Sanofi-Aventis Administrative Office | Diegem | Belgium | ||
| 5 | Sanofi-Aventis Administrative Office | Sao Paulo | Brazil | ||
| 6 | Sanofi-Aventis Administrative Office | Laval | Canada | ||
| 7 | Sanofi-Aventis Administrative Office | Providencia Santiago | Chile | ||
| 8 | Sanofi-Aventis Administrative Office | City of Zagreb | Croatia | ||
| 9 | Sanofi-Aventis Administrative Office | Praha | Czech Republic | ||
| 10 | Sanofi-Aventis Administrative Office | Horsholm | Denmark | ||
| 11 | Sanofi-Aventis Administrative Office | Tallinn | Estonia | ||
| 12 | Sanofi-Aventis Administrative Office | Paris | France | ||
| 13 | Sanofi-Aventis Administrative Office | Frankfurt | Germany | ||
| 14 | Sanofi-Aventis Administrative Office | Hong Kong | Hong Kong | ||
| 15 | Sanofi-Aventis Administrative Office | Budapest | Hungary | ||
| 16 | Sanofi-Aventis Administrative Office | Natanya | Israel | ||
| 17 | Sanofi-Aventis Administrative Office | Milan | Italy | ||
| 18 | Sanofi-Aventis Administrative Office | Seoul | Korea, Republic of | ||
| 19 | Sanofi-Aventis Administrative Office | Gouda | Netherlands | ||
| 20 | Sanofi-Aventis Administrative Office | Warsaw | Poland | ||
| 21 | Sanofi-Aventis Administrative Office | Porto Salvo | Portugal | ||
| 22 | Sanofi-Aventis Administrative Office | Moscow | Russian Federation | ||
| 23 | Sanofi-Aventis Administrative Office | Singapore | Singapore | ||
| 24 | Sanofi-Aventis Administrative Office | Gauteng | South Africa | ||
| 25 | Sanofi-Aventis Administrative Office | Barcelona | Spain | ||
| 26 | Sanofi-Aventis Administrative Office | Bromma | Sweden | ||
| 27 | Sanofi-Aventis Administrative Office | Geneva | Switzerland | ||
| 28 | Sanofi-Aventis Administrative Office | Taipei | Taiwan | ||
| 29 | Sanofi-Aventis Administrative Office | Istanbul | Turkey | ||
| 30 | Sanofi-Aventis Administrative Office | Kiev | Ukraine | ||
| 31 | Sanofi-Aventis Administrative Office | Guildford Surrey | United Kingdom |
Sponsors and Collaborators
- Sanofi
- Regeneron Pharmaceuticals
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT00519285
Other Study ID Numbers:
- EFC6546
- 2006-004756-20
First Posted:
Aug 22, 2007
Last Update Posted:
Jul 22, 2016
Last Verified:
Jun 1, 2016
Keywords provided by Sanofi
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | Between August 2007 and February 2010, a total of 1548 patients gave informed consent for this study. |
|---|---|
| Pre-assignment Detail | 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 | 612 |
| TREATED | 604 | 605 |
| Still Treated at Cut-off Date | 1 | 2 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 612 | 612 |
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 Participants | 612 | 612 | 1224 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
67.6
(8.0)
|
67.9
(7.8)
|
67.8
(7.9)
|
| Age, Customized (participants) [Number] | |||
| <65 years |
225
36.8%
|
195
31.9%
|
420
34.3%
|
| 65-74 years |
259
42.3%
|
283
46.2%
|
542
44.3%
|
| ≥75 years |
128
20.9%
|
134
21.9%
|
262
21.4%
|
| Sex/Gender, Customized (participants) [Number] | |||
| Male |
612
100%
|
612
100%
|
1224
100%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| Caucasian/White |
552
90.2%
|
560
91.5%
|
1112
90.8%
|
| Black |
17
2.8%
|
15
2.5%
|
32
2.6%
|
| Asian/Oriental |
36
5.9%
|
32
5.2%
|
68
5.6%
|
| Other |
7
1.1%
|
5
0.8%
|
12
1%
|
| Region of Enrollment (Number) [Number] | |||
| Western Europe |
219
35.8%
|
227
37.1%
|
446
36.4%
|
| Eastern Europe |
131
21.4%
|
132
21.6%
|
263
21.5%
|
| North America |
81
13.2%
|
95
15.5%
|
176
14.4%
|
| South America |
88
14.4%
|
71
11.6%
|
159
13%
|
| Other region |
93
15.2%
|
87
14.2%
|
180
14.7%
|
| Body Surface Area (BSA) (m²) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [m²] |
2.0
(0.2)
|
2.0
(0.2)
|
2.0
(0.2)
|
| Eastern Co-operative Group (ECOG) performance status (participants) [Number] | |||
| ECOG 0 |
285
46.6%
|
283
46.2%
|
568
46.4%
|
| ECOG 1 |
299
48.9%
|
303
49.5%
|
602
49.2%
|
| ECOG 2 |
28
4.6%
|
26
4.2%
|
54
4.4%
|
Outcome Measures
| 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 |
| Measure Participants | 612 | 612 |
| Median (95% Confidence Interval) [months] |
21.22
|
22.14
|
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 | ||
| 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 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | Hazard ratio (HR) aflibercept versus placebo estimated from a Cox proportional hazard model stratified on ECOG Performance Status | |
| 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 |
| Measure Participants | 559 | 560 |
| Number (95% Confidence Interval) [percentage of participants] |
63.5
10.4%
|
68.6
11.2%
|
| 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 |
| Measure Participants | 612 | 612 |
| Median (95% Confidence Interval) [months] |
14.98
|
15.31
|
| 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 |
| Measure Participants | 612 | 612 |
| Median (95% Confidence Interval) [months] |
6.24
|
6.90
|
| 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 |
| Measure Participants | 320 | 323 |
| Number (95% Confidence Interval) [percentage of participants] |
28.1
4.6%
|
38.7
6.3%
|
| 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 |
| Measure Participants | 606 | 608 |
| Median (95% Confidence Interval) [months] |
8.11
|
8.25
|
| 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 |
| Measure Participants | 301 | 287 |
| Median (95% Confidence Interval) [months] |
9.72
|
9.20
|
| 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 |
| Measure Participants | 67 | 67 |
| Number (95% Confidence Interval) [percentage of participants] |
46.3
7.6%
|
35.8
5.8%
|
| 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 |
| Measure Participants | 574 | 568 |
| 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)
|
| 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 |
| Measure Participants | 598 | 611 |
| Any Adverse Event |
585
95.6%
|
607
99.2%
|
| - Grade 3-4 AE |
290
47.4%
|
470
76.8%
|
| - Serious AE |
184
30.1%
|
331
54.1%
|
| - AE leading to death |
23
3.8%
|
46
7.5%
|
| --- Related AE leading to death |
8
1.3%
|
19
3.1%
|
| - AE leading to permanent discontinuation |
125
20.4%
|
268
43.8%
|
| - AE leading to premature discontinuation |
73
11.9%
|
116
19%
|
| 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 |
| Measure Participants | 149 | 179 |
| At baseline |
0
0%
|
2
0.3%
|
| At any time post-baseline |
4
0.7%
|
9
1.5%
|
| - Neutralizing Ab |
0
0%
|
2
0.3%
|
| - Not neutralizing Ab |
2
0.3%
|
5
0.8%
|
| - Neutralizing potential not evaluated |
2
0.3%
|
2
0.3%
|
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 (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Placebo | Aflibercept | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 184/598 (30.8%) | 331/611 (54.2%) | ||
| Blood and lymphatic system disorders | ||||
| Febrile neutropenia | 21/598 (3.5%) | 48/611 (7.9%) | ||
| Neutropenia | 8/598 (1.3%) | 30/611 (4.9%) | ||
| Anaemia | 3/598 (0.5%) | 2/611 (0.3%) | ||
| Thrombocytopenia | 0/598 (0%) | 1/611 (0.2%) | ||
| Thrombotic microangiopathy | 0/598 (0%) | 2/611 (0.3%) | ||
| Leukopenia | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Normochromic normocytic anaemia | 1/598 (0.2%) | 0/611 (0%) | ||
| Pancytopenia | 0/598 (0%) | 1/611 (0.2%) | ||
| Cardiac disorders | ||||
| Atrial fibrillation | 3/598 (0.5%) | 7/611 (1.1%) | ||
| Palpitations | 0/598 (0%) | 1/611 (0.2%) | ||
| Sinus tachycardia | 0/598 (0%) | 1/611 (0.2%) | ||
| Angina pectoris | 0/598 (0%) | 1/611 (0.2%) | ||
| Acute myocardial infarction | 5/598 (0.8%) | 0/611 (0%) | ||
| Supraventricular tachycardia | 0/598 (0%) | 1/611 (0.2%) | ||
| Myocardial infarction | 2/598 (0.3%) | 1/611 (0.2%) | ||
| Left ventricular dysfunction | 1/598 (0.2%) | 0/611 (0%) | ||
| Myocardial ischaemia | 2/598 (0.3%) | 0/611 (0%) | ||
| Ventricular extrasystoles | 0/598 (0%) | 1/611 (0.2%) | ||
| Angina unstable | 0/598 (0%) | 1/611 (0.2%) | ||
| Atrioventricular block complete | 1/598 (0.2%) | 0/611 (0%) | ||
| Cardiac arrest | 1/598 (0.2%) | 0/611 (0%) | ||
| Coronary artery stenosis | 1/598 (0.2%) | 0/611 (0%) | ||
| Left ventricular failure | 0/598 (0%) | 1/611 (0.2%) | ||
| Mitral valve incompetence | 0/598 (0%) | 1/611 (0.2%) | ||
| Restrictive cardiomyopathy | 0/598 (0%) | 1/611 (0.2%) | ||
| Tachycardia paroxysmal | 1/598 (0.2%) | 0/611 (0%) | ||
| Ventricular fibrillation | 0/598 (0%) | 1/611 (0.2%) | ||
| Endocrine disorders | ||||
| Hyperthyroidism | 0/598 (0%) | 1/611 (0.2%) | ||
| Eye disorders | ||||
| Corneal erosion | 0/598 (0%) | 1/611 (0.2%) | ||
| Pigmentary glaucoma | 0/598 (0%) | 1/611 (0.2%) | ||
| Gastrointestinal disorders | ||||
| Diarrhoea | 11/598 (1.8%) | 17/611 (2.8%) | ||
| Stomatitis | 1/598 (0.2%) | 14/611 (2.3%) | ||
| Nausea | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Constipation | 3/598 (0.5%) | 3/611 (0.5%) | ||
| Vomiting | 3/598 (0.5%) | 5/611 (0.8%) | ||
| Abdominal pain | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Abdominal pain upper | 0/598 (0%) | 1/611 (0.2%) | ||
| Rectal haemorrhage | 0/598 (0%) | 4/611 (0.7%) | ||
| Dysphagia | 0/598 (0%) | 1/611 (0.2%) | ||
| Anal fistula | 0/598 (0%) | 5/611 (0.8%) | ||
| Haematochezia | 1/598 (0.2%) | 0/611 (0%) | ||
| Oesophagitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Anal fissure | 0/598 (0%) | 3/611 (0.5%) | ||
| Gastritis | 0/598 (0%) | 1/611 (0.2%) | ||
| Gastric ulcer | 0/598 (0%) | 2/611 (0.3%) | ||
| Gastrointestinal haemorrhage | 3/598 (0.5%) | 3/611 (0.5%) | ||
| Intestinal perforation | 0/598 (0%) | 7/611 (1.1%) | ||
| Anal inflammation | 1/598 (0.2%) | 0/611 (0%) | ||
| Diverticular perforation | 0/598 (0%) | 5/611 (0.8%) | ||
| Lower gastrointestinal haemorrhage | 1/598 (0.2%) | 3/611 (0.5%) | ||
| Ileus | 0/598 (0%) | 2/611 (0.3%) | ||
| Rectal ulcer | 1/598 (0.2%) | 3/611 (0.5%) | ||
| Colitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Duodenal ulcer | 0/598 (0%) | 2/611 (0.3%) | ||
| Gastrointestinal inflammation | 0/598 (0%) | 2/611 (0.3%) | ||
| Oesophageal ulcer | 0/598 (0%) | 3/611 (0.5%) | ||
| Peptic ulcer | 0/598 (0%) | 2/611 (0.3%) | ||
| Upper gastrointestinal haemorrhage | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Colitis ischaemic | 0/598 (0%) | 2/611 (0.3%) | ||
| Diverticulum intestinal | 0/598 (0%) | 1/611 (0.2%) | ||
| Duodenal ulcer perforation | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Enteritis | 0/598 (0%) | 1/611 (0.2%) | ||
| Enterovesical fistula | 0/598 (0%) | 2/611 (0.3%) | ||
| Gastritis erosive | 0/598 (0%) | 1/611 (0.2%) | ||
| Duodenal ulcer haemorrhage | 0/598 (0%) | 1/611 (0.2%) | ||
| Faecalith | 0/598 (0%) | 1/611 (0.2%) | ||
| Gastric haemorrhage | 0/598 (0%) | 1/611 (0.2%) | ||
| Gastric ulcer haemorrhage | 0/598 (0%) | 1/611 (0.2%) | ||
| Gastrointestinal tract mucosal discolouration | 0/598 (0%) | 1/611 (0.2%) | ||
| Ileus paralytic | 1/598 (0.2%) | 0/611 (0%) | ||
| Intestinal obstruction | 0/598 (0%) | 1/611 (0.2%) | ||
| Intestinal prolapse | 0/598 (0%) | 1/611 (0.2%) | ||
| Large intestine perforation | 0/598 (0%) | 1/611 (0.2%) | ||
| Mallory-weiss syndrome | 0/598 (0%) | 1/611 (0.2%) | ||
| Necrotising colitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Neutropenic colitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Omental infarction | 0/598 (0%) | 1/611 (0.2%) | ||
| Peptic ulcer perforation | 0/598 (0%) | 1/611 (0.2%) | ||
| Periproctitis | 1/598 (0.2%) | 0/611 (0%) | ||
| Pharyngoesophageal diverticulum | 0/598 (0%) | 1/611 (0.2%) | ||
| Pneumoperitoneum | 0/598 (0%) | 1/611 (0.2%) | ||
| Rectal ulcer haemorrhage | 0/598 (0%) | 1/611 (0.2%) | ||
| Small intestinal haemorrhage | 0/598 (0%) | 1/611 (0.2%) | ||
| General disorders | ||||
| Fatigue | 0/598 (0%) | 5/611 (0.8%) | ||
| Asthenia | 3/598 (0.5%) | 6/611 (1%) | ||
| Oedema peripheral | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Pyrexia | 6/598 (1%) | 8/611 (1.3%) | ||
| Pain | 0/598 (0%) | 1/611 (0.2%) | ||
| Disease progression | 3/598 (0.5%) | 10/611 (1.6%) | ||
| Non-cardiac chest pain | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Infusion site extravasation | 0/598 (0%) | 1/611 (0.2%) | ||
| Performance status decreased | 0/598 (0%) | 1/611 (0.2%) | ||
| General physical health deterioration | 0/598 (0%) | 1/611 (0.2%) | ||
| Impaired healing | 0/598 (0%) | 1/611 (0.2%) | ||
| Death | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Injection site reaction | 1/598 (0.2%) | 0/611 (0%) | ||
| Multi-organ failure | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Sudden death | 0/598 (0%) | 2/611 (0.3%) | ||
| Sudden cardiac death | 0/598 (0%) | 1/611 (0.2%) | ||
| Hepatobiliary disorders | ||||
| Bile duct obstruction | 0/598 (0%) | 1/611 (0.2%) | ||
| Hepatitis | 1/598 (0.2%) | 0/611 (0%) | ||
| Immune system disorders | ||||
| Hypersensitivity | 1/598 (0.2%) | 3/611 (0.5%) | ||
| Drug hypersensitivity | 1/598 (0.2%) | 3/611 (0.5%) | ||
| Anaphylactic reaction | 1/598 (0.2%) | 0/611 (0%) | ||
| Infections and infestations | ||||
| Urinary tract infection | 4/598 (0.7%) | 10/611 (1.6%) | ||
| Upper respiratory tract infection | 2/598 (0.3%) | 1/611 (0.2%) | ||
| Pneumonia | 11/598 (1.8%) | 21/611 (3.4%) | ||
| Neutropenic infection | 12/598 (2%) | 22/611 (3.6%) | ||
| Bronchitis | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Oral candidiasis | 0/598 (0%) | 1/611 (0.2%) | ||
| Pharyngitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Anal abscess | 0/598 (0%) | 13/611 (2.1%) | ||
| Herpes zoster | 0/598 (0%) | 1/611 (0.2%) | ||
| Lower respiratory tract infection | 2/598 (0.3%) | 0/611 (0%) | ||
| Respiratory tract infection | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Cystitis | 1/598 (0.2%) | 0/611 (0%) | ||
| Cellulitis | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Localised infection | 0/598 (0%) | 1/611 (0.2%) | ||
| Neutropenic sepsis | 3/598 (0.5%) | 7/611 (1.1%) | ||
| Sepsis | 2/598 (0.3%) | 4/611 (0.7%) | ||
| Gastroenteritis | 0/598 (0%) | 1/611 (0.2%) | ||
| Diverticulitis | 0/598 (0%) | 4/611 (0.7%) | ||
| Skin infection | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Bronchopneumonia | 1/598 (0.2%) | 3/611 (0.5%) | ||
| Device related infection | 0/598 (0%) | 1/611 (0.2%) | ||
| Escherichia urinary tract infection | 1/598 (0.2%) | 0/611 (0%) | ||
| Infection | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Peridiverticular abscess | 0/598 (0%) | 3/611 (0.5%) | ||
| Rectal abscess | 0/598 (0%) | 3/611 (0.5%) | ||
| Abscess intestinal | 0/598 (0%) | 2/611 (0.3%) | ||
| Abscess limb | 1/598 (0.2%) | 0/611 (0%) | ||
| Anal infection | 0/598 (0%) | 1/611 (0.2%) | ||
| Erysipelas | 0/598 (0%) | 2/611 (0.3%) | ||
| Escherichia sepsis | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Osteomyelitis | 1/598 (0.2%) | 0/611 (0%) | ||
| Pneumonia staphylococcal | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Septic shock | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Abdominal abscess | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Bacteraemia | 1/598 (0.2%) | 0/611 (0%) | ||
| Gastroenteritis viral | 0/598 (0%) | 1/611 (0.2%) | ||
| Gastrointestinal infection | 1/598 (0.2%) | 0/611 (0%) | ||
| Lobar pneumonia | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Lung infection | 1/598 (0.2%) | 0/611 (0%) | ||
| Nasal abscess | 1/598 (0.2%) | 0/611 (0%) | ||
| Necrotising fasciitis | 0/598 (0%) | 2/611 (0.3%) | ||
| Pulmonary tuberculosis | 0/598 (0%) | 1/611 (0.2%) | ||
| Pyonephrosis | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Tracheobronchitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Abdominal infection | 0/598 (0%) | 1/611 (0.2%) | ||
| Appendicitis | 1/598 (0.2%) | 0/611 (0%) | ||
| Aspergillosis | 0/598 (0%) | 1/611 (0.2%) | ||
| Bronchiolitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Catheter site cellulitis | 1/598 (0.2%) | 0/611 (0%) | ||
| Cystitis bacterial | 1/598 (0.2%) | 0/611 (0%) | ||
| Cytomegalovirus hepatitis | 1/598 (0.2%) | 0/611 (0%) | ||
| Herpes oesophagitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Infected bites | 0/598 (0%) | 1/611 (0.2%) | ||
| Infectious peritonitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Listeria sepsis | 1/598 (0.2%) | 0/611 (0%) | ||
| Lung abscess | 1/598 (0.2%) | 0/611 (0%) | ||
| Perineal abscess | 1/598 (0.2%) | 0/611 (0%) | ||
| Perirectal abscess | 1/598 (0.2%) | 0/611 (0%) | ||
| Pneumonia bacterial | 0/598 (0%) | 1/611 (0.2%) | ||
| Pneumonia necrotising | 0/598 (0%) | 1/611 (0.2%) | ||
| Post procedural infection | 0/598 (0%) | 1/611 (0.2%) | ||
| Pulmonary sepsis | 1/598 (0.2%) | 0/611 (0%) | ||
| Pyelonephritis acute | 0/598 (0%) | 1/611 (0.2%) | ||
| Staphylococcal bacteraemia | 0/598 (0%) | 1/611 (0.2%) | ||
| Staphylococcal infection | 1/598 (0.2%) | 0/611 (0%) | ||
| Urosepsis | 1/598 (0.2%) | 0/611 (0%) | ||
| West nile viral infection | 1/598 (0.2%) | 0/611 (0%) | ||
| Injury, poisoning and procedural complications | ||||
| Fall | 0/598 (0%) | 1/611 (0.2%) | ||
| Traumatic fracture | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Gastroenteritis radiation | 0/598 (0%) | 1/611 (0.2%) | ||
| Abdominal wound dehiscence | 0/598 (0%) | 2/611 (0.3%) | ||
| Joint dislocation | 0/598 (0%) | 1/611 (0.2%) | ||
| Post procedural haemorrhage | 1/598 (0.2%) | 0/611 (0%) | ||
| Pelvic fracture | 1/598 (0.2%) | 0/611 (0%) | ||
| Pneumothorax traumatic | 0/598 (0%) | 1/611 (0.2%) | ||
| Procedural complication | 1/598 (0.2%) | 0/611 (0%) | ||
| Skull fracture | 1/598 (0.2%) | 0/611 (0%) | ||
| Upper limb fracture | 1/598 (0.2%) | 0/611 (0%) | ||
| Urinary bladder rupture | 0/598 (0%) | 1/611 (0.2%) | ||
| Investigations | ||||
| Haemoglobin decreased | 0/598 (0%) | 2/611 (0.3%) | ||
| Electrocardiogram t wave inversion | 0/598 (0%) | 1/611 (0.2%) | ||
| International normalised ratio increased | 0/598 (0%) | 1/611 (0.2%) | ||
| Electrocardiogram st-t segment abnormal | 0/598 (0%) | 1/611 (0.2%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 0/598 (0%) | 1/611 (0.2%) | ||
| Dehydration | 2/598 (0.3%) | 19/611 (3.1%) | ||
| Hyperglycaemia | 2/598 (0.3%) | 1/611 (0.2%) | ||
| Hypoglycaemia | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Diabetes mellitus inadequate control | 1/598 (0.2%) | 0/611 (0%) | ||
| Failure to thrive | 0/598 (0%) | 2/611 (0.3%) | ||
| Hypocalcaemia | 0/598 (0%) | 2/611 (0.3%) | ||
| Hyponatraemia | 0/598 (0%) | 2/611 (0.3%) | ||
| Hypernatraemia | 0/598 (0%) | 1/611 (0.2%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 6/598 (1%) | 0/611 (0%) | ||
| Arthralgia | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Bone pain | 1/598 (0.2%) | 0/611 (0%) | ||
| Muscular weakness | 2/598 (0.3%) | 0/611 (0%) | ||
| Pathological fracture | 3/598 (0.5%) | 2/611 (0.3%) | ||
| Osteonecrosis of jaw | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Neck pain | 1/598 (0.2%) | 0/611 (0%) | ||
| Spinal osteoarthritis | 0/598 (0%) | 1/611 (0.2%) | ||
| Intervertebral disc protrusion | 1/598 (0.2%) | 0/611 (0%) | ||
| Osteoporotic fracture | 0/598 (0%) | 1/611 (0.2%) | ||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Metastatic pain | 3/598 (0.5%) | 0/611 (0%) | ||
| Tumour pain | 1/598 (0.2%) | 0/611 (0%) | ||
| Colon cancer | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Cardiac myxoma | 1/598 (0.2%) | 0/611 (0%) | ||
| Colorectal cancer | 0/598 (0%) | 1/611 (0.2%) | ||
| Lung neoplasm malignant | 1/598 (0.2%) | 0/611 (0%) | ||
| Meningioma | 0/598 (0%) | 1/611 (0.2%) | ||
| Metastases to bone | 1/598 (0.2%) | 0/611 (0%) | ||
| Pituitary tumour benign | 1/598 (0.2%) | 0/611 (0%) | ||
| Nervous system disorders | ||||
| Peripheral sensory neuropathy | 0/598 (0%) | 1/611 (0.2%) | ||
| Syncope | 4/598 (0.7%) | 8/611 (1.3%) | ||
| Hypoaesthesia | 0/598 (0%) | 1/611 (0.2%) | ||
| Peripheral motor neuropathy | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Spinal cord compression | 8/598 (1.3%) | 2/611 (0.3%) | ||
| Loss of consciousness | 0/598 (0%) | 1/611 (0.2%) | ||
| Presyncope | 0/598 (0%) | 3/611 (0.5%) | ||
| Cerebral ischaemia | 2/598 (0.3%) | 0/611 (0%) | ||
| Convulsion | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Ataxia | 1/598 (0.2%) | 0/611 (0%) | ||
| Hypotonia | 0/598 (0%) | 1/611 (0.2%) | ||
| Ischaemic stroke | 2/598 (0.3%) | 0/611 (0%) | ||
| Transient ischaemic attack | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Cerebral infarction | 0/598 (0%) | 1/611 (0.2%) | ||
| Grand mal convulsion | 0/598 (0%) | 1/611 (0.2%) | ||
| Haemorrhagic stroke | 1/598 (0.2%) | 0/611 (0%) | ||
| Leukoencephalopathy | 0/598 (0%) | 1/611 (0.2%) | ||
| Posterior reversible encephalopathy syndrome | 0/598 (0%) | 1/611 (0.2%) | ||
| Vocal cord paralysis | 0/598 (0%) | 1/611 (0.2%) | ||
| Psychiatric disorders | ||||
| Anxiety | 0/598 (0%) | 1/611 (0.2%) | ||
| Depression | 1/598 (0.2%) | 0/611 (0%) | ||
| Confusional state | 0/598 (0%) | 1/611 (0.2%) | ||
| Mental status changes | 1/598 (0.2%) | 0/611 (0%) | ||
| Renal and urinary disorders | ||||
| Haematuria | 4/598 (0.7%) | 5/611 (0.8%) | ||
| Proteinuria | 0/598 (0%) | 1/611 (0.2%) | ||
| Urinary retention | 3/598 (0.5%) | 2/611 (0.3%) | ||
| Hydronephrosis | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Urethral stenosis | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Renal colic | 1/598 (0.2%) | 0/611 (0%) | ||
| Nephrotic syndrome | 0/598 (0%) | 1/611 (0.2%) | ||
| Renal failure | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Urinary tract obstruction | 1/598 (0.2%) | 0/611 (0%) | ||
| Bladder neck obstruction | 1/598 (0.2%) | 0/611 (0%) | ||
| Renal failure acute | 0/598 (0%) | 1/611 (0.2%) | ||
| Ureteric haemorrhage | 0/598 (0%) | 1/611 (0.2%) | ||
| Urethral meatus stenosis | 1/598 (0.2%) | 0/611 (0%) | ||
| Reproductive system and breast disorders | ||||
| Genital ulceration | 0/598 (0%) | 1/611 (0.2%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Epistaxis | 1/598 (0.2%) | 20/611 (3.3%) | ||
| Dyspnoea | 3/598 (0.5%) | 2/611 (0.3%) | ||
| Oropharyngeal pain | 0/598 (0%) | 2/611 (0.3%) | ||
| Pulmonary embolism | 17/598 (2.8%) | 13/611 (2.1%) | ||
| Dyspnoea exertional | 0/598 (0%) | 1/611 (0.2%) | ||
| Haemoptysis | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Hypoxia | 0/598 (0%) | 2/611 (0.3%) | ||
| Pleural effusion | 0/598 (0%) | 1/611 (0.2%) | ||
| Bronchospasm | 0/598 (0%) | 1/611 (0.2%) | ||
| Pneumonitis | 0/598 (0%) | 1/611 (0.2%) | ||
| Respiratory failure | 0/598 (0%) | 2/611 (0.3%) | ||
| Acute respiratory failure | 0/598 (0%) | 2/611 (0.3%) | ||
| Interstitial lung disease | 1/598 (0.2%) | 1/611 (0.2%) | ||
| Acute respiratory distress syndrome | 0/598 (0%) | 1/611 (0.2%) | ||
| Pneumothorax | 0/598 (0%) | 1/611 (0.2%) | ||
| Vascular disorders | ||||
| Hypertension | 1/598 (0.2%) | 5/611 (0.8%) | ||
| Hypotension | 3/598 (0.5%) | 4/611 (0.7%) | ||
| Deep vein thrombosis | 6/598 (1%) | 4/611 (0.7%) | ||
| Phlebitis superficial | 1/598 (0.2%) | 0/611 (0%) | ||
| Orthostatic hypotension | 1/598 (0.2%) | 2/611 (0.3%) | ||
| Hypertensive crisis | 0/598 (0%) | 1/611 (0.2%) | ||
| Subclavian artery stenosis | 1/598 (0.2%) | 0/611 (0%) | ||
| Venous thrombosis limb | 0/598 (0%) | 1/611 (0.2%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Placebo | Aflibercept | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 551/598 (92.1%) | 573/611 (93.8%) | ||
| Eye disorders | ||||
| Lacrimation increased | 71/598 (11.9%) | 119/611 (19.5%) | ||
| Gastrointestinal disorders | ||||
| Diarrhoea | 209/598 (34.9%) | 268/611 (43.9%) | ||
| Stomatitis | 123/598 (20.6%) | 340/611 (55.6%) | ||
| Nausea | 166/598 (27.8%) | 165/611 (27%) | ||
| Constipation | 131/598 (21.9%) | 133/611 (21.8%) | ||
| Vomiting | 84/598 (14%) | 90/611 (14.7%) | ||
| Abdominal pain | 45/598 (7.5%) | 47/611 (7.7%) | ||
| Dyspepsia | 29/598 (4.8%) | 31/611 (5.1%) | ||
| Haemorrhoids | 14/598 (2.3%) | 31/611 (5.1%) | ||
| Dysphagia | 1/598 (0.2%) | 31/611 (5.1%) | ||
| General disorders | ||||
| Fatigue | 241/598 (40.3%) | 243/611 (39.8%) | ||
| Asthenia | 123/598 (20.6%) | 144/611 (23.6%) | ||
| Oedema peripheral | 157/598 (26.3%) | 57/611 (9.3%) | ||
| Pyrexia | 54/598 (9%) | 61/611 (10%) | ||
| Infections and infestations | ||||
| Urinary tract infection | 38/598 (6.4%) | 39/611 (6.4%) | ||
| Nasopharyngitis | 36/598 (6%) | 23/611 (3.8%) | ||
| Investigations | ||||
| Weight decreased | 51/598 (8.5%) | 201/611 (32.9%) | ||
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 110/598 (18.4%) | 190/611 (31.1%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 83/598 (13.9%) | 55/611 (9%) | ||
| Arthralgia | 66/598 (11%) | 42/611 (6.9%) | ||
| Pain in extremity | 62/598 (10.4%) | 42/611 (6.9%) | ||
| Myalgia | 58/598 (9.7%) | 41/611 (6.7%) | ||
| Bone pain | 44/598 (7.4%) | 35/611 (5.7%) | ||
| Musculoskeletal pain | 33/598 (5.5%) | 21/611 (3.4%) | ||
| Muscle spasms | 31/598 (5.2%) | 17/611 (2.8%) | ||
| Nervous system disorders | ||||
| Dysgeusia | 107/598 (17.9%) | 108/611 (17.7%) | ||
| Headache | 45/598 (7.5%) | 95/611 (15.5%) | ||
| Neuropathy peripheral | 76/598 (12.7%) | 56/611 (9.2%) | ||
| Peripheral sensory neuropathy | 75/598 (12.5%) | 51/611 (8.3%) | ||
| Paraesthesia | 49/598 (8.2%) | 38/611 (6.2%) | ||
| Dizziness | 50/598 (8.4%) | 29/611 (4.7%) | ||
| Psychiatric disorders | ||||
| Insomnia | 44/598 (7.4%) | 45/611 (7.4%) | ||
| Renal and urinary disorders | ||||
| Proteinuria | 6/598 (1%) | 31/611 (5.1%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Dysphonia | 36/598 (6%) | 230/611 (37.6%) | ||
| Epistaxis | 55/598 (9.2%) | 199/611 (32.6%) | ||
| Cough | 77/598 (12.9%) | 111/611 (18.2%) | ||
| Dyspnoea | 62/598 (10.4%) | 89/611 (14.6%) | ||
| Oropharyngeal pain | 23/598 (3.8%) | 69/611 (11.3%) | ||
| Rhinorrhoea | 17/598 (2.8%) | 38/611 (6.2%) | ||
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 268/598 (44.8%) | 224/611 (36.7%) | ||
| Nail disorder | 97/598 (16.2%) | 94/611 (15.4%) | ||
| Rash | 33/598 (5.5%) | 49/611 (8%) | ||
| Palmar-plantar erythrodysaesthesia syndrome | 5/598 (0.8%) | 51/611 (8.3%) | ||
| Vascular disorders | ||||
| Hypertension | 66/598 (11%) | 207/611 (33.9%) | ||
Limitations/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.
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 |
| Phone | |
| Contact-Us@sanofi.com |
Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT00519285
Other Study ID Numbers:
- EFC6546
- 2006-004756-20
First Posted:
Aug 22, 2007
Last Update Posted:
Jul 22, 2016
Last Verified:
Jun 1, 2016