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Phase III Trial BI 695502 Plus Chemotherapy vs. Avastin® Plus Chemotherapy in Patients With Lung Cancer

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ClinicalTrials.gov Identifier: NCT02272413
Recruitment Status : Completed
First Posted : October 23, 2014
Results First Posted : January 13, 2020
Last Update Posted : January 13, 2020
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Carcinoma, Non-Small-Cell Lung
Interventions Drug: BI 695502
Drug: Avastin
Enrollment 671
Recruitment Details Phase III, randomized, double-blind, multicenter, active comparator, parallel 2-arm trial in patients with advanced non-squamous non-small cell lung cancer (nsNSCLC). From 21December2017, Sponsor recommended, patients to be switched from BI 695502 to reference product Avastin® (commercially available) as soon as it was available at clinical site.
Pre-assignment Details All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria were violated.
Arm/Group Title BI 695502 Avastin® US
Hide Arm/Group Description Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication.

After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Period Title: Randomized Through Treatment Start
Started [1] 338 [2] 333 [2]
Treated 335 328
Completed [3] 335 328
Not Completed 3 5
Reason Not Completed
Not treated             3             5
[1]
Started are randomized
[2]
Started for this period
[3]
Completed are treated
Period Title: Pre-switch Period
Started [1] 335 [2] 328 [2]
Completed 42 46
Not Completed 293 282
Reason Not Completed
Adverse Event             38             37
Death             26             26
Withdrawal by Subject             27             15
Physician Decision             6             18
Progressive disease             185             173
Lost to Follow-up             0             2
Protocol Violation             1             0
Other than listed             10             11
[1]
Started are treated
[2]
Started for this period
Period Title: Post-switch Period
Started 42 [1] 46 [1]
Completed 0 0
Not Completed 42 46
Reason Not Completed
Adverse Event             4             4
Death             3             2
Withdrawal by Subject             1             2
Physician Decision             1             1
Progressive disease             21             21
Study terminated by sponsor             8             11
Other than listed             4             5
[1]
Started for this period
Arm/Group Title BI 695502 Avastin® US Total
Hide Arm/Group Description Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication.

After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Total of all reporting groups
Overall Number of Baseline Participants 335 328 663
Hide Baseline Analysis Population Description
Full Analysis Set (FAS): The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 335 participants 328 participants 663 participants
61.2  (9.89) 61.3  (9.22) 61.2  (9.55)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 335 participants 328 participants 663 participants
Female
121
  36.1%
125
  38.1%
246
  37.1%
Male
214
  63.9%
203
  61.9%
417
  62.9%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 335 participants 328 participants 663 participants
Hispanic or Latino
43
  12.8%
34
  10.4%
77
  11.6%
Not Hispanic or Latino
284
  84.8%
285
  86.9%
569
  85.8%
Unknown or Not Reported
8
   2.4%
9
   2.7%
17
   2.6%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 335 participants 328 participants 663 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
64
  19.1%
71
  21.6%
135
  20.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   0.3%
1
   0.3%
2
   0.3%
White
258
  77.0%
248
  75.6%
506
  76.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
12
   3.6%
8
   2.4%
20
   3.0%
1.Primary Outcome
Title Best Overall Response Rate (ORR), Based on Unconfirmed Response Assessment, as Assessed by Central Imaging Review Until 18 Weeks After the Start of Treatment
Hide Description ORR was defined as the percentage of patients who achieved at least one visit response of complete response (CR) or partial response (PR) after the start of treatment. The response criteria evaluation was carried out according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR and PR did not need to be confirmed by a subsequent tumor assessment due to blinded central assessment. CR: Disappearance of all target lesions since baseline; PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Tumor assessments were performed prior to trial drug administration, until 18 weeks.
Time Frame Tumor assessment scans were performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12) and at Week 18 ±14 days. Best ORR evaluated until confirmed disease progression, unacceptable toxicity, death or up to 18 weeks, whichever happened earlier.
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Best ORR (CR+PR) is reported for observed values.
Arm/Group Title BI 695502 Avastin® US
Hide Arm/Group Description:
Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication.

After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Overall Number of Participants Analyzed 335 328
Measure Type: Number
Unit of Measure: Percentage of patients (%)
54.0 63.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian).
Type of Statistical Test Equivalence
Comments The null hypothesis was to be rejected in favor of equivalence if the 2-sided 90% confidence interval (CI) for the ratio in best ORR between the treatments was entirely contained within the equivalence margins of 0.736 to 1.359.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Log-binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of best ORR
Estimated Value 0.8550
Confidence Interval (2-Sided) 90%
0.7697 to 0.9506
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Analysis was based on a log-binomial regression model with subsequent transformation of the estimated parameter (ratio of best ORR) respective CIs to the ratio scale. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus Non-East Asian).
Type of Statistical Test Equivalence
Comments Additional analysis of the primary endpoint was performed for Japan according to a local protocol amendment Japan. For the submission in Japan, to conclude on equivalence, the 2-sided 95% CI for the ratio of best ORR between the treatments had to be entirely contained within the equivalence margins of 0.736 to 1.359.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Log-binomial regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio of best ORR
Estimated Value 0.8550
Confidence Interval (2-Sided) 95%
0.7543 to 0.9700
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Patients With Selected Treatment-Emergent Adverse Events (TEAEs) For Comparability Assessment of BI 695502 and US-licensed Avastin®
Hide Description

The following selected adverse events (AEs) were evaluated for comparability assessment of BI 695502 and US-licensed Avastin®:

  • Infusion reactions (anaphylactic/hypersensitivity/infusion-related reactions),
  • Thromboembolic events (arterial or venous),
  • Febrile neutropenia,
  • Gastrointestinal perforations,
  • Hypertension,
  • Proteinuria,
  • Pulmonary hemorrhage,
  • Other hemorrhages (not including pulmonary hemorrhages),
  • Wound-healing complications/abscess/fistulas. The analysis of AEs was based on the concept of TEAEs. For non-switched patients, all AEs that started or worsened in severity on or after the first dose of trial drug and prior to the date of last administration of trial medication + 16 weeks inclusive were defined as TEAEs.
Time Frame From first dose of trial drug until 16 weeks after the last dose of trial medication, up to 218 days.
Hide Outcome Measure Data
Hide Analysis Population Description
The Treated Set contained all patients who signed informed consent and who received at least one dose of trial drug.
Arm/Group Title BI 695502 Avastin® US
Hide Arm/Group Description:
Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication.

After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Overall Number of Participants Analyzed 335 328
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of patients (%)
AtLeast 1 AE selected for Comparability Assessment
52.50
(47.04 to 57.99)
45.10
(39.65 to 50.68)
Infusion reactions
16.70
(12.88 to 21.15)
13.10
(9.65 to 17.25)
Thromboembolic events
6.60
(4.16 to 9.77)
5.50
(3.28 to 8.53)
Febrile neutropenia
3.90
(2.08 to 6.54)
3.40
(1.69 to 5.92)
Gastrointestinal perforations
2.10
(0.84 to 4.26)
0.60
(0.07 to 2.19)
Hypertension
15.50
(11.82 to 19.85)
16.20
(12.34 to 20.60)
Proteinuria
15.80
(12.08 to 20.18)
14.60
(10.99 to 18.93)
Pulmonary haemorrhage
1.20
(0.33 to 3.03)
0.90
(0.19 to 2.65)
Other hemorrhages
20.00
(15.85 to 24.69)
16.20
(12.34 to 20.60)
Wound-healing complications/abscess/fistulas
2.70
(1.24 to 5.04)
2.10
(0.86 to 4.35)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments At least 1 AE selected for comparability assessment, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.16
Confidence Interval (2-Sided) 95%
0.99 to 1.37
Estimation Comments [Not Specified]
Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Infusion reactions, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.28
Confidence Interval (2-Sided) 95%
0.88 to 1.88
Estimation Comments [Not Specified]
Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Thromboembolic events, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio
Estimated Value 1.20
Confidence Interval (2-Sided) 95%
0.64 to 2.32
Estimation Comments [Not Specified]
Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Febrile neutropenia, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.16
Confidence Interval (2-Sided) 95%
0.51 to 2.76
Estimation Comments [Not Specified]
Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Gastrointestinal perforations, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 3.43
Confidence Interval (2-Sided) 95%
0.79 to 32.82
Estimation Comments [Not Specified]
Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Hypertension, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.66 to 1.39
Estimation Comments [Not Specified]
Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Proteinuria, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.08
Confidence Interval (2-Sided) 95%
0.74 to 1.57
Estimation Comments [Not Specified]
Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Pulmonary haemorrhage, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.31
Confidence Interval (2-Sided) 95%
0.28 to 10.79
Estimation Comments [Not Specified]
Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Other hemorrhages, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score exact method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.24
Confidence Interval (2-Sided) 95%
0.88 to 1.74
Estimation Comments [Not Specified]
Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Wound healing complications/ abscesses/ fistulas, risk ratio X (BI 695502) versus Y (US-licensed Avastin®) was defined as (a/(a+b))/(c/(c+d)), where 'a' was the number of patients with TEAEs selected for comparability within treatment group X, 'a+b' was the total number of patients in treatment group X, 'c' was the number of patients with TEAEs selected for comparability within treatment group Y and 'c+d' was the total number of patients in treatment group Y.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Score excat method
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 1.26
Confidence Interval (2-Sided) 95%
0.47 to 3.57
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Progression-Free Survival (PFS) Time as Determined by Investigator Assessment
Hide Description PFS was defined as the time from randomization until disease progression as determined by Investigator assessment or death from any cause, whichever occurred first during the pre-switch period. Disease progression was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 millimeters. Tumor assessments were performed prior to trial drug administration. PFS was calculated using the Kaplan-Meier technique.
Time Frame Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression. Analysis performed for pre-switch period only; maximum duration of up to 35 cycles (105 weeks).
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment.
Arm/Group Title BI 695502 Avastin® US
Hide Arm/Group Description:
Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication.

After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Overall Number of Participants Analyzed 335 328
Median (95% Confidence Interval)
Unit of Measure: Months
8.34
(7.49 to 8.77)
9.00
(8.34 to 10.38)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Cox-proportional hazards regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.22
Confidence Interval (2-Sided) 95%
1.02 to 1.45
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Overall Survival (OS) Time
Hide Description OS was defined as the time randomization until death from any cause during the pre-switch period. OS was calculated using the Kaplan-Meier technique.
Time Frame From baseline until death due to any cause, ie., up to 35 cycles (105 weeks).
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment.
Arm/Group Title BI 695502 Avastin® US
Hide Arm/Group Description:
Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication.

After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Overall Number of Participants Analyzed 335 328
Median (95% Confidence Interval)
Unit of Measure: Months
15.57
(14.16 to 17.25)
19.48
(15.87 to 20.73)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Cox-proportional hazards regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.23
Confidence Interval (2-Sided) 95%
1.00 to 1.51
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Duration of Response (DOR) as Determined by Investigator Assessment
Hide Description DOR was the time from first documented CR or PR until time of progression as determined by Investigator assessment during the pre-switch period. Tumor assessments were performed prior to trial drug administration. DOR was calculated using the Kaplan-Meier technique.
Time Frame Tumor scans performed at baseline, Cycle 3 (Week 6), Cycle 5 (Week 12), Cycle 7 (Week 18), then every 3 cycles (~9 weeks) until confirmed disease progression., ie up to 35 cycles (105 weeks).
Hide Outcome Measure Data
Hide Analysis Population Description
The FAS contained all randomized patients who received at least 1 dose of trial drug and who had a baseline tumor assessment. Only patients with an objective response were included in the analysis.
Arm/Group Title BI 695502 Avastin® US
Hide Arm/Group Description:
Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 body surface area (BSA), followed by carboplatin target area under the curve (AUC) 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication.

After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Overall Number of Participants Analyzed 175 187
Median (95% Confidence Interval)
Unit of Measure: Months
7.66
(7.03 to 9.03)
8.94
(7.26 to 10.28)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection BI 695502, Avastin® US
Comments Analysis based on a Cox-proportional hazards regression model. The model included the following explanatory variables: treatment, sex (male versus female), smoking status (never smoked versus current/ex-smoker), NSCLC stage (recurrent versus Stage IV) and ethnicity (East Asian origin versus non East Asian).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Cox-proportional hazards regression
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.14
Confidence Interval (2-Sided) 95%
0.88 to 1.48
Estimation Comments [Not Specified]
Time Frame For Pre-switch period: From first dose of trial drug until 112 days (16 weeks) after the last dose of trial medication, up to 218 days. For post-switch period: From the first dose of Avastin® until end of treatment (EOT) visit, up to 127 days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title BI 695502 (Pre-switch) US-licensed Avastin® (Pre-switch) BI 695502 (Post-switch) US-licensed Avastin® (Post-switch)
Hide Arm/Group Description Patients received BI 695502 solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles. During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with BI 695502 monotherapy could be started per the original randomization. Patients then received BI 695502 as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients received US-licensed Avastin® solution for i.v. infusion, 15 mg/kg bw, every 3 weeks for up to 6 cycles.

During the induction cycles, patients also received standard combination chemotherapy consisting of paclitaxel 200 mg/m^2 BSA, followed by carboplatin target AUC 6 mg/mL*min, with adequate pre- and concomitant medication. After Cycle 4 to 6, for responding or stabilized patients, maintenance treatment with US-licensed Avastin® monotherapy could be started per the original randomization. Patients then received US-licensed Avastin® as a single agent until disease progression, death, withdrawal of consent, unacceptable toxicity, or until the Switch Visit (when each patient was switched to receive commercially available Avastin®), whichever occurred earlier.

Patients switched from BI 695502 to receive commercially available Avastin®. Patients switched from US-licensed Avastin® to receive commercially available Avastin®.
All-Cause Mortality
BI 695502 (Pre-switch) US-licensed Avastin® (Pre-switch) BI 695502 (Post-switch) US-licensed Avastin® (Post-switch)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   193/335 (57.61%)   184/328 (56.10%)   3/42 (7.14%)   2/46 (4.35%) 
Hide Serious Adverse Events
BI 695502 (Pre-switch) US-licensed Avastin® (Pre-switch) BI 695502 (Post-switch) US-licensed Avastin® (Post-switch)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   108/335 (32.24%)   89/328 (27.13%)   5/42 (11.90%)   2/46 (4.35%) 
Blood and lymphatic system disorders         
Febrile neutropenia  1  13/335 (3.88%)  11/328 (3.35%)  0/42 (0.00%)  0/46 (0.00%) 
Anaemia  1  6/335 (1.79%)  11/328 (3.35%)  0/42 (0.00%)  0/46 (0.00%) 
Neutropenia  1  4/335 (1.19%)  9/328 (2.74%)  0/42 (0.00%)  0/46 (0.00%) 
Thrombocytopenia  1  4/335 (1.19%)  5/328 (1.52%)  0/42 (0.00%)  0/46 (0.00%) 
Bone marrow failure  1  2/335 (0.60%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Leukopenia  1  1/335 (0.30%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Pancytopenia  1  1/335 (0.30%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Disseminated intravascular coagulati  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Cardiac disorders         
Acute myocardial infarction  1  1/335 (0.30%)  0/328 (0.00%)  1/42 (2.38%)  0/46 (0.00%) 
Atrial fibrillation  1  1/335 (0.30%)  3/328 (0.91%)  0/42 (0.00%)  0/46 (0.00%) 
Cardiac arrest  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Cardiac failure acute  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Cardiopulmonary failure  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Arrhythmia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Cardiac failure  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Coronary artery occlusion  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Sinus tachycardia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Cardiac tamponade  1  0/335 (0.00%)  0/328 (0.00%)  1/42 (2.38%)  0/46 (0.00%) 
Myocardial ischaemia  1  0/335 (0.00%)  0/328 (0.00%)  1/42 (2.38%)  0/46 (0.00%) 
Myocardial rupture  1  0/335 (0.00%)  0/328 (0.00%)  1/42 (2.38%)  0/46 (0.00%) 
Congenital, familial and genetic disorders         
Pyloric stenosis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Ear and labyrinth disorders         
Deafness bilateral  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Eye disorders         
Retinal artery occlusion  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Vision blurred  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Gastrointestinal disorders         
Vomiting  1  4/335 (1.19%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Nausea  1  3/335 (0.90%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Diarrhoea  1  2/335 (0.60%)  6/328 (1.83%)  0/42 (0.00%)  1/46 (2.17%) 
Anal incontinence  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Constipation  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Diverticular perforation  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Diverticulum intestinal  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Duodenal perforation  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Duodenal ulcer  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Gastric ulcer  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Gastrointestinal perforation  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Lower gastrointestinal haemorrhage  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Upper gastrointestinal haemorrhage  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Colitis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Dyspepsia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Dysphagia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Ileus paralytic  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Small intestinal obstruction  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Oesophageal perforation  1  0/335 (0.00%)  0/328 (0.00%)  1/42 (2.38%)  0/46 (0.00%) 
Oesophagobronchial fistula  1  0/335 (0.00%)  0/328 (0.00%)  1/42 (2.38%)  0/46 (0.00%) 
General disorders         
Chest pain  1  3/335 (0.90%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Pyrexia  1  2/335 (0.60%)  5/328 (1.52%)  0/42 (0.00%)  0/46 (0.00%) 
Death  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Non-cardiac chest pain  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Pain  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Sudden cardiac death  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Sudden death  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Asthenia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Fatigue  1  0/335 (0.00%)  3/328 (0.91%)  0/42 (0.00%)  0/46 (0.00%) 
General physical health deterioratio  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Hepatobiliary disorders         
Bile duct obstruction  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Cholecystitis acute  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Hepatitis toxic  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Hepatocellular injury  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Hyperbilirubinaemia  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Jaundice cholestatic  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Cholelithiasis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Drug-induced liver injury  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Hepatic failure  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Liver injury  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Immune system disorders         
Anaphylactic reaction  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Anaphylactic shock  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Drug hypersensitivity  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Hypersensitivity  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Infections and infestations         
Pneumonia  1  9/335 (2.69%)  9/328 (2.74%)  1/42 (2.38%)  0/46 (0.00%) 
Lung infection  1  2/335 (0.60%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Peritonitis  1  2/335 (0.60%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Pyelonephritis  1  2/335 (0.60%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Anal abscess  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Anorectal infection  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Appendicitis perforated  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Klebsiella infection  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Lower respiratory tract infection  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Lung abscess  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Osteomyelitis  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Pulmonary mycosis  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Respiratory tract infection  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Urinary tract infection  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Bronchitis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Campylobacter gastroenteritis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Diverticulitis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Gastroenteritis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Herpes zoster  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Infectious pleural effusion  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Pneumonia bacterial  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  1/46 (2.17%) 
Respiratory tract infection bacteria  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Subcutaneous abscess  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Upper respiratory tract infection  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Urosepsis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Sepsis  1  0/335 (0.00%)  0/328 (0.00%)  1/42 (2.38%)  0/46 (0.00%) 
Injury, poisoning and procedural complications         
Clavicle fracture  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Femoral neck fracture  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Infusion related reaction  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Procedural pneumothorax  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Fall  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Hip fracture  1  0/335 (0.00%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Meniscus injury  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Spinal compression fracture  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Investigations         
Neutrophil count decreased  1  5/335 (1.49%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Platelet count decreased  1  2/335 (0.60%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Alanine aminotransferase increased  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Aspartate aminotransferase increased  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Blood creatinine increased  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Blood magnesium decreased  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
White blood cell count decreased  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Metabolism and nutrition disorders         
Hyponatraemia  1  4/335 (1.19%)  3/328 (0.91%)  0/42 (0.00%)  0/46 (0.00%) 
Dehydration  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Hypokalaemia  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Decreased appetite  1  0/335 (0.00%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Electrolyte imbalance  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Hyperkalaemia  1  0/335 (0.00%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Hypoalbuminaemia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Hypocalcaemia  1  0/335 (0.00%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Hypochloraemia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Hypomagnesaemia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Exposed bone in jaw  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Intervertebral disc protrusion  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Muscular weakness  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Myalgia  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Osteonecrosis of jaw  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Bone pain  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Musculoskeletal pain  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Bladder transitional cell carcinoma  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Brain neoplasm  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Intracranial tumour haemorrhage  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Nervous system disorders         
Cerebral infarction  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Headache  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Hemiparesis  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Intracranial pressure increased  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Neuropathy peripheral  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Spinal cord compression  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Transient ischaemic attack  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Brain oedema  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Cerebrovascular accident  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Seizure  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Psychiatric disorders         
Delirium  1  3/335 (0.90%)  3/328 (0.91%)  0/42 (0.00%)  0/46 (0.00%) 
Anxiety  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Suicide attempt  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Confusional state  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Renal and urinary disorders         
Bladder obstruction  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Hydronephrosis  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Renal impairment  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Acute kidney injury  1  0/335 (0.00%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Renal failure  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Urinary retention  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Reproductive system and breast disorders         
Benign prostatic hyperplasia  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Pulmonary embolism  1  11/335 (3.28%)  5/328 (1.52%)  0/42 (0.00%)  0/46 (0.00%) 
Dyspnoea  1  6/335 (1.79%)  4/328 (1.22%)  0/42 (0.00%)  0/46 (0.00%) 
Pneumothorax  1  5/335 (1.49%)  7/328 (2.13%)  0/42 (0.00%)  0/46 (0.00%) 
Respiratory failure  1  5/335 (1.49%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Haemoptysis  1  3/335 (0.90%)  2/328 (0.61%)  0/42 (0.00%)  0/46 (0.00%) 
Pulmonary haemorrhage  1  3/335 (0.90%)  1/328 (0.30%)  1/42 (2.38%)  0/46 (0.00%) 
Acquired tracheo-oesophageal fistula  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Bronchial fistula  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Chronic obstructive pulmonary diseas  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Pneumonia aspiration  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Aspiration  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Atelectasis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Bronchospasm  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Epistaxis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Idiopathic pulmonary fibrosis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Pulmonary necrosis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Skin and subcutaneous tissue disorders         
Hyperhidrosis  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Vascular disorders         
Deep vein thrombosis  1  4/335 (1.19%)  6/328 (1.83%)  0/42 (0.00%)  0/46 (0.00%) 
Shock haemorrhagic  1  3/335 (0.90%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Hypotension  1  2/335 (0.60%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Hypertensive crisis  1  1/335 (0.30%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Internal haemorrhage  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Microembolism  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Peripheral embolism  1  1/335 (0.30%)  0/328 (0.00%)  0/42 (0.00%)  0/46 (0.00%) 
Arterial thrombosis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Embolism venous  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Vascular stenosis  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
Vasoconstriction  1  0/335 (0.00%)  1/328 (0.30%)  0/42 (0.00%)  0/46 (0.00%) 
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
BI 695502 (Pre-switch) US-licensed Avastin® (Pre-switch) BI 695502 (Post-switch) US-licensed Avastin® (Post-switch)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   293/335 (87.46%)   288/328 (87.80%)   20/42 (47.62%)   22/46 (47.83%) 
Blood and lymphatic system disorders         
Anaemia  1  112/335 (33.43%)  84/328 (25.61%)  2/42 (4.76%)  4/46 (8.70%) 
Neutropenia  1  61/335 (18.21%)  52/328 (15.85%)  0/42 (0.00%)  2/46 (4.35%) 
Thrombocytopenia  1  44/335 (13.13%)  47/328 (14.33%)  1/42 (2.38%)  4/46 (8.70%) 
Leukopenia  1  18/335 (5.37%)  23/328 (7.01%)  0/42 (0.00%)  2/46 (4.35%) 
Gastrointestinal disorders         
Nausea  1  73/335 (21.79%)  75/328 (22.87%)  2/42 (4.76%)  1/46 (2.17%) 
Diarrhoea  1  60/335 (17.91%)  45/328 (13.72%)  1/42 (2.38%)  1/46 (2.17%) 
Vomiting  1  56/335 (16.72%)  37/328 (11.28%)  1/42 (2.38%)  1/46 (2.17%) 
Constipation  1  51/335 (15.22%)  44/328 (13.41%)  1/42 (2.38%)  1/46 (2.17%) 
General disorders         
Fatigue  1  54/335 (16.12%)  53/328 (16.16%)  2/42 (4.76%)  1/46 (2.17%) 
Asthenia  1  22/335 (6.57%)  29/328 (8.84%)  1/42 (2.38%)  2/46 (4.35%) 
Malaise  1  19/335 (5.67%)  13/328 (3.96%)  0/42 (0.00%)  0/46 (0.00%) 
Pyrexia  1  17/335 (5.07%)  21/328 (6.40%)  0/42 (0.00%)  1/46 (2.17%) 
Investigations         
Platelet count decreased  1  41/335 (12.24%)  33/328 (10.06%)  0/42 (0.00%)  0/46 (0.00%) 
Neutrophil count decreased  1  39/335 (11.64%)  42/328 (12.80%)  0/42 (0.00%)  0/46 (0.00%) 
White blood cell count decreased  1  30/335 (8.96%)  19/328 (5.79%)  0/42 (0.00%)  0/46 (0.00%) 
Alanine aminotransferase increased  1  24/335 (7.16%)  32/328 (9.76%)  0/42 (0.00%)  2/46 (4.35%) 
Gamma-glutamyltransferase increased  1  22/335 (6.57%)  31/328 (9.45%)  1/42 (2.38%)  6/46 (13.04%) 
Weight decreased  1  21/335 (6.27%)  22/328 (6.71%)  2/42 (4.76%)  1/46 (2.17%) 
Blood cholesterol increased  1  20/335 (5.97%)  16/328 (4.88%)  1/42 (2.38%)  3/46 (6.52%) 
Aspartate aminotransferase increased  1  19/335 (5.67%)  30/328 (9.15%)  1/42 (2.38%)  3/46 (6.52%) 
Blood alkaline phosphatase increased  1  17/335 (5.07%)  25/328 (7.62%)  0/42 (0.00%)  3/46 (6.52%) 
Haemoglobin decreased  1  5/335 (1.49%)  17/328 (5.18%)  0/42 (0.00%)  0/46 (0.00%) 
Metabolism and nutrition disorders         
Decreased appetite  1  54/335 (16.12%)  54/328 (16.46%)  2/42 (4.76%)  4/46 (8.70%) 
Hyperglycaemia  1  21/335 (6.27%)  28/328 (8.54%)  0/42 (0.00%)  4/46 (8.70%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  40/335 (11.94%)  35/328 (10.67%)  1/42 (2.38%)  0/46 (0.00%) 
Myalgia  1  38/335 (11.34%)  29/328 (8.84%)  0/42 (0.00%)  1/46 (2.17%) 
Back pain  1  22/335 (6.57%)  14/328 (4.27%)  1/42 (2.38%)  0/46 (0.00%) 
Musculoskeletal pain  1  18/335 (5.37%)  10/328 (3.05%)  0/42 (0.00%)  0/46 (0.00%) 
Pain in extremity  1  12/335 (3.58%)  18/328 (5.49%)  1/42 (2.38%)  0/46 (0.00%) 
Nervous system disorders         
Neuropathy peripheral  1  62/335 (18.51%)  59/328 (17.99%)  1/42 (2.38%)  0/46 (0.00%) 
Peripheral sensory neuropathy  1  56/335 (16.72%)  53/328 (16.16%)  0/42 (0.00%)  1/46 (2.17%) 
Headache  1  26/335 (7.76%)  25/328 (7.62%)  1/42 (2.38%)  2/46 (4.35%) 
Paraesthesia  1  20/335 (5.97%)  19/328 (5.79%)  0/42 (0.00%)  0/46 (0.00%) 
Dysgeusia  1  13/335 (3.88%)  17/328 (5.18%)  0/42 (0.00%)  0/46 (0.00%) 
Psychiatric disorders         
Insomnia  1  15/335 (4.48%)  18/328 (5.49%)  1/42 (2.38%)  0/46 (0.00%) 
Renal and urinary disorders         
Proteinuria  1  51/335 (15.22%)  46/328 (14.02%)  8/42 (19.05%)  6/46 (13.04%) 
Respiratory, thoracic and mediastinal disorders         
Cough  1  38/335 (11.34%)  32/328 (9.76%)  0/42 (0.00%)  5/46 (10.87%) 
Epistaxis  1  38/335 (11.34%)  32/328 (9.76%)  0/42 (0.00%)  0/46 (0.00%) 
Dyspnoea  1  22/335 (6.57%)  31/328 (9.45%)  0/42 (0.00%)  1/46 (2.17%) 
Haemoptysis  1  17/335 (5.07%)  10/328 (3.05%)  0/42 (0.00%)  1/46 (2.17%) 
Skin and subcutaneous tissue disorders         
Alopecia  1  155/335 (46.27%)  149/328 (45.43%)  0/42 (0.00%)  0/46 (0.00%) 
Rash  1  17/335 (5.07%)  16/328 (4.88%)  1/42 (2.38%)  0/46 (0.00%) 
Vascular disorders         
Hypertension  1  49/335 (14.63%)  51/328 (15.55%)  3/42 (7.14%)  1/46 (2.17%) 
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
From 21 December 2017, after Week 18 primary analysis data cut-off, the Sponsor recommended to switch patients from BI 695502/US-licensed Avastin® to Avastin®. The main analyses to report all endpoint and AE results was the pre-switch period.
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.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim, Call Centre
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02272413    
Other Study ID Numbers: 1302.5
2014-002161-30 ( EudraCT Number )
First Submitted: October 21, 2014
First Posted: October 23, 2014
Results First Submitted: November 15, 2019
Results First Posted: January 13, 2020
Last Update Posted: January 13, 2020