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Lume Lung 2 : BIBF 1120 Plus Pemetrexed Compared to Placebo Plus Pemetrexed in 2nd Line Nonsquamous NSCLC

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ClinicalTrials.gov Identifier: NCT00806819
Recruitment Status : Completed
First Posted : December 11, 2008
Results First Posted : November 20, 2014
Last Update Posted : February 2, 2017
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Carcinoma, Non-Small-Cell Lung
Interventions Drug: Nintedanib (BIBF1120)
Drug: Pemetrexed
Drug: pemetrexed
Drug: B12
Drug: dexamethasone (or corticosteroid equivalent)
Drug: placebo
Drug: Folic Acid
Enrollment 718
Recruitment Details  
Pre-assignment Details 5 patients at one investigator site were excluded from the enrollment count because of site non-compliance.
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Period Title: Overall Study
Started 353 [1] 360 [1]
Completed 7 [2] 2 [2]
Not Completed 346 358
Reason Not Completed
progressive disease (modified RECIST )             217             216
Worsening or AE of underlying disease             18             25
Other AE             38             40
Protocol Violation             9             4
Lost to Follow-up             1             0
Withdrawal by Subject             32             29
Not treated             6             3
Reasons other than stated above             25             41
[1]
randomised patients
[2]
On-treatment at analysis DBL date (15 February 2013)
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed Total
Hide Arm/Group Description Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Total of all reporting groups
Overall Number of Baseline Participants 353 360 713
Hide Baseline Analysis Population Description
Randomised set uncut (RS): all patients who were randomised whether patients had received study treatment or not. Patients were allocated to the treatment groups as randomised, regardless of the actual medication taken.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 353 participants 360 participants 713 participants
59.2  (10.3) 58.7  (10.9) 59.0  (10.6)
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 353 participants 360 participants 713 participants
Female
158
  44.8%
152
  42.2%
310
  43.5%
Male
195
  55.2%
208
  57.8%
403
  56.5%
1.Primary Outcome
Title Progression Free Survival (PFS) as Assessed by Central Independent Review
Hide Description

Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Progression free survival (PFS) is defined as the duration of time from date of randomisation to date of progression or death (whatever occurs earlier).

Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.

Time Frame From randomisation until cut-off date 9 July 2012
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: months
4.4
(2.3 to 9.5)
3.6
(1.4 to 7.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0435
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.70 to 0.99
Estimation Comments HR below 1 favors nintedanib
2.Secondary Outcome
Title Overall Survival (Key Secondary Endpoint)
Hide Description Overall Survival (OS) defined as the duration from randomisation to death (irrespective of the reason of death). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: months
12.0
(7.0 to 24.2)
12.7
(5.4 to 24.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8940
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.85 to 1.21
Estimation Comments HR below 1 favors nintedanib
3.Secondary Outcome
Title Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review
Hide Description Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: Months
4.4
(2.3 to 9.5)
3.4
(1.4 to 7.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0506
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.84
Confidence Interval (2-Sided) 95%
0.70 to 1.00
Estimation Comments HR below 1 favors nintedanib
4.Secondary Outcome
Title Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator
Hide Description Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by investigator according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.
Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: Months
5.3
(2.6 to 9.4)
4.3
(1.9 to 8.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0865
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval (2-Sided) 95%
0.73 to 1.02
Estimation Comments HR below 1 favors nintedanib
5.Secondary Outcome
Title Objective Tumor Response
Hide Description Confirmed objective response is defined as confirmed Complete Response (CR) and Partial Response (PR) and evaluated according to the modified RECIST criteria version 1.0. This endpoint was analysed based on the central independent reviewer as well as the investigator
Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Measure Type: Number
Unit of Measure: % of participants
Central independent reviewer 9.1 8.3
Investigator assessment 15.0 13.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis based on the central independent review
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7279
Comments Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1)
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.10
Confidence Interval (2-Sided) 95%
0.65 to 1.85
Estimation Comments An odds ratio >1 indicates a benefit to nintedanib
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis based on the investigator's assessment
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5180
Comments Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1)
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.15
Confidence Interval (2-Sided) 95%
0.75 to 1.76
Estimation Comments An odds ratio >1 indicates a benefit to nintedanib
6.Secondary Outcome
Title Duration of Confirmed Objective Tumour Response
Hide Description

The duration of objective response is the time from first documented (CR) or (PR) to the time of progression or death and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.

This endpoint was analysed based on the central independent reviewer as well as the investigator.

Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: Months
central independent reviewer (N=32, 30)
6.9
(5.1 to 11.3)
4.4
(3.3 to 8.9)
Investigator assessment (N=53, 48)
6.5
(4.4 to 12.7)
7.2
(4.2 to 16.2)
7.Secondary Outcome
Title Time to Confirmed Objective Tumour Response
Hide Description

Time to confirmed objective response is defined as time from randomisation to the date of first documented (CR) or (PR) and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.

This endpoint was analysed based on the central independent reviewer as well as the investigator.

Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: Months
Central independent review (N=32, 30)
2.6
(1.4 to 4.0)
2.7
(1.4 to 4.2)
Investigator assessment (N=53, 48)
2.6
(1.4 to 3.0)
2.8
(1.4 to 3.1)
8.Secondary Outcome
Title Disease Control
Hide Description

Disease control was defined as a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) and evaluated according to the modified RECIST criteria version 1.0.

This endpoint was analysed based on the central independent reviewer as well as the investigator.

Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Measure Type: Number
Unit of Measure: % of participants
Central independent review (N=215, 192) 60.9 53.3
Investigator assessment (N=233, 217) 66.0 60.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis based on the central independent review
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0387
Comments Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1)
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.37
Confidence Interval (2-Sided) 95%
1.02 to 1.85
Estimation Comments An odds ratio >1 indicates a benefit to nintedanib
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis based on investigator's assessment
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1071
Comments Odds ratio and p-value are obtained from logistic regression model adjusted for baseline ECOG PS (0 vs 1)
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.29
Confidence Interval (2-Sided) 95%
0.95 to 1.75
Estimation Comments An odds ratio >1 indicates a benefit to nintedanib
9.Secondary Outcome
Title Duration of Disease Control
Hide Description

The duration of disease control was defined as the time from randomisation to the date of disease progression or death (which ever occurs first) for patients with disease control. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.

This endpoint was analysed based on the central independent reviewer as well as the investigator.

Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: Months
Central independent review (N=215, 192)
7.4
(4.3 to 11.2)
6.8
(4.2 to 12.5)
Investigator assessment (N=233, 217)
6.9
(4.4 to 12.5)
6.8
(4.4 to 11.1)
10.Secondary Outcome
Title Change From Baseline in Tumour Size
Hide Description Percentage change from baseline in tumour size is defined as decrease in the sum of the longest diameter of the target lesion. Presented means are in fact adjusted best means percentage changes generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) This endpoint was analysed based on the central independent reviewer as well as the investigator.
Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Mean (95% Confidence Interval)
Unit of Measure: percentage of change in tumor size in mm
Central independent review (N=298, 305)
-10.10
(-12.63 to -7.58)
-7.53
(-10.03 to -5.04)
Investigator assessment (N=322, 325)
-15.60
(-18.75 to -12.46)
-11.28
(-14.42 to -8.15)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis based on the central independent review
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1558
Comments P-value generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
Method ANOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis based on the investigator's assessment
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0565
Comments P-value generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
Method ANOVA
Comments [Not Specified]
11.Secondary Outcome
Title Clinical Improvement.
Hide Description

Clinical improvement was defined as the time from randomisation to deterioration in body weight and/or Eastern Cooperative Oncology group performance score (ECOG PS) whichever occurred first.

Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.

Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
Hide Outcome Measure Data
Hide Analysis Population Description
RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: Months
7.2
(2.8 to 21.9)
7.5
(1.8 to 24.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments HR, CI and p-value obtained from the proportional hazards model stratified by baseline ECOG PS (0 vs 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5068
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.74 to 1.16
Estimation Comments HR below 1 favors nintedanib
12.Secondary Outcome
Title Quality of Life (QoL)
Hide Description

QoL was measured by standardised questionnaires (EQ-5D, EORTC QLQ-C30, EORTC QLQ-LC13). The EORTC QLQ-C30 comprises of 30 questions, using both multi-item scales and single-item measures. EORTC LC-13 comprises of 13 questions incorporating 1 multi-item scale and a series of single items. The following were the main points of interest: Time to deterioration of cough (QLQ-LC13 question 1), Time to deterioration of dyspnoea (QLQ-LC13, composite of questions 3 to 5), Time to deterioration of pain (QLQ- C30, composite of questions 9 and 19). Time to deterioration of cough, dyspnoea and pain was defined as the time to a 10-point increase from the baseline score.

Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.

Time Frame From randomisation until data cut-off (15 February 2013), Up to 30 months
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RS
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 353 360
Median (Inter-Quartile Range)
Unit of Measure: Months
Time to deterioration of cough
6.0
(2.2 to 23.6)
4.3 [1] 
(1.4 to NA)
Time to deterioration of dyspnoea
2.4
(0.9 to 6.4)
2.0
(0.8 to 5.7)
Time to deterioration of pain
2.8
(1.2 to 7.0)
2.7
(1.1 to 8.0)
[1]
As only 43.9% of patients had a deterioration of cough by the cut-off date, the 75th percentile was not estimable.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis evaluating the time to deterioration of cough. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >=1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no)
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1181
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.83
Confidence Interval (2-Sided) 95%
0.66 to 1.05
Estimation Comments HR below 1 favors nintedanib
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis evaluating the time to deterioration of dyspnoea. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >=1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4264
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.77 to 1.12
Estimation Comments HR below 1 favors nintedanib
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Nintedanib Plus Pemetrexed, Placebo Plus Pemetrexed
Comments Analysis evaluating the time to deterioration of pain. HR, CI and p-value obtained from the prop. hazards model stratified by baseline ECOG PS (0 vs >= 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8929
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.84 to 1.23
Estimation Comments HR below 1 favors nintedanib
13.Secondary Outcome
Title Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide
Hide Description Geometric mean of dose normalised predose plasma concentration (Cpre,ss,norm) of nintedanib and of its metabolites BIBF 1202 and BIBF 1202 glucuronide evaluated at steady state based on course 2 and 3. If only one value was available and valid, then this value was used for calculation of Cpre,ss,norm.
Time Frame Before the administration of nintedanib or placebo and between a window of 30 mins to an hour after administration of trial drug during Course 2 and between 1 and 3 hours after administration of trial drug during Course 3
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Pharmacokinetic set- all patients in the treated set who were documented to have received at least 1 dose of nintedanib and who had at least 1 valid drug plasma concentration available
Arm/Group Title Nintedanib Plus Pemetrexed Nintedanib 150 mg Bid Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Nintedanib 150 mg twice daily administered orally in a form of a soft gelatin capsule plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion.
Overall Number of Participants Analyzed 188 40
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL/mg
Nintedanib BIBF 1120 (N=188, 39)
0.0883
(66.4%)
0.103
(72.9%)
Nintedanib BIBF 1202 (N=188, 40)
0.131
(123%)
0.151
(125%)
Nintedanib BIBF 1202 glucuronide (N=184, 39)
1.40
(169%)
1.72
(185%)
14.Secondary Outcome
Title Incidence and Intensity of Adverse Events
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Incidence and intensity of adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The worst CTCAE grade per patient is reported and MedDRA version 15.1 used.

Serious signs and symptoms of progressive disease were reported as an adverse event in analysis of this endpoint.

Time Frame From the first drug administration until 28 days after the last drug administration, up to 36 months
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Treated set uncut - all randomised patients who were documented to have taken at least 1 dose of study medication . Patients were allocated to the treatment groups according to the treatment actually received.
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description:
Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 347 357
Measure Type: Number
Unit of Measure: % of participants
CTCAE grade 1 4.9 9.2
CTCAE grade 2 22.2 30.5
CTCAE grade 3 46.1 34.5
CTCAE grade 4 12.4 7.8
CTCAE grade 5 9.8 12.0
Time Frame From the first drug administration until 28 days after the last drug administration, up to 36 months
Adverse Event Reporting Description One patient in the nintedanib plus pemetrexed treatment arm reported a serious adverse event for which the preferred term was not yet coded until data cut-off (15 February 2013).
 
Arm/Group Title Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Hide Arm/Group Description Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
All-Cause Mortality
Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Affected / at Risk (%) Affected / at Risk (%)
Total   104/347 (29.97%)   117/357 (32.77%) 
Blood and lymphatic system disorders     
Anaemia  1  5/347 (1.44%)  8/357 (2.24%) 
Febrile neutropenia  1  7/347 (2.02%)  3/357 (0.84%) 
Leukocytosis  1  0/347 (0.00%)  1/357 (0.28%) 
Leukopenia  1  1/347 (0.29%)  1/357 (0.28%) 
Neutropenia  1  3/347 (0.86%)  1/357 (0.28%) 
Normochromic normocytic anaemia  1  0/347 (0.00%)  1/357 (0.28%) 
Thrombocytopenia  1  3/347 (0.86%)  2/357 (0.56%) 
Cardiac disorders     
Acute myocardial infarction  1  1/347 (0.29%)  0/357 (0.00%) 
Angina pectoris  1  0/347 (0.00%)  1/357 (0.28%) 
Angina unstable  1  1/347 (0.29%)  0/357 (0.00%) 
Atrial fibrillation  1  2/347 (0.58%)  3/357 (0.84%) 
Cardiac arrest  1  1/347 (0.29%)  1/357 (0.28%) 
Cardiac failure  1  0/347 (0.00%)  1/357 (0.28%) 
Cardiac failure congestive  1  1/347 (0.29%)  1/357 (0.28%) 
Cardiac tamponade  1  1/347 (0.29%)  0/357 (0.00%) 
Cardio-respiratory arrest  1  2/347 (0.58%)  1/357 (0.28%) 
Cardiopulmonary failure  1  1/347 (0.29%)  1/357 (0.28%) 
Congestive cardiomyopathy  1  0/347 (0.00%)  1/357 (0.28%) 
Myocardial infarction  1  2/347 (0.58%)  0/357 (0.00%) 
Myocardial ischaemia  1  1/347 (0.29%)  0/357 (0.00%) 
Pericardial effusion  1  2/347 (0.58%)  0/357 (0.00%) 
Sinus tachycardia  1  1/347 (0.29%)  0/357 (0.00%) 
Ear and labyrinth disorders     
Vertigo  1  1/347 (0.29%)  1/357 (0.28%) 
Vertigo positional  1  0/347 (0.00%)  1/357 (0.28%) 
Eye disorders     
Glaucoma  1  1/347 (0.29%)  0/357 (0.00%) 
Retinal detachment  1  1/347 (0.29%)  0/357 (0.00%) 
Gastrointestinal disorders     
Abdominal pain  1  2/347 (0.58%)  3/357 (0.84%) 
Colitis  1  0/347 (0.00%)  1/357 (0.28%) 
Colonic obstruction  1  0/347 (0.00%)  1/357 (0.28%) 
Diarrhoea  1  3/347 (0.86%)  1/357 (0.28%) 
Duodenal ulcer  1  1/347 (0.29%)  0/357 (0.00%) 
Gastritis  1  1/347 (0.29%)  0/357 (0.00%) 
Gastrooesophageal reflux disease  1  1/347 (0.29%)  0/357 (0.00%) 
Ileus  1  1/347 (0.29%)  1/357 (0.28%) 
Intestinal haemorrhage  1  0/347 (0.00%)  1/357 (0.28%) 
Large intestine perforation  1  1/347 (0.29%)  0/357 (0.00%) 
Nausea  1  2/347 (0.58%)  2/357 (0.56%) 
Oesophageal stenosis  1  0/347 (0.00%)  1/357 (0.28%) 
Small intestinal obstruction  1  1/347 (0.29%)  0/357 (0.00%) 
Vomiting  1  3/347 (0.86%)  6/357 (1.68%) 
General disorders     
Asthenia  1  0/347 (0.00%)  3/357 (0.84%) 
Chest pain  1  0/347 (0.00%)  1/357 (0.28%) 
Death  1  0/347 (0.00%)  1/357 (0.28%) 
Disease progression  1  2/347 (0.58%)  1/357 (0.28%) 
Fatigue  1  2/347 (0.58%)  3/357 (0.84%) 
General physical health deterioration  1  4/347 (1.15%)  3/357 (0.84%) 
Mass  1  0/347 (0.00%)  1/357 (0.28%) 
Multi-organ failure  1  0/347 (0.00%)  1/357 (0.28%) 
Oedema  1  0/347 (0.00%)  1/357 (0.28%) 
Oedema peripheral  1  1/347 (0.29%)  0/357 (0.00%) 
Pain  1  1/347 (0.29%)  2/357 (0.56%) 
Performance status decreased  1  1/347 (0.29%)  0/357 (0.00%) 
Pyrexia  1  3/347 (0.86%)  4/357 (1.12%) 
Spinal pain  1  1/347 (0.29%)  0/357 (0.00%) 
Sudden death  1  1/347 (0.29%)  2/357 (0.56%) 
Hepatobiliary disorders     
Bile duct stone  1  1/347 (0.29%)  0/357 (0.00%) 
Cholangitis  1  0/347 (0.00%)  1/357 (0.28%) 
Cholecystitis  1  0/347 (0.00%)  1/357 (0.28%) 
Cholecystitis acute  1  0/347 (0.00%)  1/357 (0.28%) 
Cholecystitis chronic  1  1/347 (0.29%)  0/357 (0.00%) 
Cholelithiasis  1  1/347 (0.29%)  0/357 (0.00%) 
Hepatic failure  1  1/347 (0.29%)  1/357 (0.28%) 
Hepatic function abnormal  1  0/347 (0.00%)  1/357 (0.28%) 
Hepatocellular injury  1  1/347 (0.29%)  1/357 (0.28%) 
Infections and infestations     
Amoebiasis  1  1/347 (0.29%)  0/357 (0.00%) 
Appendicitis  1  1/347 (0.29%)  0/357 (0.00%) 
Bronchitis  1  0/347 (0.00%)  3/357 (0.84%) 
Bronchopneumonia  1  0/347 (0.00%)  1/357 (0.28%) 
Cellulitis  1  1/347 (0.29%)  0/357 (0.00%) 
Herpes zoster  1  0/347 (0.00%)  1/357 (0.28%) 
Infection  1  1/347 (0.29%)  0/357 (0.00%) 
Infectious peritonitis  1  1/347 (0.29%)  0/357 (0.00%) 
Liver abscess  1  0/347 (0.00%)  1/357 (0.28%) 
Lobar pneumonia  1  1/347 (0.29%)  2/357 (0.56%) 
Lower respiratory tract infection  1  2/347 (0.58%)  1/357 (0.28%) 
Lung abscess  1  1/347 (0.29%)  0/357 (0.00%) 
Lung infection  1  0/347 (0.00%)  2/357 (0.56%) 
Lymphangitis  1  1/347 (0.29%)  0/357 (0.00%) 
Oesophageal candidiasis  1  1/347 (0.29%)  1/357 (0.28%) 
Oropharyngeal candidiasis  1  1/347 (0.29%)  0/357 (0.00%) 
Pneumonia  1  11/347 (3.17%)  16/357 (4.48%) 
Pneumonia pneumococcal  1  0/347 (0.00%)  1/357 (0.28%) 
Pneumonia streptococcal  1  0/347 (0.00%)  1/357 (0.28%) 
Pulmonary tuberculosis  1  0/347 (0.00%)  1/357 (0.28%) 
Respiratory tract infection  1  1/347 (0.29%)  3/357 (0.84%) 
Sepsis  1  0/347 (0.00%)  1/357 (0.28%) 
Septic shock  1  1/347 (0.29%)  1/357 (0.28%) 
Soft tissue infection  1  0/347 (0.00%)  1/357 (0.28%) 
Urinary tract infection  1  3/347 (0.86%)  1/357 (0.28%) 
Urosepsis  1  0/347 (0.00%)  1/357 (0.28%) 
Injury, poisoning and procedural complications     
Chemical injury  1  1/347 (0.29%)  0/357 (0.00%) 
Craniocerebral injury  1  1/347 (0.29%)  0/357 (0.00%) 
Fall  1  0/347 (0.00%)  2/357 (0.56%) 
Femoral neck fracture  1  0/347 (0.00%)  1/357 (0.28%) 
Femur fracture  1  1/347 (0.29%)  0/357 (0.00%) 
Humerus fracture  1  0/347 (0.00%)  1/357 (0.28%) 
Multiple fractures  1  0/347 (0.00%)  1/357 (0.28%) 
Pelvic fracture  1  0/347 (0.00%)  1/357 (0.28%) 
Radiation pneumonitis  1  0/347 (0.00%)  1/357 (0.28%) 
Spinal compression fracture  1  0/347 (0.00%)  1/357 (0.28%) 
Investigations     
Haemoglobin decreased  1  1/347 (0.29%)  0/357 (0.00%) 
Hepatic enzyme increased  1  1/347 (0.29%)  0/357 (0.00%) 
Liver function test abnormal  1  1/347 (0.29%)  0/357 (0.00%) 
Neutrophil count decreased  1  1/347 (0.29%)  2/357 (0.56%) 
Platelet count decreased  1  1/347 (0.29%)  0/357 (0.00%) 
White blood cell count decreased  1  1/347 (0.29%)  0/357 (0.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  1/347 (0.29%)  1/357 (0.28%) 
Dehydration  1  6/347 (1.73%)  4/357 (1.12%) 
Diabetes mellitus  1  1/347 (0.29%)  0/357 (0.00%) 
Hyperglycaemia  1  1/347 (0.29%)  0/357 (0.00%) 
Hypoglycaemia  1  1/347 (0.29%)  0/357 (0.00%) 
Hypokalaemia  1  2/347 (0.58%)  1/357 (0.28%) 
Hyponatraemia  1  2/347 (0.58%)  0/357 (0.00%) 
Hypophagia  1  1/347 (0.29%)  0/357 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthritis  1  1/347 (0.29%)  0/357 (0.00%) 
Back pain  1  0/347 (0.00%)  4/357 (1.12%) 
Muscular weakness  1  1/347 (0.29%)  0/357 (0.00%) 
Musculoskeletal chest pain  1  0/347 (0.00%)  1/357 (0.28%) 
Osteonecrosis  1  1/347 (0.29%)  0/357 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung neoplasm malignant  1  0/347 (0.00%)  1/357 (0.28%) 
Malignant neoplasm progression  1  2/347 (0.58%)  4/357 (1.12%) 
Malignant pleural effusion  1  0/347 (0.00%)  1/357 (0.28%) 
Metastases to bone  1  0/347 (0.00%)  2/357 (0.56%) 
Metastases to central nervous system  1  0/347 (0.00%)  1/357 (0.28%) 
Metastases to liver  1  1/347 (0.29%)  0/357 (0.00%) 
Metastatic pain  1  0/347 (0.00%)  1/357 (0.28%) 
Neoplasm  1  0/347 (0.00%)  2/357 (0.56%) 
Non-small cell lung cancer  1  1/347 (0.29%)  0/357 (0.00%) 
Non-small cell lung cancer metastatic  1  0/347 (0.00%)  1/357 (0.28%) 
Pericardial effusion malignant  1  1/347 (0.29%)  1/357 (0.28%) 
Tumour associated fever  1  0/347 (0.00%)  1/357 (0.28%) 
Tumour ulceration  1  0/347 (0.00%)  1/357 (0.28%) 
Nervous system disorders     
Ataxia  1  1/347 (0.29%)  0/357 (0.00%) 
Brain oedema  1  0/347 (0.00%)  1/357 (0.28%) 
Central nervous system lesion  1  0/347 (0.00%)  1/357 (0.28%) 
Central nervous system necrosis  1  0/347 (0.00%)  1/357 (0.28%) 
Convulsion  1  1/347 (0.29%)  0/357 (0.00%) 
Depressed level of consciousness  1  0/347 (0.00%)  1/357 (0.28%) 
Dizziness  1  1/347 (0.29%)  0/357 (0.00%) 
Grand mal convulsion  1  1/347 (0.29%)  0/357 (0.00%) 
Headache  1  0/347 (0.00%)  1/357 (0.28%) 
Intracranial aneurysm  1  0/347 (0.00%)  1/357 (0.28%) 
Ischaemic stroke  1  0/347 (0.00%)  1/357 (0.28%) 
Metabolic encephalopathy  1  0/347 (0.00%)  1/357 (0.28%) 
Polyneuropathy  1  0/347 (0.00%)  1/357 (0.28%) 
Spinal cord compression  1  1/347 (0.29%)  1/357 (0.28%) 
Toxic encephalopathy  1  0/347 (0.00%)  1/357 (0.28%) 
Vertebrobasilar insufficiency  1  0/347 (0.00%)  1/357 (0.28%) 
Vocal cord paralysis  1  1/347 (0.29%)  0/357 (0.00%) 
Psychiatric disorders     
Affective disorder  1  0/347 (0.00%)  1/357 (0.28%) 
Anxiety  1  1/347 (0.29%)  0/357 (0.00%) 
Confusional state  1  2/347 (0.58%)  0/357 (0.00%) 
Delirium  1  0/347 (0.00%)  1/357 (0.28%) 
Mental status changes  1  1/347 (0.29%)  0/357 (0.00%) 
Psychotic disorder  1  0/347 (0.00%)  1/357 (0.28%) 
Restlessness  1  0/347 (0.00%)  1/357 (0.28%) 
Suicide attempt  1  0/347 (0.00%)  1/357 (0.28%) 
Renal and urinary disorders     
Nephrolithiasis  1  0/347 (0.00%)  1/357 (0.28%) 
Renal failure  1  0/347 (0.00%)  2/357 (0.56%) 
Renal failure acute  1  2/347 (0.58%)  1/357 (0.28%) 
Renal injury  1  1/347 (0.29%)  0/357 (0.00%) 
Tubulointerstitial nephritis  1  1/347 (0.29%)  0/357 (0.00%) 
Urinary retention  1  0/347 (0.00%)  1/357 (0.28%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  1/347 (0.29%)  2/357 (0.56%) 
Aspiration  1  0/347 (0.00%)  1/357 (0.28%) 
Asthma  1  1/347 (0.29%)  0/357 (0.00%) 
Bronchospasm  1  0/347 (0.00%)  2/357 (0.56%) 
Chronic obstructive pulmonary disease  1  2/347 (0.58%)  3/357 (0.84%) 
Dyspnoea  1  9/347 (2.59%)  11/357 (3.08%) 
Epistaxis  1  0/347 (0.00%)  1/357 (0.28%) 
Haemoptysis  1  4/347 (1.15%)  1/357 (0.28%) 
Hypoxia  1  1/347 (0.29%)  0/357 (0.00%) 
Pleural effusion  1  5/347 (1.44%)  3/357 (0.84%) 
Pleuritic pain  1  0/347 (0.00%)  1/357 (0.28%) 
Pneumonitis  1  1/347 (0.29%)  0/357 (0.00%) 
Pneumothorax  1  3/347 (0.86%)  0/357 (0.00%) 
Pulmonary embolism  1  3/347 (0.86%)  4/357 (1.12%) 
Pulmonary haemorrhage  1  0/347 (0.00%)  2/357 (0.56%) 
Pulmonary oedema  1  1/347 (0.29%)  2/357 (0.56%) 
Respiratory distress  1  1/347 (0.29%)  1/357 (0.28%) 
Respiratory failure  1  5/347 (1.44%)  6/357 (1.68%) 
Throat irritation  1  0/347 (0.00%)  1/357 (0.28%) 
Vascular disorders     
Deep vein thrombosis  1  0/347 (0.00%)  2/357 (0.56%) 
Hypotension  1  0/347 (0.00%)  3/357 (0.84%) 
Raynaud's phenomenon  1  1/347 (0.29%)  0/357 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Nintedanib Plus Pemetrexed Placebo Plus Pemetrexed
Affected / at Risk (%) Affected / at Risk (%)
Total   320/347 (92.22%)   312/357 (87.39%) 
Blood and lymphatic system disorders     
Anaemia  1  26/347 (7.49%)  23/357 (6.44%) 
Neutropenia  1  27/347 (7.78%)  19/357 (5.32%) 
Eye disorders     
Lacrimation increased  1  15/347 (4.32%)  21/357 (5.88%) 
Gastrointestinal disorders     
Abdominal pain  1  41/347 (11.82%)  27/357 (7.56%) 
Abdominal pain upper  1  16/347 (4.61%)  22/357 (6.16%) 
Constipation  1  50/347 (14.41%)  65/357 (18.21%) 
Diarrhoea  1  118/347 (34.01%)  54/357 (15.13%) 
Nausea  1  126/347 (36.31%)  118/357 (33.05%) 
Stomatitis  1  27/347 (7.78%)  21/357 (5.88%) 
Vomiting  1  84/347 (24.21%)  68/357 (19.05%) 
General disorders     
Asthenia  1  25/347 (7.20%)  31/357 (8.68%) 
Chest pain  1  31/347 (8.93%)  29/357 (8.12%) 
Fatigue  1  116/347 (33.43%)  127/357 (35.57%) 
Oedema peripheral  1  26/347 (7.49%)  30/357 (8.40%) 
Pain  1  17/347 (4.90%)  21/357 (5.88%) 
Pyrexia  1  36/347 (10.37%)  42/357 (11.76%) 
Infections and infestations     
Upper respiratory tract infection  1  21/347 (6.05%)  20/357 (5.60%) 
Investigations     
Alanine aminotransferase increased  1  149/347 (42.94%)  87/357 (24.37%) 
Aspartate aminotransferase increased  1  129/347 (37.18%)  68/357 (19.05%) 
Blood alkaline phosphatase increased  1  33/347 (9.51%)  13/357 (3.64%) 
Haemoglobin decreased  1  41/347 (11.82%)  44/357 (12.32%) 
Neutrophil count decreased  1  74/347 (21.33%)  47/357 (13.17%) 
Platelet count decreased  1  23/347 (6.63%)  13/357 (3.64%) 
Weight decreased  1  23/347 (6.63%)  15/357 (4.20%) 
White blood cell count decreased  1  57/347 (16.43%)  38/357 (10.64%) 
Metabolism and nutrition disorders     
Decreased appetite  1  97/347 (27.95%)  89/357 (24.93%) 
Hyperglycaemia  1  24/347 (6.92%)  28/357 (7.84%) 
Hypokalaemia  1  20/347 (5.76%)  8/357 (2.24%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  23/347 (6.63%)  14/357 (3.92%) 
Back pain  1  37/347 (10.66%)  36/357 (10.08%) 
Musculoskeletal pain  1  16/347 (4.61%)  20/357 (5.60%) 
Myalgia  1  12/347 (3.46%)  27/357 (7.56%) 
Pain in extremity  1  18/347 (5.19%)  16/357 (4.48%) 
Nervous system disorders     
Dizziness  1  30/347 (8.65%)  39/357 (10.92%) 
Headache  1  44/347 (12.68%)  47/357 (13.17%) 
Psychiatric disorders     
Insomnia  1  29/347 (8.36%)  37/357 (10.36%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  55/347 (15.85%)  60/357 (16.81%) 
Dyspnoea  1  45/347 (12.97%)  70/357 (19.61%) 
Epistaxis  1  24/347 (6.92%)  12/357 (3.36%) 
Skin and subcutaneous tissue disorders     
Dermatitis acneiform  1  29/347 (8.36%)  29/357 (8.12%) 
Pruritus  1  26/347 (7.49%)  33/357 (9.24%) 
Rash  1  22/347 (6.34%)  28/357 (7.84%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.1
Recruitment for the study was stopped early based on the results of a pre defined futility analysis.
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 Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00806819     History of Changes
Other Study ID Numbers: 1199.14
2008-002072-10 ( EudraCT Number: EudraCT )
First Submitted: December 10, 2008
First Posted: December 11, 2008
Results First Submitted: November 14, 2014
Results First Posted: November 20, 2014
Last Update Posted: February 2, 2017