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Nintedanib (BIBF 1120) in Mesothelioma

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ClinicalTrials.gov Identifier: NCT01907100
Recruitment Status : Terminated
First Posted : July 24, 2013
Results First Posted : March 18, 2019
Last Update Posted : March 18, 2019
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 Mesothelioma
Interventions Drug: Nintedanib
Drug: Pemetrexed
Drug: Cisplatin
Drug: Placebo
Enrollment 545
Recruitment Details Patients were initially treated with combination therapy consisting of nintedanib or placebo plus standard chemotherapy (pemetrexed/cisplatin), for a maximum of 6 cycles of 21 days duration. After completion of combination therapy, patients who had not progressed continued with nintedanib or placebo monotherapy.
Pre-assignment Details

All participants were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the participants) met all implemented inclusion/exclusion criteria. Participants were not to be entered to trial if any of the specific entry criteria was violated.

PD: Progressive Disease

Arm/Group Title Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Hide Arm/Group Description

Phase II part:

Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Period Title: Overall Study
Started 43 44 229 229
Treated Patients 41 44 228 227
Completed [1] 1 4 82 83
Not Completed 42 40 147 146
Reason Not Completed
PD based on modified RECIST criteria             31             32             95             92
Withdrawal by Subject             2             5             10             13
Protocol Violation             0             0             1             1
Lost to Follow-up             0             0             0             1
Not treated             2             0             1             2
Other than reasons specified             1             0             10             6
Adverse event (AE)             6             3             22             23
Worsening/AE underlying cancer disease             0             0             8             8
[1]
On treatment or completed according to protocol at the time of analysis
Arm/Group Title Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III Total
Hide Arm/Group Description Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (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 43 44 229 229 545
Hide Baseline Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 43 participants 44 participants 229 participants 229 participants 545 participants
65.9  (7.6) 66.4  (8.6) 64.3  (8.9) 63.6  (9.5) 64.3  (9.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 44 participants 229 participants 229 participants 545 participants
Female
8
  18.6%
10
  22.7%
60
  26.2%
64
  27.9%
142
  26.1%
Male
35
  81.4%
34
  77.3%
169
  73.8%
165
  72.1%
403
  73.9%
Ethnicity (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 0 participants 0 participants 0 participants 0 participants 0 participants
Hispanic or Latino 0
Not Hispanic or Latino 0
Unknown or Not Reported 0
[1]
Measure Analysis Population Description: Ethnicity data were not collected from any participant
Race (NIH/OMB)   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 44 participants 229 participants 229 participants 545 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
14
   6.1%
12
   5.2%
26
   4.8%
Asian
0
   0.0%
0
   0.0%
16
   7.0%
14
   6.1%
30
   5.5%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
2
   0.9%
2
   0.4%
White
38
  88.4%
38
  86.4%
180
  78.6%
185
  80.8%
441
  80.9%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
5
  11.6%
6
  13.6%
19
   8.3%
16
   7.0%
46
   8.4%
[1]
Measure Description: Race was only collected where allowed by local law.
1.Primary Outcome
Title Progression-Free Survival (PFS)
Hide Description This outcome measure presents progression-free survival. Disease progression was defined according to the modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Progression-free survival time was calculated as the duration from the date of randomization to the date of disease progression or death, whichever occurred first. For patients with known date of progression (or death): PFS (days) = min (date of progression, date of death) - date of randomization + 1 day. For patients without progression or death, PFS was censored at the last imaging date that showed no disease progression: PFS (days, censored) = date of last imaging showing no progression - date randomization + 1 day.
Time Frame From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 272 273
Median (Inter-Quartile Range)
Unit of Measure: Months
Phase II Number Analyzed 43 participants 44 participants
5.72
(5.19 to 8.18)
9.36
(5.55 to 12.65)
Phase III Number Analyzed 229 participants 229 participants
6.97
(5.42 to 9.00)
6.77
(5.36 to 9.07)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Phase II Part
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0174
Comments [Not Specified]
Method Proportional hazards mode
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.555
Confidence Interval (2-Sided) 95%
0.340 to 0.907
Estimation Comments Hazard ratio, confidence interval and p−value obtained from proportional hazards model stratified by tumour histology (epithelioid vs. biphasic).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments

Phase III part:

A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo).

If the hazard ratio is below 1 then it favours nintedanib.

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5430
Comments one-sided p-value
Method Proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.79 to 1.30
Estimation Comments Hazard ratio, confidence interval and p−value obtained from a non-stratified proportional hazards model.
2.Secondary Outcome
Title Overall Survival (OS)
Hide Description

Overall survival was defined as the duration of time from randomization to time of death.

This is the key secondary endpoint of the trial.

Time Frame From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 272 273
Median (Inter-Quartile Range)
Unit of Measure: Months
Phase II Number Analyzed 43 participants 44 participants
14.46 [1] 
(10.41 to NA)
18.30 [1] 
(10.91 to NA)
Phase III Number Analyzed 229 participants 229 participants
16.07
(9.66 to 19.29)
14.36
(9.13 to 18.69)
[1]
The 75th percentile was not reached because of insufficient number of patients with OS event thus not calculated.
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Phase II
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4132
Comments [Not Specified]
Method Proportional hazards mode
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.782
Confidence Interval (2-Sided) 95%
0.433 to 1.412
Estimation Comments Hazard ratio, confidence interval and p−value obtained from proportional hazards model stratified by tumour histology (epithelioid vs. biphasic).
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments

Phase III:

A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo).

If the hazard ratio is below 1 then it favours nintedanib.

Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7306
Comments one-sided p-value
Method Proportional hazards model
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.12
Confidence Interval (2-Sided) 95%
0.79 to 1.58
Estimation Comments Hazard ratio, confidence interval and p−value obtained from a non-stratified proportional hazards model.
3.Secondary Outcome
Title Objective Response According to Modified RECIST− Investigator Assessment
Hide Description

Objective response (best overall tumour response of confirmed complete response [CR] or confirmed partial response [PR]).

Complete Response: disappearance of all target lesions Partial Response: at least a 30 % decrease in the total tumour measurement of target lesions, taking as reference the baseline total tumour measurement.

Percentage of Patients with confirmed objective response is presented. This endpoint was only evaluated for Phase III part.

Time Frame Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 229 229
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
42.8
(36.3 to 49.5)
45.0
(38.4 to 51.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3189
Comments one-sided p-value
Method Regression, Logistic
Comments Odds ratio and one−sided p−value are obtained from an un−adjusted logistic regression model (Nintedanib vs Placebo).
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.09
Confidence Interval (2-Sided) 95%
0.76 to 1.58
Estimation Comments Odds ratio above 1 favours nintedanib.
Other Statistical Analysis Exact 95% CI by Clopper and Pearson.
4.Secondary Outcome
Title Disease Control According to Modified RECIST− Investigator Assessment
Hide Description

Disease control (best overall response of confirmed CR or PR, or Stable Disease (SD) that lasted ≥36 days) according to modified RECIST.

Percentage of Patients with Disease control is presented. This endpoint was only evaluated for Phase III part.

Time Frame Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months
Hide Outcome Measure Data
Hide Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Arm/Group Title Placebo Nintedanib
Hide Arm/Group Description:
Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Number of Participants Analyzed 229 229
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
92.6
(88.4 to 95.6)
90.8
(86.3 to 94.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7512
Comments one-sided p-value
Method Regression, Logistic
Comments Odds ratio and one−sided p−value are obtained from an un−adjusted logistic regression model (Nintedanib vs Placebo).
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.40 to 1.55
Estimation Comments Odds ratio above 1 favours nintedanib.
Time Frame SAE & Non SAE: From first dose until 28 days (Phase II) or 30 days (Phase III) after last dose, up to approximately (approx.) 30 months in Phase II and approx. 32 months in Phase III. All-cause mortality: From randomization until end of follow-up, up to approx. 30 months in Phase II and approx. 32 months in Phase III
Adverse Event Reporting Description All-cause mortality numbers are based on randomized set whereas Serious Adverse Events (SAE) and non-SAE are based on treated set.
 
Arm/Group Title Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Hide Arm/Group Description Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
All-Cause Mortality
Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   25/43 (58.14%)   22/44 (50.00%)   63/229 (27.51%)   64/229 (27.95%) 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   17/41 (41.46%)   16/44 (36.36%)   89/228 (39.04%)   99/227 (43.61%) 
Blood and lymphatic system disorders         
Anaemia  1  1/41 (2.44%)  2/44 (4.55%)  8/228 (3.51%)  1/227 (0.44%) 
Febrile bone marrow aplasia  1  0/41 (0.00%)  1/44 (2.27%)  3/228 (1.32%)  1/227 (0.44%) 
Febrile neutropenia  1  0/41 (0.00%)  1/44 (2.27%)  3/228 (1.32%)  4/227 (1.76%) 
Leukopenia  1  0/41 (0.00%)  1/44 (2.27%)  2/228 (0.88%)  0/227 (0.00%) 
Neutropenia  1  1/41 (2.44%)  3/44 (6.82%)  7/228 (3.07%)  6/227 (2.64%) 
Thrombocytopenia  1  0/41 (0.00%)  1/44 (2.27%)  4/228 (1.75%)  1/227 (0.44%) 
Bone marrow toxicity  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Pancytopenia  1  0/41 (0.00%)  0/44 (0.00%)  2/228 (0.88%)  2/227 (0.88%) 
Splenic infarction  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Bone marrow failure  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Lymphatic obstruction  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Cardiac disorders         
Atrial fibrillation  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  2/227 (0.88%) 
Atrial flutter  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  1/227 (0.44%) 
Acute myocardial infarction  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Atrioventricular block second degree  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Bradycardia  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Bundle branch block left  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Cardiac tamponade  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Cardio-respiratory arrest  1  0/41 (0.00%)  0/44 (0.00%)  2/228 (0.88%)  1/227 (0.44%) 
Myocardial infarction  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Pericardial effusion  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Pericarditis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Sinus tachycardia  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Supraventricular tachycardia  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Tachycardia  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Angina unstable  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Tachyarrhythmia  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Congenital, familial and genetic disorders         
Aplasia  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Ear and labyrinth disorders         
Deafness  1  1/41 (2.44%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Hypoacusis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Eye disorders         
Visual acuity reduced  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Gastrointestinal disorders         
Constipation  1  0/41 (0.00%)  2/44 (4.55%)  2/228 (0.88%)  2/227 (0.88%) 
Diarrhoea  1  0/41 (0.00%)  3/44 (6.82%)  7/228 (3.07%)  8/227 (3.52%) 
Dysphagia  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  1/227 (0.44%) 
Large intestine perforation  1  1/41 (2.44%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Nausea  1  1/41 (2.44%)  2/44 (4.55%)  4/228 (1.75%)  4/227 (1.76%) 
Vomiting  1  1/41 (2.44%)  1/44 (2.27%)  8/228 (3.51%)  6/227 (2.64%) 
Abdominal pain  1  0/41 (0.00%)  0/44 (0.00%)  2/228 (0.88%)  2/227 (0.88%) 
Acute abdomen  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Ascites  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Enteritis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Gastric ulcer  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Gastritis  1  0/41 (0.00%)  0/44 (0.00%)  2/228 (0.88%)  1/227 (0.44%) 
Gastrointestinal haemorrhage  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Haemorrhoids  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Intestinal obstruction  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Intestinal perforation  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Pneumoperitoneum  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Stomatitis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
General disorders         
Asthenia  1  0/41 (0.00%)  1/44 (2.27%)  1/228 (0.44%)  1/227 (0.44%) 
Fatigue  1  0/41 (0.00%)  1/44 (2.27%)  3/228 (1.32%)  2/227 (0.88%) 
General physical health deterioration  1  1/41 (2.44%)  0/44 (0.00%)  2/228 (0.88%)  4/227 (1.76%) 
Pyrexia  1  2/41 (4.88%)  3/44 (6.82%)  10/228 (4.39%)  4/227 (1.76%) 
Chest pain  1  0/41 (0.00%)  0/44 (0.00%)  5/228 (2.19%)  5/227 (2.20%) 
Death  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Malaise  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Mucosal inflammation  1  0/41 (0.00%)  0/44 (0.00%)  3/228 (1.32%)  2/227 (0.88%) 
Pain  1  0/41 (0.00%)  0/44 (0.00%)  2/228 (0.88%)  1/227 (0.44%) 
Performance status decreased  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Chills  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Feeling of body temperature change  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Hepatobiliary disorders         
Cholecystitis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Immune system disorders         
Drug hypersensitivity  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Infections and infestations         
Lower respiratory tract infection  1  2/41 (4.88%)  0/44 (0.00%)  2/228 (0.88%)  4/227 (1.76%) 
Sepsis  1  1/41 (2.44%)  0/44 (0.00%)  2/228 (0.88%)  0/227 (0.00%) 
Bronchitis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Cellulitis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Device related infection  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Endocarditis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Escherichia bacteraemia  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Gastroenteritis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Gastroenteritis norovirus  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Infection  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Influenza  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Lung infection  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Neutropenic sepsis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  3/227 (1.32%) 
Oesophageal candidiasis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Onychomycosis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Oral bacterial infection  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Peritonitis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Pneumonia  1  0/41 (0.00%)  0/44 (0.00%)  4/228 (1.75%)  6/227 (2.64%) 
Tooth abscess  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Urinary tract infection  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Urosepsis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Pneumonia klebsiella  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Injury, poisoning and procedural complications         
Overdose  1  1/41 (2.44%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Rib fracture  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Toxicity to various agents  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Investigations         
Blood creatinine increased  1  1/41 (2.44%)  2/44 (4.55%)  1/228 (0.44%)  3/227 (1.32%) 
Fibrin D dimer increased  1  0/41 (0.00%)  1/44 (2.27%)  1/228 (0.44%)  0/227 (0.00%) 
Alanine aminotransferase increased  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  2/227 (0.88%) 
Aspartate aminotransferase increased  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
C-reactive protein increased  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Ejection fraction decreased  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Hepatic enzyme increased  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  2/227 (0.88%) 
Neutrophil count decreased  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  3/227 (1.32%) 
Platelet count decreased  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Transaminases increased  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
White blood cell count decreased  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Blood potassium decreased  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Gamma-glutamyltransferase increased  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Glomerular filtration rate decreased  1  1/41 (2.44%)  0/44 (0.00%)  0/228 (0.00%)  0/227 (0.00%) 
Metabolism and nutrition disorders         
Dehydration  1  2/41 (4.88%)  2/44 (4.55%)  8/228 (3.51%)  4/227 (1.76%) 
Hypokalaemia  1  0/41 (0.00%)  1/44 (2.27%)  2/228 (0.88%)  1/227 (0.44%) 
Hypomagnesaemia  1  0/41 (0.00%)  1/44 (2.27%)  1/228 (0.44%)  0/227 (0.00%) 
Decreased appetite  1  0/41 (0.00%)  0/44 (0.00%)  3/228 (1.32%)  3/227 (1.32%) 
Hyponatraemia  1  0/41 (0.00%)  0/44 (0.00%)  2/228 (0.88%)  2/227 (0.88%) 
Lactic acidosis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Flank pain  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Muscular weakness  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Pain in extremity  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Malignant neoplasm progression  1  2/41 (4.88%)  1/44 (2.27%)  2/228 (0.88%)  0/227 (0.00%) 
Basal cell carcinoma  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Cancer pain  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  2/227 (0.88%) 
Malignant pleural effusion  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Pleural mesothelioma malignant  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Tumour associated fever  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Neuroendocrine tumour  1  1/41 (2.44%)  0/44 (0.00%)  0/228 (0.00%)  0/227 (0.00%) 
Nervous system disorders         
Cerebrovascular accident  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Dizziness postural  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Encephalopathy  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Headache  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Neuropathy peripheral  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Peripheral motor neuropathy  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Seizure  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Spinal cord compression  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Syncope  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Transient ischaemic attack  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Dizziness  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Psychiatric disorders         
Depression  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Hallucination  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Confusional state  1  1/41 (2.44%)  0/44 (0.00%)  0/228 (0.00%)  0/227 (0.00%) 
Renal and urinary disorders         
Acute kidney injury  1  0/41 (0.00%)  0/44 (0.00%)  5/228 (2.19%)  9/227 (3.96%) 
Calculus bladder  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Renal failure  1  0/41 (0.00%)  0/44 (0.00%)  4/228 (1.75%)  0/227 (0.00%) 
Nephrotic syndrome  1  1/41 (2.44%)  0/44 (0.00%)  0/228 (0.00%)  0/227 (0.00%) 
Urinary retention  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Reproductive system and breast disorders         
Erosive balanitis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Respiratory, thoracic and mediastinal disorders         
Dyspnoea  1  2/41 (4.88%)  2/44 (4.55%)  6/228 (2.63%)  5/227 (2.20%) 
Pleural effusion  1  2/41 (4.88%)  0/44 (0.00%)  6/228 (2.63%)  4/227 (1.76%) 
Pneumonitis  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  1/227 (0.44%) 
Pulmonary embolism  1  4/41 (9.76%)  0/44 (0.00%)  7/228 (3.07%)  13/227 (5.73%) 
Cough  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Epistaxis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Hiccups  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Hyperventilation  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Pneumothorax  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  3/227 (1.32%) 
Pulmonary hypertension  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Respiratory failure  1  0/41 (0.00%)  0/44 (0.00%)  4/228 (1.75%)  0/227 (0.00%) 
Laryngeal oedema  1  0/41 (0.00%)  1/44 (2.27%)  0/228 (0.00%)  0/227 (0.00%) 
Skin and subcutaneous tissue disorders         
Stasis dermatitis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Subcutaneous emphysema  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Rash erythematous  1  1/41 (2.44%)  0/44 (0.00%)  0/228 (0.00%)  0/227 (0.00%) 
Vascular disorders         
Deep vein thrombosis  1  1/41 (2.44%)  0/44 (0.00%)  2/228 (0.88%)  3/227 (1.32%) 
Aortic aneurysm  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Aortic thrombosis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  2/227 (0.88%) 
Embolism  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Hypertension  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Hypotension  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  1/227 (0.44%) 
Jugular vein thrombosis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Peripheral ischaemia  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Subclavian artery thrombosis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Subclavian vein thrombosis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  2/227 (0.88%) 
Thrombophlebitis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Vena cava thrombosis  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
Venous thrombosis  1  0/41 (0.00%)  0/44 (0.00%)  1/228 (0.44%)  0/227 (0.00%) 
Venous thrombosis limb  1  0/41 (0.00%)  0/44 (0.00%)  0/228 (0.00%)  1/227 (0.44%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   41/41 (100.00%)   44/44 (100.00%)   219/228 (96.05%)   218/227 (96.04%) 
Blood and lymphatic system disorders         
Anaemia  1  9/41 (21.95%)  16/44 (36.36%)  94/228 (41.23%)  76/227 (33.48%) 
Leukopenia  1  5/41 (12.20%)  2/44 (4.55%)  28/228 (12.28%)  20/227 (8.81%) 
Neutropenia  1  9/41 (21.95%)  22/44 (50.00%)  82/228 (35.96%)  83/227 (36.56%) 
Thrombocytopenia  1  1/41 (2.44%)  7/44 (15.91%)  18/228 (7.89%)  13/227 (5.73%) 
Ear and labyrinth disorders         
Tinnitus  1  9/41 (21.95%)  4/44 (9.09%)  24/228 (10.53%)  15/227 (6.61%) 
Hypoacusis  1  1/41 (2.44%)  4/44 (9.09%)  4/228 (1.75%)  7/227 (3.08%) 
Eye disorders         
Dry eye  1  3/41 (7.32%)  0/44 (0.00%)  4/228 (1.75%)  12/227 (5.29%) 
Lacrimation increased  1  4/41 (9.76%)  7/44 (15.91%)  18/228 (7.89%)  14/227 (6.17%) 
Gastrointestinal disorders         
Abdominal pain  1  3/41 (7.32%)  11/44 (25.00%)  10/228 (4.39%)  24/227 (10.57%) 
Abdominal pain upper  1  3/41 (7.32%)  9/44 (20.45%)  11/228 (4.82%)  14/227 (6.17%) 
Constipation  1  19/41 (46.34%)  17/44 (38.64%)  73/228 (32.02%)  60/227 (26.43%) 
Diarrhoea  1  15/41 (36.59%)  29/44 (65.91%)  47/228 (20.61%)  118/227 (51.98%) 
Dyspepsia  1  11/41 (26.83%)  3/44 (6.82%)  20/228 (8.77%)  14/227 (6.17%) 
Nausea  1  34/41 (82.93%)  37/44 (84.09%)  134/228 (58.77%)  156/227 (68.72%) 
Stomatitis  1  5/41 (12.20%)  3/44 (6.82%)  16/228 (7.02%)  22/227 (9.69%) 
Vomiting  1  20/41 (48.78%)  24/44 (54.55%)  66/228 (28.95%)  96/227 (42.29%) 
Dry mouth  1  4/41 (9.76%)  2/44 (4.55%)  2/228 (0.88%)  4/227 (1.76%) 
Gastrooesophageal reflux disease  1  4/41 (9.76%)  3/44 (6.82%)  11/228 (4.82%)  7/227 (3.08%) 
Haemorrhoids  1  0/41 (0.00%)  3/44 (6.82%)  2/228 (0.88%)  5/227 (2.20%) 
General disorders         
Asthenia  1  12/41 (29.27%)  14/44 (31.82%)  46/228 (20.18%)  53/227 (23.35%) 
Chest pain  1  9/41 (21.95%)  7/44 (15.91%)  23/228 (10.09%)  23/227 (10.13%) 
Fatigue  1  15/41 (36.59%)  18/44 (40.91%)  62/228 (27.19%)  60/227 (26.43%) 
Mucosal inflammation  1  4/41 (9.76%)  7/44 (15.91%)  22/228 (9.65%)  16/227 (7.05%) 
Oedema peripheral  1  5/41 (12.20%)  5/44 (11.36%)  16/228 (7.02%)  16/227 (7.05%) 
Pyrexia  1  4/41 (9.76%)  7/44 (15.91%)  22/228 (9.65%)  17/227 (7.49%) 
Infections and infestations         
Nasopharyngitis  1  1/41 (2.44%)  4/44 (9.09%)  12/228 (5.26%)  9/227 (3.96%) 
Upper respiratory tract infection  1  5/41 (12.20%)  2/44 (4.55%)  6/228 (2.63%)  16/227 (7.05%) 
Urinary tract infection  1  5/41 (12.20%)  0/44 (0.00%)  14/228 (6.14%)  12/227 (5.29%) 
Conjunctivitis  1  2/41 (4.88%)  4/44 (9.09%)  11/228 (4.82%)  11/227 (4.85%) 
Influenza  1  2/41 (4.88%)  3/44 (6.82%)  4/228 (1.75%)  5/227 (2.20%) 
Investigations         
Alanine aminotransferase increased  1  1/41 (2.44%)  17/44 (38.64%)  10/228 (4.39%)  35/227 (15.42%) 
Aspartate aminotransferase increased  1  1/41 (2.44%)  13/44 (29.55%)  9/228 (3.95%)  32/227 (14.10%) 
Blood creatinine increased  1  4/41 (9.76%)  6/44 (13.64%)  26/228 (11.40%)  21/227 (9.25%) 
Blood magnesium decreased  1  6/41 (14.63%)  10/44 (22.73%)  12/228 (5.26%)  17/227 (7.49%) 
Gamma-glutamyltransferase increased  1  1/41 (2.44%)  10/44 (22.73%)  13/228 (5.70%)  25/227 (11.01%) 
Neutrophil count decreased  1  3/41 (7.32%)  8/44 (18.18%)  26/228 (11.40%)  28/227 (12.33%) 
Weight decreased  1  9/41 (21.95%)  8/44 (18.18%)  23/228 (10.09%)  20/227 (8.81%) 
White blood cell count decreased  1  1/41 (2.44%)  2/44 (4.55%)  15/228 (6.58%)  18/227 (7.93%) 
Blood alkaline phosphatase increased  1  1/41 (2.44%)  9/44 (20.45%)  6/228 (2.63%)  7/227 (3.08%) 
Blood glucose increased  1  1/41 (2.44%)  5/44 (11.36%)  1/228 (0.44%)  0/227 (0.00%) 
Blood lactate dehydrogenase increased  1  0/41 (0.00%)  3/44 (6.82%)  1/228 (0.44%)  1/227 (0.44%) 
Blood potassium decreased  1  2/41 (4.88%)  4/44 (9.09%)  0/228 (0.00%)  0/227 (0.00%) 
Blood urea increased  1  3/41 (7.32%)  8/44 (18.18%)  10/228 (4.39%)  9/227 (3.96%) 
Haemoglobin decreased  1  2/41 (4.88%)  4/44 (9.09%)  2/228 (0.88%)  1/227 (0.44%) 
Platelet count decreased  1  4/41 (9.76%)  8/44 (18.18%)  7/228 (3.07%)  9/227 (3.96%) 
Metabolism and nutrition disorders         
Decreased appetite  1  16/41 (39.02%)  17/44 (38.64%)  66/228 (28.95%)  66/227 (29.07%) 
Hypokalaemia  1  2/41 (4.88%)  4/44 (9.09%)  13/228 (5.70%)  12/227 (5.29%) 
Hypomagnesaemia  1  8/41 (19.51%)  13/44 (29.55%)  20/228 (8.77%)  20/227 (8.81%) 
Hyperglycaemia  1  1/41 (2.44%)  2/44 (4.55%)  15/228 (6.58%)  8/227 (3.52%) 
Hyponatraemia  1  2/41 (4.88%)  1/44 (2.27%)  14/228 (6.14%)  14/227 (6.17%) 
Dehydration  1  3/41 (7.32%)  4/44 (9.09%)  8/228 (3.51%)  4/227 (1.76%) 
Hypocalcaemia  1  3/41 (7.32%)  0/44 (0.00%)  7/228 (3.07%)  4/227 (1.76%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  2/41 (4.88%)  3/44 (6.82%)  5/228 (2.19%)  4/227 (1.76%) 
Back pain  1  4/41 (9.76%)  4/44 (9.09%)  9/228 (3.95%)  8/227 (3.52%) 
Musculoskeletal chest pain  1  4/41 (9.76%)  2/44 (4.55%)  10/228 (4.39%)  4/227 (1.76%) 
Musculoskeletal pain  1  4/41 (9.76%)  2/44 (4.55%)  11/228 (4.82%)  5/227 (2.20%) 
Nervous system disorders         
Dizziness  1  5/41 (12.20%)  3/44 (6.82%)  18/228 (7.89%)  14/227 (6.17%) 
Dysgeusia  1  11/41 (26.83%)  11/44 (25.00%)  27/228 (11.84%)  27/227 (11.89%) 
Headache  1  4/41 (9.76%)  5/44 (11.36%)  23/228 (10.09%)  16/227 (7.05%) 
Lethargy  1  13/41 (31.71%)  6/44 (13.64%)  5/228 (2.19%)  13/227 (5.73%) 
Neuropathy peripheral  1  6/41 (14.63%)  9/44 (20.45%)  18/228 (7.89%)  13/227 (5.73%) 
Paraesthesia  1  4/41 (9.76%)  4/44 (9.09%)  19/228 (8.33%)  20/227 (8.81%) 
Neurotoxicity  1  3/41 (7.32%)  1/44 (2.27%)  4/228 (1.75%)  8/227 (3.52%) 
Psychiatric disorders         
Insomnia  1  4/41 (9.76%)  8/44 (18.18%)  12/228 (5.26%)  11/227 (4.85%) 
Depression  1  3/41 (7.32%)  1/44 (2.27%)  2/228 (0.88%)  6/227 (2.64%) 
Respiratory, thoracic and mediastinal disorders         
Cough  1  6/41 (14.63%)  15/44 (34.09%)  33/228 (14.47%)  29/227 (12.78%) 
Dyspnoea  1  7/41 (17.07%)  7/44 (15.91%)  26/228 (11.40%)  34/227 (14.98%) 
Hiccups  1  3/41 (7.32%)  1/44 (2.27%)  20/228 (8.77%)  8/227 (3.52%) 
Epistaxis  1  2/41 (4.88%)  1/44 (2.27%)  13/228 (5.70%)  20/227 (8.81%) 
Dysphonia  1  0/41 (0.00%)  3/44 (6.82%)  2/228 (0.88%)  4/227 (1.76%) 
Oropharyngeal pain  1  6/41 (14.63%)  2/44 (4.55%)  4/228 (1.75%)  6/227 (2.64%) 
Skin and subcutaneous tissue disorders         
Alopecia  1  5/41 (12.20%)  6/44 (13.64%)  8/228 (3.51%)  12/227 (5.29%) 
Rash  1  7/41 (17.07%)  11/44 (25.00%)  23/228 (10.09%)  22/227 (9.69%) 
Dry skin  1  3/41 (7.32%)  0/44 (0.00%)  7/228 (3.07%)  4/227 (1.76%) 
Pruritus  1  1/41 (2.44%)  3/44 (6.82%)  10/228 (4.39%)  3/227 (1.32%) 
Vascular disorders         
Hypertension  1  6/41 (14.63%)  6/44 (13.64%)  21/228 (9.21%)  26/227 (11.45%) 
1
Term from vocabulary, MedDRA 20.1
Indicates events were collected by systematic assessment
In accordance with the specifications in the protocol, the trial was discontinued prematurely after the primary PFS analysis not because of any safety concerns but rather due to failure to meet the efficacy target.
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
Name/Title: Boehringer Ingelheim, Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01907100     History of Changes
Other Study ID Numbers: 1199.93
2012-005201-48 ( EudraCT Number )
First Submitted: July 22, 2013
First Posted: July 24, 2013
Results First Submitted: September 11, 2018
Results First Posted: March 18, 2019
Last Update Posted: March 18, 2019