Nintedanib (BIBF 1120) in Mesothelioma

• 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: Boehringer Ingelheim
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Placebo_Phase II	Nintedanib_Phase II	Placebo_Phase III	Nintedanib_Phase III	Total
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
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.

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
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)

Outcome Measure Data

Analysis Population Description

Randomised Set: This patient set included all randomized patients.

Arm/Group Title		Placebo	Nintedanib
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)

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).

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)
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)

Outcome Measure Data

Analysis Population Description

Randomised Set: This patient set included all randomized patients.

Arm/Group Title		Placebo	Nintedanib
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.

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).

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
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

Outcome Measure Data

Analysis Population Description

Randomised Set: This patient set included all randomized patients.

Arm/Group Title	Placebo	Nintedanib
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)

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
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

Outcome Measure Data

Analysis Population Description

Randomised Set: This patient set included all randomized patients.

Arm/Group Title	Placebo	Nintedanib
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)

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.

Adverse Events

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
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%)
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
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

Limitations and Caveats

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.

More Information

Certain Agreements

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

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

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
• EMail: clintriage.rdg@boehringer-ingelheim.com

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

Scagliotti GV, Gaafar R, Nowak AK, Nakano T, van Meerbeeck J, Popat S, Vogelzang NJ, Grosso F, Aboelhassan R, Jakopovic M, Ceresoli GL, Taylor P, Orlandi F, Fennell DA, Novello S, Scherpereel A, Kuribayashi K, Cedres S, Sorensen JB, Pavlakis N, Reck M, Velema D, von Wangenheim U, Kim M, Barrueco J, Tsao AS. Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2019 Jul;7(7):569-580. doi: 10.1016/S2213-2600(19)30139-0. Epub 2019 May 15.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01907100
• 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