LUME-Ovar 1: Nintedanib (BIBF 1120) or Placebo in Combination With Paclitaxel and Carboplatin in First Line Treatment of Ovarian Cancer

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ClinicalTrials.gov Identifier: NCT01015118

Recruitment Status : Completed

First Posted : November 18, 2009

Results First Posted : January 15, 2015

Last Update Posted : December 7, 2017

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Sponsor:

Information provided by (Responsible Party):

Boehringer Ingelheim

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
Conditions	Ovarian Neoplasms Peritoneal Neoplasms
Interventions	Drug: Placebo Drug: Paclitaxel Drug: BIBF 1120 Drug: Carboplatin
Enrollment	1366

Participant Flow

Recruitment Details
Pre-assignment Details	1366 patients were randomised for this study.


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Period Title: Overall Study
Started	911	455
Completed	242 ^[1]	128 ^[1]
Not Completed	669	327
Reason Not Completed
Protocol Violation	5	6
Withdrawal by Subject	103	27
Other Adverse Event (AE)	141	33
Worsening or AE of underlying disease	5	4
Progressive disease	364	229
Not treated	9	5
Other than stated above	42	23
[1] Patients who completed max trial therapy duration.

Baseline Characteristics

Arm/Group Title		Nintedanib	Placebo	Total
Arm/Group Description		Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...	Total of all reporting groups
Arm/Group Description		Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Total of all reporting groups
Overall Number of Baseline Participants		911	455	1366
Baseline Analysis Population Description		...
Baseline Analysis Population Description		Randomised Set (RS): included all randomised patients, regardless of whether or not they had received treatment. Patients were assigned to nintedanib or placebo as randomised.
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	911 participants	455 participants	1366 participants
		57.5 (11.0)	56.9 (11.1)	57.3 (11.1)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	911 participants	455 participants	1366 participants
	Female	911 100.0%	455 100.0%	1366 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1.Primary Outcome


Title	PFS Based on Investigator Assessment According to Modified Response Evaluation Criteria in Solid Tumors, Version 1.1 (mRECIST), and Additional Clinical Criteria.
Description	Progression free survival (PFS) is calculated as the time from randomi...
Description	Progression free survival (PFS) is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first according to the Investigator assessment. The primary PFS analysis of this trial was performed when approximately 753 patients had experienced a PFS event Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
Time Frame	First drug administration to date of disease progression or death whichever occurs first , upto 29 months

Outcome Measure Data

Analysis Population Description

Randomised Set (RS)


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Median (Inter-Quartile Range) Unit of Measure: Months
	17.2 (11.1 to 32.5)	16.6 (10.8 to 30.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	Hazard ratio (HR), Confidence Interval (CI) and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level Area under curve 5 (AUC5) vs. Area under curve 6 (AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0239
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Breslow method was used for handling ties.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95% 0.72 to 0.98
	Estimation Comments	If hazard ratio is below 1 then favours nintedanib.

2.Primary Outcome


Title	PFS Based on Investigator Assessment According to Modified Response Evaluation Criteria in Solid Tumors, Version 1.1 (mRECIST), and Additional Clinical Criteria (Follow up Analysis).
Description	Follow-up analysis was conducted at the time of overall survival analy...
Description	Follow-up analysis was conducted at the time of overall survival analysis. Progression free survival (PFS) is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first according to the Investigator assessment. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
Time Frame	First drug administration to date of disease progression or death whichever occurs first until final Data Base Lock (DBL) 26September16, upto 62 months

Outcome Measure Data

Analysis Population Description

Randomised Set (RS)


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Median (Inter-Quartile Range) Unit of Measure: Months
	17.6 (11.1 to 38.0)	16.6 (10.8 to 37.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	Hazard ratio (HR), Confidence Interval (CI) and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0286
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Breslow method was used for handling ties.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95% 0.75 to 0.98
	Estimation Comments	If hazard ratio is below 1 then favours nintedanib.

3.Secondary Outcome


Title	PFS Based on Investigator Assessment According to mRECIST Version 1.1 (Key Secondary Endpoint).
Description	Progression free survival is calculated as the time from randomisation...
Description	Progression free survival is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first based on the Investigator assessment according to Modified Response Evaluation Criteria (mRECIST), version 1.1. The primary PFS analysis of this trial was performed when approximately 753 patients had experienced a PFS event. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
Time Frame	First drug administration to date of disease progression or death whichever occurs first , upto 29 months

Outcome Measure Data

Analysis Population Description

Randomised Set (RS)


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Median (Inter-Quartile Range) Unit of Measure: Months
	18.3 (11.1 to 32.5)	16.6 (10.8 to 30.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0186
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Breslow method was used for handling ties.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.72 to 0.97
	Estimation Comments	If hazard ratio is below 1 then favours nintedanib.

4.Secondary Outcome


Title	PFS Based on Investigator Assessment According to mRECIST Version 1.1 (Key Secondary Endpoint - Follow up Analysis).
Description	Follow-up analysis was conducted at the time of overall survival analy...
Description	Follow-up analysis was conducted at the time of overall survival analysis. Progression free survival is calculated as the time from randomisation to the date of disease progression, or to the date of death, whichever occurs first based on the Investigator assessment according to Modified Response Evaluation Criteria (mRECIST), version 1.1. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
Time Frame	First drug administration to date of disease progression or death whichever occurs first until final Data Base Lock (DBL) 26September16, upto 62 months

Outcome Measure Data

Analysis Population Description

Randomised Set (RS)


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Median (Inter-Quartile Range) Unit of Measure: Months
	18.4 (11.1 to 38.5)	16.6 (10.8 to 37.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0256
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Breslow method was used for handling ties.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% 0.74 to 0.98
	Estimation Comments	If hazard ratio is below 1 then favours nintedanib.

5.Secondary Outcome


Title	Overall Survival
Description	Overall survival is defined as time from randomization to date of deat...
Description	Overall survival is defined as time from randomization to date of death (irrespective of reason). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve for each treatment arm.
Time Frame	First drug administration to date of death until final DBL 26September16, upto 62 months

Outcome Measure Data

Analysis Population Description

Randomised Set (RS)


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Median (Inter-Quartile Range) Unit of Measure: Months
	62.0 ^[1] (30.0 to NA)	62.8 ^[1] (30.6 to NA)

[1]

Not calculable because of insufficient number of participants with events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8653
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Breslow method was used for handling ties.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95% 0.83 to 1.17
	Estimation Comments	If hazard ratio is below 1 then favours nintedanib.

6.Secondary Outcome


Title	Time to CA-125 Tumour Marker Progression
Description	Time to tumour-marker progression was defined as the time from randomi...
Description	Time to tumour-marker progression was defined as the time from randomisation until the date when Carbohydrate (cancer) antigen (CA-125) values increased to higher than twice the nadir value. CA-125 >=2 x nadir in case nadir value > Upper limit of normal (ULN) or CA-125 >=2 x ULN in case nadir value <= ULN.
Time Frame	First drug administration until final DBL 26September16, upto 62 months

Outcome Measure Data

Analysis Population Description

Randomised set (RS)


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Median (Inter-Quartile Range) Unit of Measure: Months
	16.6 (10.6 to 47.0)	14.1 (8.6 to 42.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	HR, CI and P-value obtained from a proportional-hazards model stratified by Macroscopic residual postoperative tumour (Yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) Stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0749
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Breslow method was used for handling ties.

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95% 0.77 to 1.01
	Estimation Comments	If hazard ratio is below 1 then favours nintedanib.

7.Secondary Outcome


Title	Objective Response Based on Investigator Assessment
Description	Objective tumour response defined as either complete response [CR] or ...
Description	Objective tumour response defined as either complete response [CR] or partial response [PR] in patients with at least 1 target lesion reported at baseline
Time Frame	First drug administration until final DBL 26September16, upto 62 months

Outcome Measure Data

Analysis Population Description

Randomised Set (RS) for patients with at least 1 target lesion reported at baseline


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Measure Type: Number Unit of Measure: percentage of participants
	74.3	70.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	Odds ratio and p-value are obtained from logistic regression model adjusting for, macroscopic residual postoperative tumour (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB-III vs. IV) and carboplatin level (AUC5 vs. AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3490
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95% 0.81 to 1.82
	Estimation Comments	An odds ratio >1 favours nintedanib.

8.Secondary Outcome


Title	Change in Abdominal/Gastro-intestinal Symptoms Over Time
Description	Change in abdominal/gastro-intestinal over time was calculated on symp...
Description	Change in abdominal/gastro-intestinal over time was calculated on symptoms (scale composite of items 31 to 37 of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Module for Ovarian Cancer 28 (EORTC QLQ OV-28). As specified in the EORTC scoring manual, for each scale or item, a linear transformation was applied to standardize the raw score to a range from 0 to 100 (high scores represent a high/severe level of symptomatology). Mean presented is Adjusted mean. Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), FIGO stage (IIB-III vs IV), and Carboplatin level (AUC5 vs. AUC6).
Time Frame	First drug administration until final DBL 26September16, upto 62 months

Outcome Measure Data

Analysis Population Description

Randomised Set (RS) for patients with abdominal/gastro-intestinal symptoms


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Mean (Standard Error) Unit of Measure: units on a scale
	24.63 (0.49)	19.34 (0.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB-III vs IV), and carboplatin level (AUC5 vs. AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Mixed effect growth curve model
	Comments	Mixed-effects growth curve models (longitudinal models) with the average profile over time for each endpoint described by a piecewise linear model.

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	5.29
	Confidence Interval	(2-Sided) 95% 3.88 to 6.69
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.72
	Estimation Comments	Mean difference presented is the Adjusted mean difference. Difference calculated as nintedanib minus placebo. High values represent a worse level of symptoms.

9.Secondary Outcome


Title	Change in Global Health Status/ Quality of Life (QoL) Scale Over Time.
Description	Change in Global Health Status/ Quality of life (QoL) over time was ca...
Description	Change in Global Health Status/ Quality of life (QoL) over time was calculated on Global Health Status/QoL scale (composite of items 29 and 30 of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 (EORTC QLQ-C30) as a general measure. As specified in the EORTC scoring manual, for each scale or item, a linear transformation was applied to standardize the raw score to a range from 0 to 100 (high scores represent a high/healthy level of functioning). Mean presented is Adjusted mean. Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), FIGO stage (IIB-III vs IV), and Carboplatin level (AUC5 vs. AUC6).
Time Frame	First drug administration until final DBL 26September16, upto 62 months

Outcome Measure Data

Analysis Population Description

Randomised Set (RS) for patients with global health status/QoL


Arm/Group Title	Nintedanib	Placebo
Arm/Group Description:	Patients to receive Nintedanib 200 ...	Patients to receive matching placeb...
Arm/Group Description:	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
Overall Number of Participants Analyzed	911	455
Mean (Standard Error) Unit of Measure: units on a scale
	68.79 (0.48)	70.67 (0.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Nintedanib, Placebo
	Comments	Adjusted for the stratification factors macroscopic residual postoperative tumour at baseline (yes vs. no), the International Federation of Gynecology and Obstetrics (FIGO) stage (IIB-III vs IV), and carboplatin level (AUC5 vs. AUC6).
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0124
	Comments	[Not Specified]
	Method	Mixed effect growth curve model
	Comments	Mixed-effects growth curve models (longitudinal models) with the average profile over time for each endpoint described by a piecewise linear model.

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.88
	Confidence Interval	(2-Sided) 95% -3.35 to -0.41
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.75
	Estimation Comments	Mean difference calculated is the Adjusted mean. High values represent a better level of functioning. Difference calculated as nintedanib minus placebo.

Adverse Events

Time Frame	First drug administration until data cut-off 26September16, up to 62 months
Adverse Event Reporting Description	Adverse Events were reported for the treated patients.

Arm/Group Title	Placebo	Nintedanib
Arm/Group Description	Patients to receive matching placeb...	Patients to receive Nintedanib 200 ...
Arm/Group Description	Patients to receive matching placebo soft gelatine capsule identical to those containing Nintedanib, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.	Patients to receive Nintedanib 200 milligram (mg) soft gelatine capsule, taken orally twice daily, except the day of chemotherapy (carboplatin and paclitaxel) infusion, every 21 days for six courses.
All-Cause Mortality
	Placebo	Nintedanib
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events Serious Adverse Events
	Placebo	Nintedanib
	Affected / at Risk (%)	Affected / at Risk (%)
Total	157/450 (34.89%)	379/902 (42.02%)
Blood and lymphatic system disorders
Anaemia ^† 1	9/450 (2.00%)	36/902 (3.99%)
Febrile bone marrow aplasia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Febrile neutropenia ^† 1	6/450 (1.33%)	20/902 (2.22%)
Haemolytic uraemic syndrome ^† 1	0/450 (0.00%)	1/902 (0.11%)
Haemorrhagic anaemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Leukopenia ^† 1	1/450 (0.22%)	8/902 (0.89%)
Lymphadenopathy ^† 1	2/450 (0.44%)	1/902 (0.11%)
Microangiopathic haemolytic anaemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Neutropenia ^† 1	6/450 (1.33%)	24/902 (2.66%)
Pancytopenia ^† 1	1/450 (0.22%)	8/902 (0.89%)
Splenic infarction ^† 1	1/450 (0.22%)	0/902 (0.00%)
Splenic vein thrombosis ^† 1	1/450 (0.22%)	0/902 (0.00%)
Thrombocytopenia ^† 1	6/450 (1.33%)	21/902 (2.33%)
Thrombotic thrombocytopenic purpura ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cardiac disorders
Acute coronary syndrome ^† 1	1/450 (0.22%)	1/902 (0.11%)
Acute myocardial infarction ^† 1	0/450 (0.00%)	1/902 (0.11%)
Angina pectoris ^† 1	0/450 (0.00%)	3/902 (0.33%)
Atrial fibrillation ^† 1	2/450 (0.44%)	1/902 (0.11%)
Atrioventricular block ^† 1	0/450 (0.00%)	1/902 (0.11%)
Bundle branch block left ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cardiac arrest ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cardio-respiratory arrest ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cardiogenic shock ^† 1	0/450 (0.00%)	2/902 (0.22%)
Cardiovascular disorder ^† 1	1/450 (0.22%)	0/902 (0.00%)
Mitral valve incompetence ^† 1	1/450 (0.22%)	0/902 (0.00%)
Myocardial infarction ^† 1	1/450 (0.22%)	3/902 (0.33%)
Myocardial ischaemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Palpitations ^† 1	1/450 (0.22%)	0/902 (0.00%)
Sinus tachycardia ^† 1	0/450 (0.00%)	2/902 (0.22%)
Supraventricular tachyarrhythmia ^† 1	1/450 (0.22%)	0/902 (0.00%)
Tachycardia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Ventricular tachycardia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Congenital, familial and genetic disorders
Cancer gene carrier ^† 1	0/450 (0.00%)	1/902 (0.11%)
Ear and labyrinth disorders
Deafness ^† 1	0/450 (0.00%)	1/902 (0.11%)
Tinnitus ^† 1	0/450 (0.00%)	1/902 (0.11%)
Vertigo ^† 1	2/450 (0.44%)	0/902 (0.00%)
Endocrine disorders
Goitre ^† 1	0/450 (0.00%)	1/902 (0.11%)
Toxic nodular goitre ^† 1	0/450 (0.00%)	1/902 (0.11%)
Eye disorders
Vision blurred ^† 1	1/450 (0.22%)	0/902 (0.00%)
Gastrointestinal disorders
Abdominal adhesions ^† 1	1/450 (0.22%)	0/902 (0.00%)
Abdominal discomfort ^† 1	1/450 (0.22%)	1/902 (0.11%)
Abdominal distension ^† 1	1/450 (0.22%)	1/902 (0.11%)
Abdominal hernia ^† 1	2/450 (0.44%)	2/902 (0.22%)
Abdominal pain ^† 1	6/450 (1.33%)	30/902 (3.33%)
Abdominal pain upper ^† 1	0/450 (0.00%)	8/902 (0.89%)
Abdominal wall haematoma ^† 1	1/450 (0.22%)	0/902 (0.00%)
Acute abdomen ^† 1	0/450 (0.00%)	1/902 (0.11%)
Anal fissure ^† 1	0/450 (0.00%)	1/902 (0.11%)
Anal fistula ^† 1	0/450 (0.00%)	1/902 (0.11%)
Anal haemorrhage ^† 1	0/450 (0.00%)	1/902 (0.11%)
Aphthous ulcer ^† 1	0/450 (0.00%)	1/902 (0.11%)
Ascites ^† 1	8/450 (1.78%)	14/902 (1.55%)
Colitis ^† 1	2/450 (0.44%)	0/902 (0.00%)
Colonic fistula ^† 1	0/450 (0.00%)	2/902 (0.22%)
Constipation ^† 1	10/450 (2.22%)	13/902 (1.44%)
Diaphragmatic hernia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Diarrhoea ^† 1	8/450 (1.78%)	41/902 (4.55%)
Diverticulum intestinal ^† 1	1/450 (0.22%)	0/902 (0.00%)
Dysphagia ^† 1	1/450 (0.22%)	0/902 (0.00%)
Enteritis ^† 1	1/450 (0.22%)	1/902 (0.11%)
Enterocutaneous fistula ^† 1	0/450 (0.00%)	2/902 (0.22%)
Faecaloma ^† 1	1/450 (0.22%)	1/902 (0.11%)
Femoral hernia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Fistula of small intestine ^† 1	0/450 (0.00%)	2/902 (0.22%)
Functional gastrointestinal disorder ^† 1	0/450 (0.00%)	1/902 (0.11%)
Gastritis ^† 1	2/450 (0.44%)	2/902 (0.22%)
Gastrointestinal haemorrhage ^† 1	0/450 (0.00%)	1/902 (0.11%)
Gastrointestinal inflammation ^† 1	0/450 (0.00%)	2/902 (0.22%)
Gastrointestinal pain ^† 1	1/450 (0.22%)	0/902 (0.00%)
Haematemesis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Haemorrhoidal haemorrhage ^† 1	0/450 (0.00%)	1/902 (0.11%)
Ileus ^† 1	8/450 (1.78%)	17/902 (1.88%)
Impaired gastric emptying ^† 1	0/450 (0.00%)	1/902 (0.11%)
Intestinal obstruction ^† 1	4/450 (0.89%)	7/902 (0.78%)
Intestinal perforation ^† 1	1/450 (0.22%)	5/902 (0.55%)
Intussusception ^† 1	0/450 (0.00%)	1/902 (0.11%)
Large intestinal obstruction ^† 1	0/450 (0.00%)	1/902 (0.11%)
Mallory-Weiss syndrome ^† 1	1/450 (0.22%)	0/902 (0.00%)
Mechanical ileus ^† 1	0/450 (0.00%)	1/902 (0.11%)
Nausea ^† 1	10/450 (2.22%)	24/902 (2.66%)
Pancreatitis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Pancreatitis acute ^† 1	1/450 (0.22%)	0/902 (0.00%)
Rectal haemorrhage ^† 1	0/450 (0.00%)	1/902 (0.11%)
Small intestinal obstruction ^† 1	4/450 (0.89%)	12/902 (1.33%)
Small intestinal perforation ^† 1	1/450 (0.22%)	1/902 (0.11%)
Stomatitis ^† 1	0/450 (0.00%)	2/902 (0.22%)
Subileus ^† 1	2/450 (0.44%)	8/902 (0.89%)
Umbilical hernia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Vomiting ^† 1	12/450 (2.67%)	33/902 (3.66%)
General disorders
Asthenia ^† 1	2/450 (0.44%)	13/902 (1.44%)
Catheter site haematoma ^† 1	1/450 (0.22%)	0/902 (0.00%)
Chest pain ^† 1	4/450 (0.89%)	4/902 (0.44%)
Chills ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cyst ^† 1	1/450 (0.22%)	0/902 (0.00%)
Death ^† 1	0/450 (0.00%)	2/902 (0.22%)
Fatigue ^† 1	2/450 (0.44%)	10/902 (1.11%)
General physical health deterioration ^† 1	5/450 (1.11%)	17/902 (1.88%)
Hernia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Impaired healing ^† 1	0/450 (0.00%)	1/902 (0.11%)
Implant site erythema ^† 1	1/450 (0.22%)	0/902 (0.00%)
Influenza like illness ^† 1	1/450 (0.22%)	2/902 (0.22%)
Infusion site extravasation ^† 1	0/450 (0.00%)	1/902 (0.11%)
Mucosal inflammation ^† 1	0/450 (0.00%)	1/902 (0.11%)
Nodule ^† 1	1/450 (0.22%)	0/902 (0.00%)
Oedema ^† 1	1/450 (0.22%)	0/902 (0.00%)
Oedema peripheral ^† 1	1/450 (0.22%)	1/902 (0.11%)
Pain ^† 1	2/450 (0.44%)	1/902 (0.11%)
Performance status decreased ^† 1	1/450 (0.22%)	1/902 (0.11%)
Pyrexia ^† 1	8/450 (1.78%)	23/902 (2.55%)
Sudden death ^† 1	2/450 (0.44%)	0/902 (0.00%)
Surgical failure ^† 1	0/450 (0.00%)	1/902 (0.11%)
Hepatobiliary disorders
Cholecystitis ^† 1	0/450 (0.00%)	4/902 (0.44%)
Cholelithiasis ^† 1	1/450 (0.22%)	2/902 (0.22%)
Hyperbilirubinaemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Immune system disorders
Allergy to arthropod bite ^† 1	0/450 (0.00%)	1/902 (0.11%)
Anaphylactic reaction ^† 1	0/450 (0.00%)	2/902 (0.22%)
Anaphylactoid reaction ^† 1	1/450 (0.22%)	0/902 (0.00%)
Contrast media allergy ^† 1	1/450 (0.22%)	0/902 (0.00%)
Drug hypersensitivity ^† 1	3/450 (0.67%)	9/902 (1.00%)
Hypersensitivity ^† 1	1/450 (0.22%)	1/902 (0.11%)
Infections and infestations
Abdominal abscess ^† 1	0/450 (0.00%)	1/902 (0.11%)
Abdominal wall abscess ^† 1	0/450 (0.00%)	2/902 (0.22%)
Abscess ^† 1	0/450 (0.00%)	1/902 (0.11%)
Appendicitis ^† 1	1/450 (0.22%)	0/902 (0.00%)
Bacteraemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Beta haemolytic streptococcal infection ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cellulitis ^† 1	0/450 (0.00%)	3/902 (0.33%)
Clostridial infection ^† 1	1/450 (0.22%)	0/902 (0.00%)
Clostridium difficile colitis ^† 1	0/450 (0.00%)	2/902 (0.22%)
Clostridium difficile infection ^† 1	1/450 (0.22%)	1/902 (0.11%)
Cystitis ^† 1	0/450 (0.00%)	6/902 (0.67%)
Device related infection ^† 1	3/450 (0.67%)	4/902 (0.44%)
Diverticulitis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Endocarditis bacterial ^† 1	1/450 (0.22%)	0/902 (0.00%)
Enteritis infectious ^† 1	1/450 (0.22%)	0/902 (0.00%)
Enterobacter infection ^† 1	0/450 (0.00%)	1/902 (0.11%)
Enterocolitis bacterial ^† 1	0/450 (0.00%)	1/902 (0.11%)
Erysipelas ^† 1	0/450 (0.00%)	2/902 (0.22%)
Escherichia urinary tract infection ^† 1	0/450 (0.00%)	1/902 (0.11%)
Febrile infection ^† 1	0/450 (0.00%)	1/902 (0.11%)
Gastroenteritis ^† 1	3/450 (0.67%)	4/902 (0.44%)
Gastrointestinal infection ^† 1	0/450 (0.00%)	2/902 (0.22%)
Infected lymphocele ^† 1	0/450 (0.00%)	1/902 (0.11%)
Infection ^† 1	1/450 (0.22%)	3/902 (0.33%)
Infectious pleural effusion ^† 1	0/450 (0.00%)	1/902 (0.11%)
Joint abscess ^† 1	0/450 (0.00%)	1/902 (0.11%)
Klebsiella infection ^† 1	1/450 (0.22%)	0/902 (0.00%)
Liver abscess ^† 1	1/450 (0.22%)	1/902 (0.11%)
Lung infection ^† 1	0/450 (0.00%)	2/902 (0.22%)
Mesenteric abscess ^† 1	0/450 (0.00%)	1/902 (0.11%)
Nasopharyngitis ^† 1	1/450 (0.22%)	0/902 (0.00%)
Neutropenic sepsis ^† 1	0/450 (0.00%)	2/902 (0.22%)
Pelvic abscess ^† 1	0/450 (0.00%)	1/902 (0.11%)
Peritonitis ^† 1	1/450 (0.22%)	2/902 (0.22%)
Pharyngeal abscess ^† 1	1/450 (0.22%)	0/902 (0.00%)
Pneumonia ^† 1	3/450 (0.67%)	6/902 (0.67%)
Postoperative abscess ^† 1	0/450 (0.00%)	1/902 (0.11%)
Postoperative wound infection ^† 1	0/450 (0.00%)	1/902 (0.11%)
Pseudomonal sepsis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Pulpitis dental ^† 1	1/450 (0.22%)	0/902 (0.00%)
Pyelonephritis ^† 1	2/450 (0.44%)	2/902 (0.22%)
Pyelonephritis acute ^† 1	0/450 (0.00%)	2/902 (0.22%)
Rectal abscess ^† 1	0/450 (0.00%)	1/902 (0.11%)
Respiratory tract infection ^† 1	2/450 (0.44%)	0/902 (0.00%)
Sepsis ^† 1	1/450 (0.22%)	4/902 (0.44%)
Septic shock ^† 1	0/450 (0.00%)	2/902 (0.22%)
Sinusitis ^† 1	1/450 (0.22%)	0/902 (0.00%)
Subdiaphragmatic abscess ^† 1	1/450 (0.22%)	0/902 (0.00%)
Tooth abscess ^† 1	0/450 (0.00%)	1/902 (0.11%)
Upper respiratory tract infection ^† 1	1/450 (0.22%)	2/902 (0.22%)
Urinary tract infection ^† 1	3/450 (0.67%)	17/902 (1.88%)
Urinary tract infection bacterial ^† 1	1/450 (0.22%)	0/902 (0.00%)
Urinary tract infection enterococcal ^† 1	1/450 (0.22%)	0/902 (0.00%)
Urosepsis ^† 1	2/450 (0.44%)	2/902 (0.22%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence ^† 1	0/450 (0.00%)	1/902 (0.11%)
Ankle fracture ^† 1	0/450 (0.00%)	1/902 (0.11%)
Facial bones fracture ^† 1	1/450 (0.22%)	0/902 (0.00%)
Fall ^† 1	2/450 (0.44%)	1/902 (0.11%)
Femoral neck fracture ^† 1	1/450 (0.22%)	0/902 (0.00%)
Femur fracture ^† 1	1/450 (0.22%)	1/902 (0.11%)
Fibula fracture ^† 1	0/450 (0.00%)	1/902 (0.11%)
Fractured coccyx ^† 1	0/450 (0.00%)	1/902 (0.11%)
Gastrointestinal anastomotic leak ^† 1	0/450 (0.00%)	2/902 (0.22%)
Gastrointestinal stoma complication ^† 1	1/450 (0.22%)	1/902 (0.11%)
Head injury ^† 1	1/450 (0.22%)	0/902 (0.00%)
Humerus fracture ^† 1	1/450 (0.22%)	2/902 (0.22%)
Iatrogenic injury ^† 1	1/450 (0.22%)	0/902 (0.00%)
Incisional hernia ^† 1	4/450 (0.89%)	8/902 (0.89%)
Inflammation of wound ^† 1	0/450 (0.00%)	1/902 (0.11%)
Infusion related reaction ^† 1	0/450 (0.00%)	1/902 (0.11%)
Ligament sprain ^† 1	1/450 (0.22%)	0/902 (0.00%)
Meniscus injury ^† 1	1/450 (0.22%)	1/902 (0.11%)
Post procedural diarrhoea ^† 1	0/450 (0.00%)	1/902 (0.11%)
Postoperative fever ^† 1	0/450 (0.00%)	1/902 (0.11%)
Procedural haemorrhage ^† 1	0/450 (0.00%)	1/902 (0.11%)
Scar ^† 1	1/450 (0.22%)	0/902 (0.00%)
Stoma site haemorrhage ^† 1	1/450 (0.22%)	0/902 (0.00%)
Tibia fracture ^† 1	1/450 (0.22%)	1/902 (0.11%)
Vulvovaginal injury ^† 1	0/450 (0.00%)	1/902 (0.11%)
Wound dehiscence ^† 1	2/450 (0.44%)	1/902 (0.11%)
Investigations
Alanine aminotransferase increased ^† 1	0/450 (0.00%)	1/902 (0.11%)
Aspartate aminotransferase increased ^† 1	0/450 (0.00%)	1/902 (0.11%)
Biopsy vulva ^† 1	0/450 (0.00%)	1/902 (0.11%)
Blood creatinine increased ^† 1	0/450 (0.00%)	1/902 (0.11%)
Blood glucose increased ^† 1	1/450 (0.22%)	0/902 (0.00%)
Body temperature increased ^† 1	0/450 (0.00%)	2/902 (0.22%)
C-reactive protein increased ^† 1	0/450 (0.00%)	1/902 (0.11%)
Creatinine renal clearance decreased ^† 1	0/450 (0.00%)	1/902 (0.11%)
Eastern Cooperative Oncology Group performance status worsened ^† 1	0/450 (0.00%)	3/902 (0.33%)
Electrocardiogram abnormal ^† 1	1/450 (0.22%)	0/902 (0.00%)
Fibrin D dimer increased ^† 1	0/450 (0.00%)	1/902 (0.11%)
Gamma-glutamyltransferase increased ^† 1	0/450 (0.00%)	2/902 (0.22%)
Glomerular filtration rate decreased ^† 1	1/450 (0.22%)	0/902 (0.00%)
Haemoglobin decreased ^† 1	0/450 (0.00%)	3/902 (0.33%)
Lipase increased ^† 1	0/450 (0.00%)	1/902 (0.11%)
Neutrophil count decreased ^† 1	2/450 (0.44%)	1/902 (0.11%)
Platelet count decreased ^† 1	0/450 (0.00%)	5/902 (0.55%)
Troponin increased ^† 1	0/450 (0.00%)	1/902 (0.11%)
Weight decreased ^† 1	0/450 (0.00%)	3/902 (0.33%)
White blood cell count decreased ^† 1	1/450 (0.22%)	3/902 (0.33%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	0/450 (0.00%)	4/902 (0.44%)
Dehydration ^† 1	6/450 (1.33%)	21/902 (2.33%)
Electrolyte imbalance ^† 1	0/450 (0.00%)	2/902 (0.22%)
Failure to thrive ^† 1	0/450 (0.00%)	1/902 (0.11%)
Hypercalcaemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Hypoalbuminaemia ^† 1	1/450 (0.22%)	0/902 (0.00%)
Hypocalcaemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Hypoglycaemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Hypokalaemia ^† 1	2/450 (0.44%)	6/902 (0.67%)
Hypomagnesaemia ^† 1	0/450 (0.00%)	3/902 (0.33%)
Hyponatraemia ^† 1	0/450 (0.00%)	3/902 (0.33%)
Hypovolaemia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Malnutrition ^† 1	0/450 (0.00%)	1/902 (0.11%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	1/450 (0.22%)	0/902 (0.00%)
Arthritis ^† 1	2/450 (0.44%)	0/902 (0.00%)
Back pain ^† 1	1/450 (0.22%)	1/902 (0.11%)
Bone pain ^† 1	2/450 (0.44%)	0/902 (0.00%)
Intervertebral disc protrusion ^† 1	0/450 (0.00%)	3/902 (0.33%)
Lumbar spinal stenosis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Muscle haemorrhage ^† 1	0/450 (0.00%)	1/902 (0.11%)
Musculoskeletal chest pain ^† 1	0/450 (0.00%)	1/902 (0.11%)
Musculoskeletal pain ^† 1	0/450 (0.00%)	1/902 (0.11%)
Myalgia ^† 1	2/450 (0.44%)	1/902 (0.11%)
Osteoarthritis ^† 1	2/450 (0.44%)	1/902 (0.11%)
Pain in extremity ^† 1	1/450 (0.22%)	0/902 (0.00%)
Rhabdomyolysis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Spinal column stenosis ^† 1	1/450 (0.22%)	0/902 (0.00%)
Spinal osteoarthritis ^† 1	1/450 (0.22%)	0/902 (0.00%)
Synovial cyst ^† 1	1/450 (0.22%)	0/902 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Abdominal wall neoplasm ^† 1	1/450 (0.22%)	0/902 (0.00%)
Basal cell carcinoma ^† 1	1/450 (0.22%)	0/902 (0.00%)
Benign neoplasm of thyroid gland ^† 1	0/450 (0.00%)	1/902 (0.11%)
Bladder cancer ^† 1	0/450 (0.00%)	1/902 (0.11%)
Brain cancer metastatic ^† 1	0/450 (0.00%)	1/902 (0.11%)
Breast cancer ^† 1	1/450 (0.22%)	2/902 (0.22%)
Breast cancer recurrent ^† 1	0/450 (0.00%)	1/902 (0.11%)
Bronchioloalveolar carcinoma ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cerebellar tumour ^† 1	1/450 (0.22%)	0/902 (0.00%)
Clear cell renal cell carcinoma ^† 1	1/450 (0.22%)	0/902 (0.00%)
Invasive ductal breast carcinoma ^† 1	0/450 (0.00%)	1/902 (0.11%)
Malignant melanoma ^† 1	0/450 (0.00%)	1/902 (0.11%)
Malignant neoplasm progression ^† 1	7/450 (1.56%)	15/902 (1.66%)
Metastases to central nervous system ^† 1	2/450 (0.44%)	1/902 (0.11%)
Metastases to large intestine ^† 1	1/450 (0.22%)	0/902 (0.00%)
Metastases to reproductive organ ^† 1	1/450 (0.22%)	0/902 (0.00%)
Metastases to small intestine ^† 1	1/450 (0.22%)	1/902 (0.11%)
Neoplasm ^† 1	0/450 (0.00%)	2/902 (0.22%)
Neoplasm progression ^† 1	0/450 (0.00%)	1/902 (0.11%)
Ovarian cancer ^† 1	2/450 (0.44%)	0/902 (0.00%)
Ovarian epithelial cancer ^† 1	0/450 (0.00%)	1/902 (0.11%)
Papillary thyroid cancer ^† 1	0/450 (0.00%)	1/902 (0.11%)
Paraneoplastic syndrome ^† 1	0/450 (0.00%)	1/902 (0.11%)
Pelvic neoplasm ^† 1	0/450 (0.00%)	1/902 (0.11%)
Peritoneal neoplasm ^† 1	0/450 (0.00%)	1/902 (0.11%)
Renal cell carcinoma ^† 1	1/450 (0.22%)	0/902 (0.00%)
Thyroid cancer ^† 1	1/450 (0.22%)	0/902 (0.00%)
Tumour associated fever ^† 1	1/450 (0.22%)	0/902 (0.00%)
Nervous system disorders
Amnesia ^† 1	1/450 (0.22%)	0/902 (0.00%)
Asterixis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Carpal tunnel syndrome ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cerebral infarction ^† 1	0/450 (0.00%)	2/902 (0.22%)
Cerebrovascular accident ^† 1	1/450 (0.22%)	1/902 (0.11%)
Coma ^† 1	0/450 (0.00%)	1/902 (0.11%)
Dizziness ^† 1	1/450 (0.22%)	5/902 (0.55%)
Guillain-Barre syndrome ^† 1	0/450 (0.00%)	1/902 (0.11%)
Headache ^† 1	0/450 (0.00%)	5/902 (0.55%)
Hemianopia homonymous ^† 1	0/450 (0.00%)	1/902 (0.11%)
Intracranial aneurysm ^† 1	0/450 (0.00%)	1/902 (0.11%)
Ischaemic stroke ^† 1	0/450 (0.00%)	1/902 (0.11%)
Myoclonus ^† 1	1/450 (0.22%)	0/902 (0.00%)
Neuralgia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Neuropathy peripheral ^† 1	1/450 (0.22%)	1/902 (0.11%)
Paraesthesia ^† 1	1/450 (0.22%)	1/902 (0.11%)
Peripheral sensorimotor neuropathy ^† 1	0/450 (0.00%)	1/902 (0.11%)
Sciatica ^† 1	0/450 (0.00%)	1/902 (0.11%)
Syncope ^† 1	1/450 (0.22%)	6/902 (0.67%)
Transient ischaemic attack ^† 1	1/450 (0.22%)	1/902 (0.11%)
Trigeminal neuralgia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Product Issues
Device dislocation ^† 1	0/450 (0.00%)	1/902 (0.11%)
Thrombosis in device ^† 1	0/450 (0.00%)	1/902 (0.11%)
Psychiatric disorders
Anxiety ^† 1	2/450 (0.44%)	0/902 (0.00%)
Conversion disorder ^† 1	0/450 (0.00%)	1/902 (0.11%)
Depression ^† 1	1/450 (0.22%)	3/902 (0.33%)
Hallucination ^† 1	0/450 (0.00%)	1/902 (0.11%)
Mental disorder ^† 1	1/450 (0.22%)	0/902 (0.00%)
Personality change ^† 1	1/450 (0.22%)	0/902 (0.00%)
Renal and urinary disorders
Acute kidney injury ^† 1	3/450 (0.67%)	4/902 (0.44%)
Bladder tamponade ^† 1	0/450 (0.00%)	1/902 (0.11%)
Haematuria ^† 1	1/450 (0.22%)	1/902 (0.11%)
Hydronephrosis ^† 1	2/450 (0.44%)	7/902 (0.78%)
Incontinence ^† 1	0/450 (0.00%)	1/902 (0.11%)
Proteinuria ^† 1	0/450 (0.00%)	1/902 (0.11%)
Renal failure ^† 1	1/450 (0.22%)	4/902 (0.44%)
Ureteric obstruction ^† 1	0/450 (0.00%)	4/902 (0.44%)
Ureteric stenosis ^† 1	1/450 (0.22%)	1/902 (0.11%)
Urinary bladder haemorrhage ^† 1	1/450 (0.22%)	0/902 (0.00%)
Urinary retention ^† 1	0/450 (0.00%)	3/902 (0.33%)
Urinary tract obstruction ^† 1	0/450 (0.00%)	2/902 (0.22%)
Urogenital fistula ^† 1	0/450 (0.00%)	1/902 (0.11%)
Vesicocutaneous fistula ^† 1	1/450 (0.22%)	0/902 (0.00%)
Reproductive system and breast disorders
Cervical polyp ^† 1	1/450 (0.22%)	0/902 (0.00%)
Metrorrhagia ^† 1	0/450 (0.00%)	1/902 (0.11%)
Pelvic pain ^† 1	0/450 (0.00%)	2/902 (0.22%)
Uterine fistula ^† 1	0/450 (0.00%)	1/902 (0.11%)
Vaginal fistula ^† 1	0/450 (0.00%)	1/902 (0.11%)
Vaginal haemorrhage ^† 1	2/450 (0.44%)	1/902 (0.11%)
Vaginal prolapse ^† 1	0/450 (0.00%)	1/902 (0.11%)
Vaginal ulceration ^† 1	0/450 (0.00%)	1/902 (0.11%)
Respiratory, thoracic and mediastinal disorders
Asthma ^† 1	1/450 (0.22%)	0/902 (0.00%)
Cough ^† 1	1/450 (0.22%)	1/902 (0.11%)
Dyspnoea ^† 1	4/450 (0.89%)	10/902 (1.11%)
Dyspnoea at rest ^† 1	0/450 (0.00%)	1/902 (0.11%)
Hydrothorax ^† 1	1/450 (0.22%)	2/902 (0.22%)
Pleural effusion ^† 1	1/450 (0.22%)	6/902 (0.67%)
Pneumonitis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Pneumothorax ^† 1	0/450 (0.00%)	3/902 (0.33%)
Pulmonary embolism ^† 1	5/450 (1.11%)	11/902 (1.22%)
Pulmonary haemorrhage ^† 1	1/450 (0.22%)	0/902 (0.00%)
Respiratory failure ^† 1	1/450 (0.22%)	1/902 (0.11%)
Skin and subcutaneous tissue disorders
Dermatomyositis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Drug eruption ^† 1	0/450 (0.00%)	1/902 (0.11%)
Psoriasis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Rash ^† 1	0/450 (0.00%)	1/902 (0.11%)
Skin erosion ^† 1	1/450 (0.22%)	0/902 (0.00%)
Urticarial vasculitis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Surgical and medical procedures
Catheter placement ^† 1	1/450 (0.22%)	0/902 (0.00%)
Central venous catheter removal ^† 1	1/450 (0.22%)	0/902 (0.00%)
Chemotherapy ^† 1	1/450 (0.22%)	1/902 (0.11%)
Cholecystectomy ^† 1	0/450 (0.00%)	1/902 (0.11%)
Cytoreductive surgery ^† 1	2/450 (0.44%)	0/902 (0.00%)
Ileostomy ^† 1	0/450 (0.00%)	1/902 (0.11%)
Intestinal resection ^† 1	0/450 (0.00%)	1/902 (0.11%)
Laparotomy ^† 1	0/450 (0.00%)	2/902 (0.22%)
Large intestine anastomosis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Vaginal operation ^† 1	1/450 (0.22%)	0/902 (0.00%)
Vascular disorders
Accelerated hypertension ^† 1	0/450 (0.00%)	1/902 (0.11%)
Aortic aneurysm ^† 1	1/450 (0.22%)	0/902 (0.00%)
Axillary vein thrombosis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Circulatory collapse ^† 1	0/450 (0.00%)	1/902 (0.11%)
Deep vein thrombosis ^† 1	5/450 (1.11%)	4/902 (0.44%)
Haematoma ^† 1	0/450 (0.00%)	1/902 (0.11%)
Hypertension ^† 1	0/450 (0.00%)	5/902 (0.55%)
Hypertensive crisis ^† 1	0/450 (0.00%)	2/902 (0.22%)
Hypotension ^† 1	1/450 (0.22%)	4/902 (0.44%)
Lymphocele ^† 1	2/450 (0.44%)	6/902 (0.67%)
Lymphoedema ^† 1	0/450 (0.00%)	1/902 (0.11%)
Malignant hypertension ^† 1	0/450 (0.00%)	1/902 (0.11%)
Orthostatic hypotension ^† 1	0/450 (0.00%)	1/902 (0.11%)
Pelvic venous thrombosis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Thrombophlebitis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Thrombosis ^† 1	1/450 (0.22%)	6/902 (0.67%)
Varicose vein ^† 1	0/450 (0.00%)	1/902 (0.11%)
Vasculitis ^† 1	1/450 (0.22%)	0/902 (0.00%)
Vena cava thrombosis ^† 1	0/450 (0.00%)	1/902 (0.11%)
Venous occlusion ^† 1	1/450 (0.22%)	0/902 (0.00%)
Venous thrombosis limb ^† 1	0/450 (0.00%)	2/902 (0.22%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 19.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Nintedanib
	Affected / at Risk (%)	Affected / at Risk (%)
Total	442/450 (98.22%)	891/902 (98.78%)
Blood and lymphatic system disorders
Anaemia ^† 1	129/450 (28.67%)	317/902 (35.14%)
Leukopenia ^† 1	78/450 (17.33%)	165/902 (18.29%)
Neutropenia ^† 1	203/450 (45.11%)	419/902 (46.45%)
Thrombocytopenia ^† 1	87/450 (19.33%)	301/902 (33.37%)
Gastrointestinal disorders
Abdominal distension ^† 1	20/450 (4.44%)	55/902 (6.10%)
Abdominal pain ^† 1	111/450 (24.67%)	281/902 (31.15%)
Abdominal pain upper ^† 1	58/450 (12.89%)	125/902 (13.86%)
Constipation ^† 1	151/450 (33.56%)	254/902 (28.16%)
Diarrhoea ^† 1	114/450 (25.33%)	692/902 (76.72%)
Dyspepsia ^† 1	24/450 (5.33%)	77/902 (8.54%)
Flatulence ^† 1	9/450 (2.00%)	53/902 (5.88%)
Nausea ^† 1	231/450 (51.33%)	583/902 (64.63%)
Stomatitis ^† 1	24/450 (5.33%)	51/902 (5.65%)
Vomiting ^† 1	119/450 (26.44%)	391/902 (43.35%)
General disorders
Asthenia ^† 1	65/450 (14.44%)	163/902 (18.07%)
Fatigue ^† 1	201/450 (44.67%)	388/902 (43.02%)
Mucosal inflammation ^† 1	30/450 (6.67%)	62/902 (6.87%)
Oedema peripheral ^† 1	47/450 (10.44%)	48/902 (5.32%)
Pain ^† 1	27/450 (6.00%)	35/902 (3.88%)
Pyrexia ^† 1	46/450 (10.22%)	64/902 (7.10%)
Immune system disorders
Drug hypersensitivity ^† 1	21/450 (4.67%)	58/902 (6.43%)
Hypersensitivity ^† 1	32/450 (7.11%)	53/902 (5.88%)
Infections and infestations
Cystitis ^† 1	17/450 (3.78%)	66/902 (7.32%)
Nasopharyngitis ^† 1	36/450 (8.00%)	73/902 (8.09%)
Urinary tract infection ^† 1	50/450 (11.11%)	131/902 (14.52%)
Investigations
Alanine aminotransferase increased ^† 1	49/450 (10.89%)	259/902 (28.71%)
Aspartate aminotransferase increased ^† 1	41/450 (9.11%)	219/902 (24.28%)
Blood alkaline phosphatase increased ^† 1	16/450 (3.56%)	74/902 (8.20%)
Haemoglobin decreased ^† 1	24/450 (5.33%)	56/902 (6.21%)
Neutrophil count decreased ^† 1	23/450 (5.11%)	74/902 (8.20%)
Platelet count decreased ^† 1	17/450 (3.78%)	63/902 (6.98%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	63/450 (14.00%)	168/902 (18.63%)
Hypokalaemia ^† 1	25/450 (5.56%)	85/902 (9.42%)
Hypomagnesaemia ^† 1	25/450 (5.56%)	92/902 (10.20%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	137/450 (30.44%)	242/902 (26.83%)
Back pain ^† 1	54/450 (12.00%)	83/902 (9.20%)
Bone pain ^† 1	39/450 (8.67%)	62/902 (6.87%)
Musculoskeletal pain ^† 1	29/450 (6.44%)	56/902 (6.21%)
Myalgia ^† 1	107/450 (23.78%)	201/902 (22.28%)
Pain in extremity ^† 1	56/450 (12.44%)	95/902 (10.53%)
Nervous system disorders
Dizziness ^† 1	36/450 (8.00%)	77/902 (8.54%)
Dysgeusia ^† 1	37/450 (8.22%)	126/902 (13.97%)
Headache ^† 1	53/450 (11.78%)	140/902 (15.52%)
Neuropathy peripheral ^† 1	85/450 (18.89%)	172/902 (19.07%)
Paraesthesia ^† 1	64/450 (14.22%)	100/902 (11.09%)
Peripheral sensory neuropathy ^† 1	114/450 (25.33%)	214/902 (23.73%)
Polyneuropathy ^† 1	25/450 (5.56%)	50/902 (5.54%)
Psychiatric disorders
Anxiety ^† 1	27/450 (6.00%)	36/902 (3.99%)
Depression ^† 1	32/450 (7.11%)	51/902 (5.65%)
Insomnia ^† 1	57/450 (12.67%)	105/902 (11.64%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	34/450 (7.56%)	57/902 (6.32%)
Dyspnoea ^† 1	55/450 (12.22%)	109/902 (12.08%)
Epistaxis ^† 1	17/450 (3.78%)	72/902 (7.98%)
Skin and subcutaneous tissue disorders
Alopecia ^† 1	278/450 (61.78%)	519/902 (57.54%)
Pruritus ^† 1	32/450 (7.11%)	44/902 (4.88%)
Rash ^† 1	50/450 (11.11%)	95/902 (10.53%)
Vascular disorders
Hot flush ^† 1	45/450 (10.00%)	73/902 (8.09%)
Hypertension ^† 1	23/450 (5.11%)	119/902 (13.19%)
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 19.0

Limitations and Caveats

[Not Specified]

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

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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):

du Bois A, Kristensen G, Ray-Coquard I, Reuss A, Pignata S, Colombo N, Denison U, Vergote I, Del Campo JM, Ottevanger P, Heubner M, Minarik T, Sevin E, de Gregorio N, Bidzinski M, Pfisterer J, Malander S, Hilpert F, Mirza MR, Scambia G, Meier W, Nicoletto MO, Bjorge L, Lortholary A, Sailer MO, Merger M, Harter P; AGO Study Group led Gynecologic Cancer Intergroup/European Network of Gynaecologic Oncology Trials Groups Intergroup Consortium. Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2016 Jan;17(1):78-89. doi: 10.1016/S1470-2045(15)00366-6. Epub 2015 Nov 16.

Layout table for additonal information

Responsible Party:	Boehringer Ingelheim
ClinicalTrials.gov Identifier:	NCT01015118
Other Study ID Numbers:	1199.15 AGO-OVAR12 ( Other Identifier: OTHER ) 2008-006831-10 ( EudraCT Number: EudraCT )
First Submitted:	November 9, 2009
First Posted:	November 18, 2009
Results First Submitted:	November 14, 2014
Results First Posted:	January 15, 2015
Last Update Posted:	December 7, 2017

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