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Clinical Trial Results:
A randomised, open label, parallel group Phase II study comparing the efficacy and tolerability of BIBF 1120 versus sunitinib in previously untreated patients with Renal Cell Cancer

Summary
EudraCT number	2009-009516-44
Trial protocol	GB HU
Global end of trial date	19 Jun 2020

Results information
Results version number	v2(current)
This version publication date	24 Nov 2021
First version publication date	02 Jul 2021
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

1199.26

ISRCTN number

US NCT number

NCT01024920

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Jul 2020

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Nov 2011

Global end of trial reached?

Yes

Global end of trial date

19 Jun 2020

Was the trial ended prematurely?

Main objective of the trial

The objectives of this trial were to compare the efficacy and safety of nintedanib (BIBF 1120) versus sunitinib in patients with advanced renal cell cancer (RCC) and to investigate the effects of nintedanib on the heart rate corrected QT interval (QTcF).

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Mar 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Hungary: 4

Country: Number of subjects enrolled

Poland: 25

Country: Number of subjects enrolled

Romania: 7

Country: Number of subjects enrolled

Ukraine: 56

Country: Number of subjects enrolled

United Kingdom: 21

Worldwide total number of subjects

113

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

An open-label, 2:1 randomised, parallel-arm comparison of nintedanib versus sunitinib in patients with advanced renal cell cancer (RCC) who had not received prior systemic therapy.

Screening details

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Period 1 title

Randomised

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

This was an open-label study and patients were randomised to receive either nintedanib (BIBF 1120), or sunitinib treatment. The electrocardiogram and pharmacokinetic (PK) sampleswere identified by patient and study number only.

Are arms mutually exclusive

Yes

Nintedanib (BIBF 1120)

Arm description

Participants received orally (swallowed) soft gelatine capsules of nintedanib (BIBF 1120) twice daily (bid) starting with a dose of 200 milligram (mg) bid given continuously in 4-week cycles. Nintedanib was to be swallowed unchewed with about 200 milliliter (mL) of water after food intake with a dosing interval of approximately 12 hours. In case of Adverse Events, the dose was to be reduced to 150 mg bid and 100 mg bid, respectively. The dose was continued daily until withdrawal criteria were fulfilled.

Arm type

Experimental

Investigational medicinal product name

Nintedanib

Investigational medicinal product code

Other name

BIBF 1120

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Sunitinib

Arm description

Participants received orally (swallowed) hard capsule of sunitinib starting with a dose of 50 milligram (mg) once daily (qd). In case of Adverse Events the dose was to be reduced to 37.5 mg once daily and 25 mg once daily, respectively. The daily dosing was performed in 6-week cycles (4 weeks on and 2 weeks off) until withdrawal criteria were fulfilled.

Arm type

Active comparator

Investigational medicinal product name

Sunitinib

Investigational medicinal product code

Other name

Sutent ®

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Nintedanib (BIBF 1120)	Sunitinib
Started	67	32
Completed	64	32
Not completed	3	0
Not treated	3	-

Period 2 title

Treated

Is this the baseline period?

Yes ^[1]

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Are arms mutually exclusive

Yes

Nintedanib (BIBF 1120)

Arm description

Arm type

Experimental

Investigational medicinal product name

Nintedanib

Investigational medicinal product code

Other name

BIBF 1120

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Sunitinib

Arm description

Arm type

Active comparator

Investigational medicinal product name

Sunitinib

Investigational medicinal product code

Other name

Sutent ®

Pharmaceutical forms

Capsule, hard

Routes of administration

Oral use

Dosage and administration details

Notes
[1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
Justification: Period 1 are the randomised subjects, period 2 the treated, baseline characteristics are reported for the treated subjects.

Number of subjects in period 2 ^[2]	Nintedanib (BIBF 1120)	Sunitinib
Started	64	32
Treated	64	32
Completed	0	0
Not completed	64	32
Patient refusal to continue	4	-
Adverse event, non-fatal	8	4
Progressive disease	47	25
Lost to follow-up	-	1
Other than listed	5	1
Protocol deviation	-	1

Notes
[2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of 113 enrolled participants, 96 were treated, which are reported in the baseline characteristics.

Baseline characteristics

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Reporting group title

Nintedanib (BIBF 1120)

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Reporting group values	Nintedanib (BIBF 1120)	Sunitinib	Total
Number of subjects	64	32	96
Age categorical
Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	42	25	67
From 65-84 years	21	7	28
85 years and over	1	0	1
Age Continuous
Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
Units: years
arithmetic mean (standard deviation)	60.4 ( 9.7 )	55.5 ( 11.4 )	-
Sex: Female, Male
Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
Units:
Female	20	10	30
Male	44	22	66
Race (NIH/OMB)
Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	64	32	96
More than one race	0	0	0
Unknown or Not Reported	0	0	0
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at -5 minutes (min) on Day -1 (prior to the first dosing of nintedanib). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	405.2 ( 19.6 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at 1 hour (h) on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	406.0 ( 20.3 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were at 2 h on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	405.3 ( 19.4 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at 3 h on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	406.7 ( 19.4 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at 4 h on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	407.0 ( 17.8 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at 5 h on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	407.2 ( 18.0 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at 6 h on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	405.9 ( 18.3 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at 7 h on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	405.4 ( 19.2 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at 10 h on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	406.6 ( 19.2 )	99999 ( 99999 )	-
QTcF interval baseline values
QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) baseline values were measured at 12 h on Day -1 (prior to the first dosing of nintedanib (BIBF 1120)). 99999= Not applicable Full analysis set electrocardiogram (FAS-ECG).
Units: millisecconds (ms)
arithmetic mean (standard deviation)	406.0 ( 19.2 )	99999 ( 99999 )	-

End points

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Reporting group title

Nintedanib (BIBF 1120)

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Reporting group title

Nintedanib (BIBF 1120)

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Primary: Probability rates of progression-free survival at 9 months

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End point title

Probability rates of progression-free survival at 9 months

End point description

Progression free survival rate at 9 months is the estimated probability of being alive and not having progressive disease at 9 months after randomisation. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria version 1.1 (RECIST v1.1), at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started together with an absolute increase in the sum of the longest diameters of at least 5 mm, or the appearance of one or more new lesions. Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Primary

End point timeframe

At 9 months after randomisation.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[1]	32 ^[2]
Units: Probability
number (confidence interval 95%)	0.431 (0.306 to 0.550)	0.452 (0.274 to 0.614)

Notes
[1] - TS
[2] - TS

Statistical Analysis 1

Comparison groups

Nintedanib (BIBF 1120) v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8531 ^[3]

Method

Normal approximation test

Confidence interval

Notes
[3] - P−value for comparison of Kaplan−Meier estimates at 9 months using normal approximation test (two−sided).

Primary: Time-matched change from baseline to Day 15 in QTcF (QT interval corrected by the Fridericia formula) at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

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End point title

Time-matched change from baseline to Day 15 in QTcF (QT interval corrected by the Fridericia formula) at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120) ^[4] ^[5]

End point description

QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate by the Fridericia formula. Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 15 in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 15 obtained at time t minus baseline QTcF measurement at time t. 0 h is 5 min prior to dosing at Day 15. Time-matched change from baseline to Day 15 in QTcF was modelled using a linear mixed-effects model for repeated measures which included ‘time’ as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals are reported. FAS-ECG.

End point type

Primary

End point timeframe

At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 15. Baseline (Day -1) values were taken at exactly the same time points as on Day 15.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Endpoint was analyzed only descriptively.
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[6]
Units: milliseconds (ms)
least squares mean (confidence interval 90%)
Time-matched change from Day-1 to Day 15 at -5 min	2.6 (-0.7 to 5.9)
Time-matched change from Day-1 to Day 15 at 1 h	0.4 (-2.8 to 3.7)
Time-matched change from Day-1 to Day 15 at 2 h	-1.7 (-4.9 to 1.6)
Time-matched change from DAy -1 to Day 15 at 3 h	-0.5 (-3.8 to 2.8)
Time-matched change from Day -1 to Day 15 at 4 h	-0.5 (-3.8 to 2.8)
Time-matched change from Day -1 to Day 15 at 5 h	0.3 (-3.0 to 3.6)
Time-matched change from baseline to Day 15 at 6 h	2.2 (-1.1 to 5.5)
Time-matched change from Day -1 to Day 15 at 7 h	3.1 (-0.2 to 6.4)
Time-matched change from Day -1 to Day 15 at 10 h	0.1 (-3.2 to 3.4)
Time-matched change from Day-1 to Day 15 at 12 h	1.6 (-1.7 to 4.9)

Notes
[6] - FAS-ECG

No statistical analyses for this end point

Secondary: Progression free survival (PFS)

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End point title

Progression free survival (PFS)

End point description

Progression free survival (PFS) from randomisation to the occurrence of disease progression (by RECIST Version 1.1) or death, whichever occurred first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started together with an absolute increase in the sum of the longest diameters of at least 5 mm, or the appearance of one or more new lesions. Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication. The Kaplan-Meier method was used to calculate the estimates. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From the start of study until the cut-off date for 3 year efficacy analysis, up to 3 years.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[7]	32 ^[8]
Units: Months
median (confidence interval 95%)	8.44 (5.59 to 11.10)	8.38 (5.59 to 13.86)

Notes
[7] - TS
[8] - TS

Statistical Analysis 2

Statistical analysis description

A stratified log-rank test (two-sided, 0.05 significance level) was used to test the effect of nintedanib on PFS compared with sunitinib. The test was stratified by Motzer risk score category (low/intermediate or high) and prior nephrectomy surgery for Renal Cell Cancer (yes or no).

Comparison groups

Nintedanib (BIBF 1120) v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6395

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.697

upper limit

1.8

Secondary: Objective response according to RECIST criteria

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End point title

Objective response according to RECIST criteria

End point description

Objective response was defined as complete response (CR, the disappearance of all target and non-target lesions and no new lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum of the longest diameters and no new lesions) as determined by RECIST Version 1.1. Numbers of participants with objective response are reported. Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From the start of study until the cut-off date for 3 year efficacy analysis, up to 3 years.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[9]	32 ^[10]
Units: Participants
Complete Response	0	1
Partial response	14	11

Notes
[9] - TS
[10] - TS

Statistical Analysis 3

Statistical analysis description

A logistic regression model stratified by Motzer risk score category and prior surgery for renal cell cancer (RCC) was used to compare the objective response rate between the two treatment arms. The corresponding odds ratio and 95% CI was also presented. Odds ratio > 1 favours nintedanib.

Comparison groups

Nintedanib (BIBF 1120) v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1213

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.484

Confidence interval

level

95%

sides

2-sided

lower limit

0.193

upper limit

1.212

Secondary: Duration of objective response

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End point title

Duration of objective response

End point description

Duration (months) of objective response was measured from the time of first objective response to the time of disease progression (by RECIST Version 1.1) or death, whichever occurred first. Objective response was defined as complete response (CR, the disappearance of all target and non-target lesions and no new lesions) or partial response (PR, at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum of the longest diameters and no new lesions) as determined by RECIST Version 1.1. Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication. The Kaplan-Meier method was used to calculate the estimates. 99999= Not applicable. Upper Interquartile-Range cannot be estimated based on the current limited data in a small sample−sized study. Treated set (TS)

End point type

Secondary

End point timeframe

From the time of first objective response to the time of disease progression or death (whichever comes first), up to 3 years.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	14 ^[11]	12 ^[12]
Units: Months
median (inter-quartile range (Q1-Q3))	19.42 (8.31 to 99999)	11.66 (7.06 to 28.45)

Notes
[11] - TS
[12] - TS

No statistical analyses for this end point

Secondary: Overall survival

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End point title

Overall survival

End point description

Overall survival was calculated as the time (months) from randomisation to death. Patients for whom there was no evidence of death at the time of analysis were censored on the date that they were last known to have been alive. The Kaplan-Meier method was used to calculate the estimates. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From randomisation to death, up to 3 years.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[13]	32 ^[14]
Units: Months
median (confidence interval 95%)	20.37 (13.86 to 29.01)	21.22 (11.01 to 31.74)

Notes
[13] - TS
[14] - TS

Statistical Analysis 4

Statistical analysis description

Hazard ratio from Cox proportional hazards model stratified by Motzer risk score and previous surgery. Hazard ratio < 1 favours nintedanib.

Comparison groups

Nintedanib (BIBF 1120) v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7593 ^[15]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.542

upper limit

1.564

Notes
[15] - P−value from log−rank stratified by Motzer risk score and previous surgery.

Secondary: Time to progression

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End point title

Time to progression

End point description

Time to progression is defined as the time period from randomisation to objective tumour progression. Patients with no progression (by RECIST Version 1.1) were censored at the date of the last evaluable imaging. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of the longest diameters recorded since the treatment started together with an absolute increase in the sum of the longest diameters of at least 5 mm, or the appearance of one or more new lesions. Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication. The Kaplan-Meier method was used to calculate the estimates. Treated set (TS).

End point type

Secondary

End point timeframe

From randomisation up to objective tumour progression, up to 3 years.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[16]	32 ^[17]
Units: Months
median (confidence interval 95%)	8.48 (7.56 to 11.20)	8.54 (5.68 to 13.90)

Notes
[16] - TS
[17] - TS

Statistical Analysis 5

Statistical analysis description

P−value from log−rank stratified by Motzer risk score and previous surgery. Hazard ratio from Cox proportional hazards model stratified by Motzer risk score and previous surgery. Hazard ratio < 1 favours nintedanib.

Comparison groups

Nintedanib (BIBF 1120) v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5958

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.143

Confidence interval

level

95%

sides

2-sided

lower limit

0.697

upper limit

1.873

Secondary: Time to treatment failure

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End point title

Time to treatment failure

End point description

Time to treatment failure was defined as the time from randomisation to objective tumour progression (by RECIST Version 1.1), death, global deterioration of health status requiring treatment discontinuation, or start of new anticancer treatment, whichever came first. Tumour imaging was made by investigators using Computed tomography (CT)/Magnetic Resonance imaging (MRI) every 12 weeks after the first administration of the trial medication.The Kaplan-Meier method was used to calculate the estimates. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From randomisation up to objective tumour progression, up to 3 years.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[18]	32 ^[19]
Units: Month
median (confidence interval 95%)	8.44 (5.62 to 10.97)	8.36 (5.55 to 13.86)

Notes
[18] - TS
[19] - TS

Statistical Analysis 6

Statistical analysis description

P−value from log−rank stratified by Motzer risk score and previous surgery (two−sided). Hazard ratio from Cox proportional hazards model stratified by Motzer risk score and previous surgery. Hazard ratio < 1 favours nintedanib.

Comparison groups

Nintedanib (BIBF 1120) v Sunitinib

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5712

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.142

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.812

Secondary: Time-matched change from baseline to Day 1 in QTcF (QT interval corrected by the Fridericia formula) at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

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End point title

Time-matched change from baseline to Day 1 in QTcF (QT interval corrected by the Fridericia formula) at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120) ^[20]

End point description

QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate by the Fridericia formula. Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 1 obtained at time t minus baseline QTcF measurement at time t. Time-matched change from baseline to Day 1 in QTcF was modelled using a linear mixed-effects model for repeated measures which included ‘time’ as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals are reported. FAS-ECG.

End point type

Secondary

End point timeframe

At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1. Baseline (Day -1) values were taken at exactly the same time points as on Day 1.

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[21]
Units: milliseconds (ms)
least squares mean (confidence interval 90%)
Time-matched change from baseline to Day 1 at 1 h	-1.6 (-4.4 to 1.2)
Time-matched change from baseline to Day 1 at 2 h	-3.1 (-6.0 to -0.3)
Time-matched change from baseline to Day 1 at 3 h	-2.6 (-5.5 to 0.2)
Time-matched change from baseline to Day 1 at 4 h	-2.6 (-5.4 to 0.3)
Time-matched change from baseline to Day 1 at 5 h	-1.4 (-4.3 to 1.4)
Time-matched change from baseline to Day 1 at 6 h	-2.0 (-4.8 to 0.9)
Time-matched change from baseline to Day 1 at 7 h	-1.5 (-4.4 to 1.3)
Time-matched change from baseline to Day 1 at 10 h	-3.6 (-6.4 to -0.7)
Time-matched change from baseline to Day 1 at 12 h	-2.2 (-5.0 to 0.7)

Notes
[21] - FAS-ECG

No statistical analyses for this end point

Secondary: Time-matched change from baseline in QTcF interval (QT interval corrected by the Fridericia formula) at the time of each participant’s maximum plasma concentration of nintedanib (BIBF 1120), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Time-matched change from baseline in QTcF interval (QT interval corrected by the Fridericia formula) at the time of each participant’s maximum plasma concentration of nintedanib (BIBF 1120), calculated separately for Days 1 and 15 of treatment cycle 1 ^[22]

End point description

QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula. Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QTcF measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in QTcF’ at the time of the participant's maximum nintedanib plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of the first treatment cycle. Continues in the description.

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[23]
Units: milliseconds (ms)
arithmetic mean (confidence interval 90%)
Day 1	-2.8 (-5.0 to -0.6)
Day 15	-3.2 (-5.9 to -0.4)

Notes
[23] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched change from baseline in QTcF interval at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Time−matched change from baseline in QTcF interval at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1 ^[24]

End point description

Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QTcF measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in QTcF’ at the time of the participant's maximum BIBF 1202 (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[25]
Units: milliseconds (ms)
arithmetic mean (confidence interval 90%)
Day 1	-2.5 (-4.6 to -0.5)
Day 15	-1.1 (-3.8 to 1.6)

Notes
[25] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched change from baseline in QTcF interval at the time of each patient’s maximum plasma concentration of BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Time−matched change from baseline in QTcF interval at the time of each patient’s maximum plasma concentration of BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1 ^[26]

End point description

Baseline QTcF measurement at time t was defined as the QTcF measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QTcF at time t was defined as the QTcF measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QTcF measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in QTcF’ at the time of the participant's maximum BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported. Time frame: Baseline values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[27]
Units: milliseconds (ms)
arithmetic mean (confidence interval 90%)
Day 1	-2.4 (-4.9 to 0.0)
Day 15	-1.5 (-4.2 to 1.2)

Notes
[27] - FAS-ECG

No statistical analyses for this end point

Secondary: Average time-matched changes from baseline in QTcF interval over 1 h to 12 h after dosing on Days 1 and 15 of treatment cycle 1

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End point title

Average time-matched changes from baseline in QTcF interval over 1 h to 12 h after dosing on Days 1 and 15 of treatment cycle 1 ^[28]

End point description

Average time-matched in QTcF interval (QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula) changes over 1 to 12 hours was evaluated using a t-test for paired observation. The mean differences between post-treatment values (Days 1 and 15) and baseline (Day -1) along with two-sided 90% confidence limits are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Continues in the description.

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[29]
Units: milliseconds (ms)
arithmetic mean (confidence interval 90%)
Day 1	-2.2 (-3.5 to -0.8)
Day 15	0.5 (-1.4 to 2.3)

Notes
[29] - FAS-ECG

No statistical analyses for this end point

Secondary: Time-matched changes from baseline to Day 15 in QT interval at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

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End point title

Time-matched changes from baseline to Day 15 in QT interval at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120) ^[30]

End point description

QT interval is the electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 15 in QT at time t was defined as the QT measurement following administration of nintedanib on Day 15 obtained at time t minus baseline QT measurement at time t. 0 h is 5 min prior to dosing at Day 15. Time-matched change from baseline to Day 15 in QT was modelled using a linear mixed-effects model for repeated measures which included ‘time’ as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals are reported. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[31]
Units: milliseconds (ms)
least squares mean (confidence interval 90%)
Time-matched change from Day-1 to Day15 at -5 min	1.0 (-3.6 to 5.6)
Time-matched change from Day -1 to Day 15 at 1 h	0.5 (-4.1 to 5.1)
Time-matched change from Day -1 to Day 15 at 2 h	1.6 (-3.0 to 6.2)
Time-matched change from Day -1 to Day 15 at 3 h	4.4 (-0.2 to 9.0)
Time-matched change from Day -1 to Day 15 at 4 h	4.7 (0.0 to 9.3)
Time-matched change from Day-1 to Day 15 at 5 h	5.1 (0.5 to 9.7)
Time-matched change from Day -1 to Day 15 at 6 h	7.7 (3.1 to 12.3)
Time-matched change from Day-1 to Day 15 at 7 h	7.1 (2.5 to 11.7)
Time-matched change from Day-1 to Day 15 at 10 h	3.4 (-1.2 to 8.0)
Time-matched change from Day-1 to Day 15 at 12 h	4.2 (-0.4 to 8.8)

Notes
[31] - FAS-ECG

No statistical analyses for this end point

Secondary: Time-matched changes from baseline to Day 1 in QT interval at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Top of page

End point title

Time-matched changes from baseline to Day 1 in QT interval at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120) ^[32]

End point description

QT interval is the electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 in QT at time t was defined as the QT measurement following administration of nintedanib on Day 1 obtained at time t minus baseline QT measurement at time t. Time-matched change from baseline to Day 1 in QT was modelled using a linear mixed-effects model for repeated measures which included ‘time’ as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals are reported. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[33]
Units: millisecond (ms)
least squares mean (confidence interval 90%)
Time−matched change from Day -1 to Day 1 at 1 h	-2.0 (-6.3 to 2.3)
Time−matched change from Day-1 to Day 1 at 2 h	1.6 (-2.8 to 5.9)
Time−matched change from Day-1 to Day 1 at 3 h	3.5 (-0.8 to 7.8)
Time−matched change from Day-1 to Day 1 at 4 h	1.4 (-2.9 to 5.7)
Time−matched change from Day-1 to Day 1 at 5 h	1.4 (-2.9 to 5.7)
Time−matched change from Day-1 to Day 1 at 6 h	1.8 (-2.6 to 6.1)
Time−matched change from Day-1 to Day 1 at 7 h	0.7 (-3.6 to 5.0)
Time−matched change from Day-1 to Day 1 at 10 h	-1.7 (-6.0 to 2.7)
Time−matched change from Day-1 to Day 1at 12 h	-2.2 (-6.5 to 2.2)

Notes
[33] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration of nintedanib (BIBF 1120), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration of nintedanib (BIBF 1120), calculated separately for Days 1 and 15 of treatment cycle 1 ^[34]

End point description

QT interval is the (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QT at time t was defined as the QT measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QT measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in QT’ at the time of the participant's maximum nintedanib plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[35]
Units: millisecond (ms)
arithmetic mean (confidence interval 90%)
Day 1	0.9 (-2.3 to 4.0)
Day 15	-0.4 (-5.0 to 4.1)

Notes
[35] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Top of page

End point title

Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1 ^[36]

End point description

QT interval is the (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QT at time t was defined as the QT measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QT measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in QT’ at the time of the participant's maximum BIBF 1202 (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle. Continues in the description.

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[37]
Units: millisecond (ms)
arithmetic mean (confidence interval 90%)
Day 1	1.2 (-1.9 to 4.3)
Day 15	1.8 (-2.7 to 6.3)

Notes
[37] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1 ^[38]

End point description

QT interval is the (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave. Baseline QT measurement at time t was defined as the QT measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in QT at time t was defined as the QT measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline QT measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in QT’ at the time of the participant's maximum BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[39]
Units: millisecond (ms)
arithmetic mean (confidence interval 90%)
Day 1	-0.4 (-4.0 to 3.1)
Day 15	1.3 (-3.2 to 5.9)

Notes
[39] - FAS-ECG

No statistical analyses for this end point

Secondary: Averaged time-matched changes from baseline in QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) over 1 h to 12 h after dosing on Days 1 and 15 of treatment cycle 1

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End point title

Averaged time-matched changes from baseline in QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) over 1 h to 12 h after dosing on Days 1 and 15 of treatment cycle 1 ^[40]

End point description

Averaged time-matched QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) changes from baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120) to Day 1 (first drug dose nintedanib (BIBF 1120)) and to Day 15 (steady state) over 1 to 12 hours was evaluated using a t-test for paired observation. The mean differences between post-treatment values (Days 1 and 15) and baseline (Day -1) along with two-sided 90% confidence limits are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of first treatment cycle.

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[41]
Units: millisecond (ms)
arithmetic mean (confidence interval 90%)
Day 1	0.9 (-1.3 to 3.0)
Day 15	4.2 (0.6 to 7.7)

Notes
[41] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched heart rate (HR) changes from baseline to Day 15 at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

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End point title

Time−matched heart rate (HR) changes from baseline to Day 15 at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120) ^[42]

End point description

Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib (BIBF 1120) at time t. Time-matched change from baseline to Day 15 in HR at time t was defined as the HR measurement following administration of nintedanib (BIBF 1120) on Day 15 obtained at time t minus baseline HR measurement at time t. 0 h is 5 min prior to dosing at Day 15. Time-matched change from baseline to Day 15 in HR was modelled using a linear mixed-effects model for repeated measures which included ‘time’ as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals are reported. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[43]
Units: beats per minute (bpm)
least squares mean (confidence interval 90%)
Time−matched change from Day-1 to Day15 at -5 min	0.9 (-1.2 to 3.0)
Time−matched change from Day-1 to Day 15 at 1 h	-0.3 (-2.4 to 1.9)
Time−matched change from Day-1 to Day 15 at 2 h	-2.0 (-4.2 to 0.1)
Time−matched change from Day-1 to Day 15 at 3 h	-3.3 (-5.4 to -1.2)
Time−matched change from Day-1 to Day 15 at 4 h	-3.4 (-5.5 to -1.3)
Time−matched change from Day-1 to Day 15 at 5 h	-3.1 (-5.2 to -1.0)
Time−matched change from Day-1 to Day 15 at 6 h	-3.8 (-5.9 to -1.7)
Time−matched change from Day-1 to Day 15 at 7 h	-2.8 (-4.9 to -0.7)
Time−matched change from Day-1 to Day 15 at 10 h	-2.4 (-4.5 to -0.5)
Time−matched change from Day-1 to Day 15 at 12 h	-1.6 (-3.8 to 0.5)

Notes
[43] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched heart rate (HR) changes from baseline to Day 1 at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

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End point title

Time−matched heart rate (HR) changes from baseline to Day 1 at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120) ^[44]

End point description

Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib (BIBF 1120) at time t. Time-matched change from baseline to Day 1 in HR at time t was defined as the HR measurement following administration of nintedanib (BIBF 1120) on Day 1 obtained at time t minus baseline HR measurement at time t. Time-matched change from baseline to Day 1 in HR was modelled using a linear mixed-effects model for repeated measures which included ‘time’ as repeated measures and the time-matched baseline value as a covariate. Adjusted means with corresponding 2-sided 90% confidence intervals are reported. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[45]
Units: beats per minute (bpm)
least squares mean (confidence interval 90%)
Time−matched change from Day-1 to Day 1 at 1 h	-0.0 (-1.9 to 1.8)
Time−matched change from Day-1 to Day 1 at 2 h	-2.9 (-4.7 to -1.0)
Time−matched change from Day-1 to Day 1 at 3 h	-3.8 (-5.7 to -2.0)
Time−matched change from Day-1 to Day 1 at 4 h	-2.5 (-4.3 to -0.6)
Time−matched change from Day-1 to Day 1 at 5 h	-1.8 (-3.7 to 0.0)
Time−matched change from Day-1 to Day 1 at 6 h	-2.2 (-4.1 to -0.4)
Time−matched change from Day-1 to Day 1 at 7 h	-1.4 (-3.3 to 0.4)
Time−matched change from Day-1 to Day 1at 10 h	-1.3 (-3.2 to 0.6)
Time−matched change from Day-1 to Day 1at 12 h	0.0 (-1.8 to 1.9)

Notes
[45] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum nintedanib (BIBF 1120) plasma concentration, calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum nintedanib (BIBF 1120) plasma concentration, calculated separately for Days 1 and 15 of treatment cycle 1 ^[46]

End point description

Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in HR at time t was defined as the HR measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline HR measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in HR’ at the time of the participant's maximum nintedanib plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[47]
Units: beats per minute (bpm)
arithmetic mean (confidence interval 90%)
Day 1	-2.0 (-3.4 to -0.7)
Day 15	-2.1 (-4.3 to 0.1)

Notes
[47] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1 ^[48]

End point description

Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in HR at time t was defined as the HR measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline HR measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in HR’ at the time of the participant's maximum BIBF 1202 (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15.

End point type

Secondary

End point timeframe

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[49]
Units: beats per minute (bpm)
arithmetic mean (confidence interval 90%)
Day 1	-2.3 (-3.8 to -0.8)
Day 15	-2.0 (-4.2 to 0.1)

Notes
[49] - FAS-ECG

No statistical analyses for this end point

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum plasma concentration of BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum plasma concentration of BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1 ^[50]

End point description

Baseline heart rate (HR) measurement at time t was defined as the HR measurement collected 1 day prior to the day of the first administration of nintedanib at time t. Time-matched change from baseline to Day 1 (Day 15) in HR at time t was defined as the HR measurement following administration of nintedanib on Day 1 (Day 15) obtained at time t minus baseline HR measurement at time t. For each participant ‘Time-matched change from baseline to Day 1 (Day 15) in HR’ at the time of the participant's maximum BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite) plasma concentration was obtained and the mean across all participants calculated. Corresponding two-sided 90% confidence intervals based on the t-distribution are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

At 5 minutes (min) before the first dose on Day 15 and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15 of treatment cycle 1. Continues in the description.

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[51]
Units: beats per minute (bpm)
arithmetic mean (confidence interval 90%)
Day 1	-1.2 (-2.6 to 0.3)
Day 15	-1.6 (-3.6 to 0.4)

Notes
[51] - FAS-ECG

No statistical analyses for this end point

Secondary: Averaged time−matched heart rate (HR) change from baseline over 1 to 12 hours, calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Averaged time−matched heart rate (HR) change from baseline over 1 to 12 hours, calculated separately for Days 1 and 15 of treatment cycle 1 ^[52]

End point description

Averaged time-matched heart rate changes from baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) to Day 1 (first drug dose nintedanib (BIBF 1120)) and to Day 15 (steady state) over 1 to 12 hours was evaluated using a t-test for paired observation. The mean differences between post-treatment values (Days 1 and 15) and baseline (Day -1) along with two-sided 90% confidence limits are reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 1 and on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

At 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1 and on Day 15.

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[53]
Units: beats per minute (bpm)
arithmetic mean (confidence interval 90%)
Day 1	-1.9 (-2.8 to -1.1)
Day 15	-2.5 (-4.0 to -0.9)

Notes
[53] - FAS-ECG

No statistical analyses for this end point

Secondary: Frequency of patients with maximum time−matched QTcF interval change from baseline categorized by magnitude of change, calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Frequency of patients with maximum time−matched QTcF interval change from baseline categorized by magnitude of change, calculated separately for Days 1 and 15 of treatment cycle 1 ^[54]

End point description

QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula. Number of patients with maximum time-matched change from baseline in the QTcF interval observed at each point in time, i.e., 9 time points on Day 1 and 10 timepoints on Day 15 is reported. 3 categories of individual QTcF increases from baseline to maximum value were defined: <= 30 milliseconds (ms) > 30 to 60 milliseconds (ms) > 60 milliseconds (ms) Changes more than 60 ms in the QTcF interval represent notable changes. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[55]
Units: Participants
Day 1, 1-12 hours (h)\|<= 30 ms	64
Day 15, -0:05-12 h\|<= 30 ms	57
Day 1, 1-12 hours (h)\|> 30 to 60 ms	0
Day 15, -0:05-12 h\|> 30 to 60 ms	6
Day 1, 1-12 hours (h)\|> 60 ms	0
Day 15, -0:05-12 h\|> 60 ms	0

Notes
[55] - FAS-ECG

No statistical analyses for this end point

Secondary: Frequency of patients with maximum time−matched QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) change from baseline categorized by magnitude of change, Days 1 and 15

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End point title

Frequency of patients with maximum time−matched QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) change from baseline categorized by magnitude of change, Days 1 and 15 ^[56]

End point description

Number of patients with maximum time-matched change from baseline in the QT interval observed at each point in time, i.e., 9 time points on Day 1 and 10 timepoints on Day 15 is reported. 3 categories of individual QTcF increases from baseline to maximum value were defined: <= 30 milliseconds (ms) > 30 to 60 milliseconds (ms) > 60 milliseconds (ms) Changes more than 60 ms in the QT interval represent notable changes. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[57]
Units: Participants
Day 1, 1-12 hour (h)\|<= 60 ms	64
Day 15, -0:05-12 h\|<= 60 ms	62
Day 1, 1-12 hour (h)\|> 60 ms	0
Day 15, -0:05-12 h\|> 60 ms	1

Notes
[57] - FAS-ECG

No statistical analyses for this end point

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF ≤450 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Number of participants with new (not present at any time pre-dose) onset of QTcF ≤450 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1 ^[58]

End point description

QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula. Number of participants with new onset (not present at any time pre-dose) of QTcF ≤450 milliseconds (ms) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[59]
Units: Participants
Day 1	3
Day 15	2

Notes
[59] - FAS-ECG

No statistical analyses for this end point

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF >450 to 470 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Number of participants with new (not present at any time pre-dose) onset of QTcF >450 to 470 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1 ^[60]

End point description

QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula. Number of participants with new onset of QTcF >450 to 470 milliseconds (ms) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[61]
Units: Participants
Day 1	1
Day 15	1

Notes
[61] - FAS-ECG

No statistical analyses for this end point

Secondary: Number of participants with new onset of QTcF> 470 to 500 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Number of participants with new onset of QTcF> 470 to 500 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1 ^[62]

End point description

QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula. Number of participants with new onset of QTcF> 470 to 500 milliseconds (ms) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[63]
Units: Participants
Day 1	0
Day 15	1

Notes
[63] - FAS-ECG

No statistical analyses for this end point

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF> 500 milliseconds (ms) (notable prolongation), calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Number of participants with new (not present at any time pre-dose) onset of QTcF> 500 milliseconds (ms) (notable prolongation), calculated separately for Days 1 and 15 of treatment cycle 1 ^[64]

End point description

QTcF interval is the QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) corrected for the effects of heart rate (HR) by the Fridericia formula. Number of participants with new onset of QTcF> 500 milliseconds (ms) (notable prolongation) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[65]
Units: Participants
Day 1	0
Day 15	0

Notes
[65] - FAS-ECG

No statistical analyses for this end point

Secondary: Number of participants with new (not present at any time pre-dose) onset of QT (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) > 500 ms (notable prolongation), Days 1 and 15 of treatment cycle 1

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End point title

Number of participants with new (not present at any time pre-dose) onset of QT (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) > 500 ms (notable prolongation), Days 1 and 15 of treatment cycle 1 ^[66]

End point description

Number of participants with new onset of QT (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave)> 500 milliseconds (ms) (notable prolongation) on Day 1 (first drug dose nintedanib (BIBF 1120)) and Day 15 (steady state) compared to the baseline (Day -1 prior to the first dosing of nintedanib (BIBF 1120)) is reported. Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[67]
Units: Participants
Day 1	0
Day 15	0

Notes
[67] - FAS-ECG

No statistical analyses for this end point

Secondary: Absolute values at baseline (Day -1) and Day 1 and changes from baseline to Day 1 at each point in time in PR interval

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End point title

Absolute values at baseline (Day -1) and Day 1 and changes from baseline to Day 1 at each point in time in PR interval ^[68]

End point description

The PR interval is an electrocardiogram (ECG) interval and is the time from the onset of the P wave to the start of the QRS complex (combination of the Q wave, R wave and S wave). It reflects conduction through the atrioventricular node (AV) node. The normal PR interval is between 120 – 200 milliseconds (ms) (0.12-0.20s) in duration. Absolute values at baseline (Day-1 prior to the first dosing of nintedanib) and at Day 1 (first drug dose of nintedanib (BIBF 1120)) and changes from baseline to Day 1 at each point in time i.e., 10 time points from 0 to 12 in the PR interval are reported. FAS-ECG.

End point type

Secondary

End point timeframe

At 5 minutes (min) before the first dose and at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after the first dose of nintedanib on Day 1. Baseline (Day -1) values were taken at exactly the same time points as on Day 1.

Notes
[68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[69]
Units: milliseconds (ms)
arithmetic mean (standard deviation)
Absolute value on Day -1 at −5 min	164.7 ( 23.8 )
Absolute value on Day -1 at 1 h	165.7 ( 24.9 )
Absolute value on Day −1 at 2 h	166.8 ( 24.9 )
Absolute value on Day −1 at 3 h	166.6 ( 24.0 )
Absolute value on Day −1 at 4 h	168.1 ( 26.9 )
Absolute value on Day −1 at 5 h	167.2 ( 26.3 )
Absolute value on Day −1 at 6 h	168.1 ( 26.4 )
Absolute value on Day −1 at 7 h	168.9 ( 27.5 )
Absolute value on Day −1 at 10 h	168.0 ( 26.7 )
Absolute value on Day −1 at 12 h	170.0 ( 29.4 )
Absolute value on Day 1 at −5 min	165.7 ( 25.6 )
Absolute value on Day 1 at 1 h	167.4 ( 28.2 )
Absolute value on Day 1 at 2 h	169.4 ( 28.2 )
Absolute value on Day 1 at 3 h	170.0 ( 27.3 )
Absolute value on Day 1 at 4 h	170.0 ( 28.2 )
Absolute value on Day 1 at 5 h	169.4 ( 27.5 )
Absolute value on Day 1 at 6 h	170.8 ( 27.9 )
Absolute value on Day 1 at 7 h	169.9 ( 27.0 )
Absolute value on Day 1 at 10 h	169.8 ( 26.3 )
Absolute value on Day 1 at 12 h	171.3 ( 28.7 )
Time-matched change from Day-1 to Day1 at -5 min	0.7 ( 7.6 )
Time-matched change from Day -1 to Day 1 at 1 h	1.7 ( 11.6 )
Time-matched change from Day -1 to Day 1 at 2 h	2.6 ( 10.3 )
Time-matched change from Day -1 to Day 1 at 3 h	3.4 ( 9.1 )
Time-matched change from Day -1 to Day 1 at 4 h	2.2 ( 9.1 )
Time-matched change from Day -1 to Day 1 at 5 h	2.8 ( 10.7 )
Time-matched change from Day -1 to Day 1 at 6 h	3.3 ( 9.8 )
Time-matched change from Day -1 to Day 1 at 7 h	1.6 ( 9.3 )
Time-matched change from Day -1 to Day 1 at 10 h	1.8 ( 8.6 )
Time-matched change from Day -1 to Day 1 at 12 h	0.7 ( 9.4 )

Notes
[69] - FAS-ECG

No statistical analyses for this end point

Secondary: Absolute values at baseline (Day -1) and Day 15 and changes from baseline to Day 15 at each point in time in PR interval

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End point title

Absolute values at baseline (Day -1) and Day 15 and changes from baseline to Day 15 at each point in time in PR interval ^[70]

End point description

The PR interval is an electrocardiogram (ECG) interval and is the time from the onset of the P wave to the start of the QRS complex (combination of the Q wave, R wave and S wave). It reflects conduction through the atrioventricular node (AV) node. The normal PR interval is between 120 – 200 milliseconds (ms) (0.12-0.20s) in duration. Absolute values at baseline (Day-1 prior to the first dosing of nintedanib (BIBF 1120) and at Day 15 (steady state) and changes from baseline to Day 15 at each point in time i.e., 10 time points from 0 to 12 in the PR interval are reported. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[71]
Units: milliseconds (ms)
arithmetic mean (standard deviation)
Absolute value on Day −1 at −5 min	164.7 ( 24.0 )
Absolute value on Day −1 at 1 h	165.7 ( 25.1 )
Absolute value on Day −1 at 2 h	166.8 ( 25.1 )
Absolute value on Day −1 at 3 h	166.5 ( 24.2 )
Absolute value on Day −1 at 4 h	168.0 ( 27.2 )
Absolute value on Day −1 at 5 h	167.2 ( 26.5 )
Absolute value on Day −1 at 6 h	168.3 ( 26.6 )
Absolute value on Day −1 at 7 h	168.9 ( 27.7 )
Absolute value on Day −1 at 10 h	168.1 ( 26.9 )
Absolute value on Day −1 at 12 h	170.1 ( 29.7 )
Absolute value on Day 15 at −5 min	164.5 ( 24.4 )
Absolute value on Day 15 at 1 h	166.1 ( 25.3 )
Absolute value on Day 15 at 2 h	166.8 ( 26.2 )
Absolute value on Day 15 at 3 h	167.4 ( 25.3 )
Absolute value on Day 15 at 4 h	168.7 ( 27.4 )
Absolute value on Day 15 at 5 h	167.7 ( 27.8 )
Absolute value on Day 15 at 6 h	169.3 ( 26.7 )
Absolute value on Day 15 at 7 h	169.0 ( 27.9 )
Absolute value on Day 15 at 10 h	169.1 ( 27.9 )
Absolute value on Day 15 at 12 h	168.8 ( 27.9 )
Time-matched change from Day-1 to Day15 at −5 min	-0.1 ( 10.6 )
Time-matched change from Day -1 to Day 15 at 1 h	0.5 ( 12.5 )
Time-matched change from Day -1 to Day 15 at 2 h	-0.0 ( 12.7 )
Time-matched change from Day -1 to Day 15 at 3 h	0.9 ( 14.6 )
Time-matched change from Day -1 to Day 15 at 4 h	0.9 ( 12.2 )
Time-matched change from Day -1 to Day 15 at 5 h	0.9 ( 13.7 )
Time-matched change from Day -1 to Day 15 at 6 h	1.3 ( 11.8 )
Time-matched change from Day -1 to Day 15 at 7 h	0.6 ( 13.2 )
Time-matched change from Day -1 to Day 15 at 10 h	1.2 ( 11.2 )
Time-matched change from Day -1 to Day 15 at 12 h	-1.5 ( 12.5 )

Notes
[71] - FAS-ECG

No statistical analyses for this end point

Secondary: Absolute values at baseline (Day -1) and Day 1 and changes from baseline to Day 1 at each point in time in QRS interval

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End point title

Absolute values at baseline (Day -1) and Day 1 and changes from baseline to Day 1 at each point in time in QRS interval ^[72]

End point description

QRS interval is an electrocardiogram (ECG) interval and is the time interval from the onset to the end of the QRS complex (combination of the Q wave, R wave and S wave). The normal QRS duration is less than 120 milliseconds (ms). Absolute values and changes from baseline (Day-1 prior to the first dosing of nintedanib) to Day 1 (first drug dose of nintedanib (BIBF 1120)) at each point in time i.e., 10 time points from 0 to 12 in the QRS interval are reported. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[73]
Units: milliseconds (ms)
arithmetic mean (standard deviation)
Absolute value on Day −1 at −5 min	92.4 ( 11.8 )
Absolute value on Day −1 at 1 h	93.7 ( 11.0 )
Absolute value on Day −1 at 2 h	93.2 ( 10.5 )
Absolute value on Day −1 at 3 h	93.6 ( 10.8 )
Absolute value on Day −1 at 4 h	92.7 ( 9.8 )
Absolute value on Day −1 at 5 h	92.6 ( 11.0 )
Absolute value on Day −1 at 6 h	92.5 ( 10.3 )
Absolute value on Day −1 at 7 h	93.0 ( 10.6 )
Absolute value on Day −1 at 10 h	92.8 ( 11.7 )
Absolute value on Day −1, 12 h	92.5 ( 10.4 )
Absolute value on Day 1 at −5 min	92.6 ( 10.1 )
Absolute value on Day 1 at 1 h	93.2 ( 11.0 )
Absolute value in QRS interval on Day 1 at 2 h	93.0 ( 10.4 )
Absolute value on Day 1 at 3 h	93.3 ( 10.3 )
Absolute value on Day 1 at 4 h	93.5 ( 11.1 )
Absolute value on Day 1 at 5 h	93.4 ( 11.5 )
Absolute value on Day 1 at 6 h	93.4 ( 10.7 )
Absolute value on Day 1 at 7 h	93.2 ( 11.3 )
Absolute value on Day 1 at 10 h	92.3 ( 10.6 )
Absolute value on Day 1 at 12 h	92.8 ( 10.9 )
Time-matched change from Day -1 to Day 1 at −5 min	0.7 ( 5.1 )
Time-matched change from Day -1 to Day 1 at 1 h	-0.5 ( 5.2 )
Time-matched change from Day -1 to Day 1 at 2 h	-0.2 ( 4.4 )
Time-matched change from Day -1 to Day 1 at 3h	-0.3 ( 4.4 )
Time-matched change from Day -1 to Day 1 at 4 h	0.2 ( 4.7 )
Time-matched change from Day -1 to Day 1 at 5 h	0.2 ( 5.4 )
Time-matched change from Day -1 to Day 1 at 6 h	0.3 ( 5.6 )
Time-matched change from Day -1 to Day 1 at 7 h	-0.2 ( 4.7 )
Time-matched change from Day -1 to Day 1 at 10 h	-0.5 ( 4.9 )
Time-matched change from Day -1 to Day 1 at 12 h	0.3 ( 4.9 )

Notes
[73] - FAS-ECG

No statistical analyses for this end point

Secondary: Absolute values at baseline (Day -1) and Day 15 and changes from baseline to day 15 at each point in time in QRS interval

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End point title

Absolute values at baseline (Day -1) and Day 15 and changes from baseline to day 15 at each point in time in QRS interval ^[74]

End point description

QRS interval is an electrocardiogram (ECG) interval and is the time interval from the onset to the end of the QRS complex (combination of the Q wave, R wave and S wave). The normal QRS duration is less than 120 milliseconds (ms). Absolute values and changes from baseline (Day-1 prior to the first dosing of nintedanib) to Day 15 (steady state) at each point in time i.e., 10 time points from 0 to 12 in the QRS interval are reported. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[75]
Units: milliseconds (ms)
arithmetic mean (standard deviation)
Absolute value on Day −1 at −5 minutes (min)	92.5 ( 11.8 )
Absolute value on Day −1 at 1 hour (h)	93.8 ( 11.1 )
Absolute value on Day −1 at 2 h	93.3 ( 10.6 )
Absolute value on Day −1 at 3 h	93.6 ( 10.9 )
Absolute value on Day −1 at 4 h	92.7 ( 9.9 )
Absolute value on Day −1 at 5 h	92.7 ( 11.0 )
Absolute value on Day −1 at 6 h	92.7 ( 10.3 )
Absolute value on Day −1 at 7 h	93.1 ( 10.6 )
Absolute value on Day −1 at 10 h	92.8 ( 11.8 )
Absolute value on Day −1 at 12 h	92.6 ( 10.4 )
Absolute value on Day 15 at −5 min	93.3 ( 11.0 )
Absolute value on Day 15 at 1 h	93.9 ( 10.3 )
Absolute value on Day 15 at 2 h	93.0 ( 11.5 )
Absolute value on Day 15 at 3 h	92.9 ( 11.1 )
Absolute value on Day 15 at 4 h	92.6 ( 11.2 )
Absolute value on Day 15 at 5 h	93.6 ( 10.9 )
Absolute value on Day 15 at 6 h	93.1 ( 11.1 )
Absolute value on Day 15 at 7 h	93.1 ( 11.3 )
Absolute value on Day 15 at 10 h	92.8 ( 10.7 )
Absolute value on Day 15 at 12 h	93.7 ( 11.5 )
Time-matched change from Day -1 to Day15 at −5 min	0.8 ( 5.4 )
Time-matched change from Day -1 to Day 15 at 1 h	0.0 ( 5.1 )
Time-matched change from Day -1 to Day 15 at 2 h	-0.3 ( 5.3 )
Time-matched change from Day -1 to Day 15 at 3 h	-0.8 ( 5.7 )
Time-matched change from Day -1 to Day 15 at 4 h	-0.6 ( 5.4 )
Time-matched change from Day -1 to Day 15 at 5h	0.5 ( 7.3 )
Time-matched change from Day -1 to Day 15 at 6 h	-0.1 ( 5.3 )
Time-matched change from Day -1 to Day 15 at 7 h	-0.4 ( 5.3 )
Time-matched change from Day -1 to Day 15 at 10 h	0.1 ( 5.1 )
Time-matched change from Day -1 to Day 15 at 12 h	1.0 ( 4.7 )

Notes
[75] - FAS-ECG

No statistical analyses for this end point

Secondary: Frequency of patients by clinical electrocardiogram (ECG) measurement interpretation, calculated separately for Days 1 and 15 of treatment cycle 1

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End point title

Frequency of patients by clinical electrocardiogram (ECG) measurement interpretation, calculated separately for Days 1 and 15 of treatment cycle 1 ^[76]

End point description

Based on the interpretation of the electrocardiogram (ECG) patients were classified in 3 categories: - Normal (a normal ECG reading would be a reading that includes the following normal findings: 1) normal general features; 2) no arrhythmia; 3) no conduction delays; 4) T-wave morphology of normal; and 5) normal U-wave morphology) on Day 1 or on Day 15) - Not normal and not normal at baseline (an abnormal ECG reading would be a reading that includes one or more of the following abnormal findings: 1) abnormal general features; 2) arrhythmia; 3) conduction delays; 4) T-wave morphology of flat, inverted or biphasic; and 5) abnormal U-wave morphology) on Day 1 or on Day 15) - Not normal and new onset of finding Time frame: Baseline (Day -1) values were taken at exactly the same time points as on Day 15. FAS-ECG.

End point type

Secondary

End point timeframe

Notes
[76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was defined only for the nintedanib (BIBF 1120) arm.

End point values	Nintedanib (BIBF 1120)
Number of subjects analysed	64 ^[77]
Units: Participants
Day 1\|Normal	39
Day 15\|Normal	37
Day 1\|Not normal and not normal at baseline	24
Day 15\|Not normal and not normal at baseline	25
Day 1\|Not normal and new onset of finding	1
Day 15\|Not normal and new onset of finding	1

Notes
[77] - FAS-ECG

No statistical analyses for this end point

Secondary: Frequency of Adverse Events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0

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End point title

Frequency of Adverse Events graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0

End point description

The number of participants who experienced adverse events graded according to NCI CTCAE version 3.0, is reported below.The maximum grade of adverse event intesnisty for each type of treatment-related adverse event was recorded for each patient. Grade 1 - Mild AE Grade 2 - Moderate AE Grade 3 - Severe AE Grade 4 - Life-threatening or disabling AE Grade 5 - Death related to AE Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[78]	32 ^[79]
Units: Participants
Grade 1	11	5
Grade 2	16	6
Grade 3	14	16
Grade 4	10	2
Grade 5	7	1

Notes
[78] - TS
[79] - TS

No statistical analyses for this end point

Secondary: Number of participants with Adverse Events leading to dose reduction

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End point title

Number of participants with Adverse Events leading to dose reduction

End point description

Number of participants who experienced Adverse Events which led to dose reduction of the trial medication is reported for each treatment arm. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[80]	32 ^[81]
Units: Participants	16	8

Notes
[80] - TS
[81] - TS

No statistical analyses for this end point

Secondary: Number of participants with Adverse Events leading to discontinuation of trial drug

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End point title

Number of participants with Adverse Events leading to discontinuation of trial drug

End point description

Number of participants with Adverse Events which lead to discontinuation of trial medication drug is reported for each treatment arm. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[82]	32 ^[83]
Units: Participants	11	5

Notes
[82] - TS
[83] - TS

No statistical analyses for this end point

Secondary: Number of participants with Adverse Events requiring or prolonging hospitalisation

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End point title

Number of participants with Adverse Events requiring or prolonging hospitalisation

End point description

Number of participants who experienced Adverse Events which required or prolonged hospitalisation of patients is reported for each treatment arm. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[84]	32 ^[85]
Units: Participants	15	10

Notes
[84] - TS
[85] - TS

No statistical analyses for this end point

Secondary: Duration of hospital stays due to Adverse Events requiring or prolonging hospitalisation

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End point title

Duration of hospital stays due to Adverse Events requiring or prolonging hospitalisation

End point description

Duration of hospitalisation in days for each treatment arm is reported for those patients who experienced adverse events which required or prolonged hospitalisation (of the patients). All patients who were dispensed trial medication and were documented to have taken at least 1 dose of investigational treatment and experienced Adverse Events requiring or prolonging hospitalisation.

End point type

Secondary

End point timeframe

From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	15	10
Units: days
arithmetic mean (standard deviation)	11.40 ( 8.56 )	13.10 ( 8.32 )

No statistical analyses for this end point

Secondary: Frequency of patients with possible clinically significant abnormal lab values

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End point title

Frequency of patients with possible clinically significant abnormal lab values

End point description

Number of patients with possible clinically significant abnormal lab values for the lab parameters alkaline phosphatase, activated partial thromboplastin time (APTT), creatinine, haemoglobin, prothrombin time (PT)−international normalized ratio (INR), potassium, lymphocytes, sodium, neutrophils, platelets, aspartate amino transferase (AST), alanine aminotransferase (ALT), bilirubin and white blood cell count is reported. Only lab values with CTCAE rule for possible clinical significance are displayed. Treated set (TS): All participants who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.

End point type

Secondary

End point timeframe

From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months.

End point values	Nintedanib (BIBF 1120)	Sunitinib
Number of subjects analysed	64 ^[86]	31 ^[87]
Units: Participants
Alkaline phosphatase	2	3
APTT (Activated partial thrombopl. time)	7	0
Creatinine	4	5
Haemoglobin	6	6
PT−INR	5	0
Potassium	14	4
Lymphocytes	8	11
Sodium	14	3
Neutrophils	3	9
Platelets	2	3
Aspartate amino Transferase (AST)	10	1
Alanine aminotransferase (ALT)	14	3
Bilirubin, total	4	3
White blood cell count	0	7

Notes
[86] - TS
[87] - TS

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

From first dose of study drug administration up to 28 days after last dose of study drug, up to 121 months.

Adverse event reporting additional description

Treated set (TS): All patients who were dispensed trial medication and were documented to have taken at least 1 dose of investigational treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Nintedanib (BIBF 1120)

Reporting group description

Reporting group title

Sunitinib

Reporting group description

Serious adverse events	Nintedanib (BIBF 1120)	Sunitinib
Total subjects affected by serious adverse events
subjects affected / exposed	20 / 64 (31.25%)	11 / 32 (34.38%)
number of deaths (all causes)	50	25
number of deaths resulting from adverse events	6	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to spine
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	7 / 64 (10.94%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 6	0 / 0
Vascular disorders
Thrombophlebitis
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Hernia repair
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hernia
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	1 / 64 (1.56%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	1 / 64 (1.56%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood pressure increased
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Incisional hernia, obstructive
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Poisoning
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Myocardial infarction
subjects affected / exposed	1 / 64 (1.56%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Quadriparesis
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestinal haemorrhage
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 64 (0.00%)	3 / 32 (9.38%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Jaundice
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Decubitus ulcer
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary bladder haemorrhage
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	1 / 64 (1.56%)	0 / 32 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 64 (0.00%)	1 / 32 (3.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Nintedanib (BIBF 1120)	Sunitinib
Total subjects affected by non serious adverse events
subjects affected / exposed	55 / 64 (85.94%)	27 / 32 (84.38%)
Vascular disorders
Aortic arteriosclerosis
subjects affected / exposed	2 / 64 (3.13%)	2 / 32 (6.25%)
occurrences all number	2	2
Hypertension
subjects affected / exposed	2 / 64 (3.13%)	5 / 32 (15.63%)
occurrences all number	2	9
General disorders and administration site conditions
Asthenia
subjects affected / exposed	5 / 64 (7.81%)	2 / 32 (6.25%)
occurrences all number	5	2
Fatigue
subjects affected / exposed	17 / 64 (26.56%)	8 / 32 (25.00%)
occurrences all number	18	12
Hyperthermia
subjects affected / exposed	2 / 64 (3.13%)	2 / 32 (6.25%)
occurrences all number	2	3
Mucosal inflammation
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Pain
subjects affected / exposed	4 / 64 (6.25%)	0 / 32 (0.00%)
occurrences all number	4	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 64 (3.13%)	3 / 32 (9.38%)
occurrences all number	2	7
Dyspnoea
subjects affected / exposed	1 / 64 (1.56%)	4 / 32 (12.50%)
occurrences all number	1	5
Investigations
Alanine aminotransferase increased
subjects affected / exposed	5 / 64 (7.81%)	1 / 32 (3.13%)
occurrences all number	8	1
Aspartate aminotransferase increased
subjects affected / exposed	6 / 64 (9.38%)	1 / 32 (3.13%)
occurrences all number	7	1
Blood creatinine increased
subjects affected / exposed	3 / 64 (4.69%)	3 / 32 (9.38%)
occurrences all number	3	3
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	2
Gamma-glutamyltransferase increased
subjects affected / exposed	8 / 64 (12.50%)	1 / 32 (3.13%)
occurrences all number	13	1
Lipase increased
subjects affected / exposed	2 / 64 (3.13%)	4 / 32 (12.50%)
occurrences all number	3	4
Weight decreased
subjects affected / exposed	8 / 64 (12.50%)	2 / 32 (6.25%)
occurrences all number	8	2
Weight increased
subjects affected / exposed	2 / 64 (3.13%)	3 / 32 (9.38%)
occurrences all number	2	3
Amylase increased
subjects affected / exposed	1 / 64 (1.56%)	2 / 32 (6.25%)
occurrences all number	1	2
Blood glucose increased
subjects affected / exposed	2 / 64 (3.13%)	2 / 32 (6.25%)
occurrences all number	4	2
Cardiac disorders
Aortic valve sclerosis
subjects affected / exposed	1 / 64 (1.56%)	2 / 32 (6.25%)
occurrences all number	1	2
Tachycardia
subjects affected / exposed	1 / 64 (1.56%)	2 / 32 (6.25%)
occurrences all number	1	2
Nervous system disorders
Dysgeusia
subjects affected / exposed	3 / 64 (4.69%)	3 / 32 (9.38%)
occurrences all number	3	3
Headache
subjects affected / exposed	7 / 64 (10.94%)	1 / 32 (3.13%)
occurrences all number	7	1
Lethargy
subjects affected / exposed	3 / 64 (4.69%)	2 / 32 (6.25%)
occurrences all number	3	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 64 (6.25%)	5 / 32 (15.63%)
occurrences all number	8	5
Neutropenia
subjects affected / exposed	0 / 64 (0.00%)	3 / 32 (9.38%)
occurrences all number	0	4
Thrombocytopenia
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	3
Eye disorders
Periorbital oedema
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	3
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	5 / 64 (7.81%)	1 / 32 (3.13%)
occurrences all number	7	1
Abdominal pain upper
subjects affected / exposed	5 / 64 (7.81%)	2 / 32 (6.25%)
occurrences all number	8	6
Constipation
subjects affected / exposed	5 / 64 (7.81%)	4 / 32 (12.50%)
occurrences all number	5	5
Diarrhoea
subjects affected / exposed	40 / 64 (62.50%)	15 / 32 (46.88%)
occurrences all number	109	46
Dry mouth
subjects affected / exposed	5 / 64 (7.81%)	1 / 32 (3.13%)
occurrences all number	5	1
Dyspepsia
subjects affected / exposed	3 / 64 (4.69%)	7 / 32 (21.88%)
occurrences all number	6	15
Flatulence
subjects affected / exposed	4 / 64 (6.25%)	3 / 32 (9.38%)
occurrences all number	5	5
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 64 (0.00%)	3 / 32 (9.38%)
occurrences all number	0	3
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	7
Nausea
subjects affected / exposed	25 / 64 (39.06%)	8 / 32 (25.00%)
occurrences all number	41	13
Stomatitis
subjects affected / exposed	0 / 64 (0.00%)	10 / 32 (31.25%)
occurrences all number	0	22
Vomiting
subjects affected / exposed	10 / 64 (15.63%)	6 / 32 (18.75%)
occurrences all number	25	13
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	4
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 64 (0.00%)	10 / 32 (31.25%)
occurrences all number	0	42
Rash
subjects affected / exposed	1 / 64 (1.56%)	3 / 32 (9.38%)
occurrences all number	2	4
Dry skin
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	3
Renal and urinary disorders
Haematuria
subjects affected / exposed	5 / 64 (7.81%)	0 / 32 (0.00%)
occurrences all number	6	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 64 (1.56%)	2 / 32 (6.25%)
occurrences all number	1	2
Hypothyroidism
subjects affected / exposed	2 / 64 (3.13%)	5 / 32 (15.63%)
occurrences all number	2	5
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	4 / 64 (6.25%)	1 / 32 (3.13%)
occurrences all number	6	2
Osteoarthritis
subjects affected / exposed	0 / 64 (0.00%)	2 / 32 (6.25%)
occurrences all number	0	3
Infections and infestations
Nasopharyngitis
subjects affected / exposed	2 / 64 (3.13%)	2 / 32 (6.25%)
occurrences all number	3	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	12 / 64 (18.75%)	6 / 32 (18.75%)
occurrences all number	17	10
Hyponatraemia
subjects affected / exposed	4 / 64 (6.25%)	0 / 32 (0.00%)
occurrences all number	4	0

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Were there any global substantial amendments to the protocol? Yes

09 Mar 2010

Global amendment No. 1: Clarified some discrepancies within the trial protocol, namely to adjust the flow charts to the corresponding written paragraphs. Likewise, the time schedule for PK sampling given in Appendix 10 of the trial protocol was corrected to accurately reflect the written parts of the protocol. Moreover, Global Amendment No. 1 stated that a minimisation approach was unnecessary as a stratified randomisation would be sufficient to ensure a 2:1 ratio of the treatment arms overall and within each stratum.

11 Jul 2017

Global amendment No. 2: Clarified that the follow-up for progressive disease was now no longer required.

11 Jul 2019

Global amendment No. 3: Clarified the future handling for clinical laboratory assessments, vital signs, physical findings, and other observations related to safety. It also introduced the possibility to remove patients from the trial after completion of the primary efficacy analysis, given that the patient consented and given that the patient had access to the study medication through marketed product.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A randomised, open label, parallel group Phase II study comparing the efficacy and tolerability of BIBF 1120 versus sunitinib in previously untreated patients with Renal Cell Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Probability rates of progression-free survival at 9 months

Primary: Probability rates of progression-free survival at 9 months

Primary: Time-matched change from baseline to Day 15 in QTcF (QT interval corrected by the Fridericia formula) at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Primary: Time-matched change from baseline to Day 15 in QTcF (QT interval corrected by the Fridericia formula) at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Progression free survival (PFS)

Secondary: Progression free survival (PFS)

Secondary: Objective response according to RECIST criteria

Secondary: Objective response according to RECIST criteria

Secondary: Duration of objective response

Secondary: Duration of objective response

Secondary: Overall survival

Secondary: Overall survival

Secondary: Time to progression

Secondary: Time to progression

Secondary: Time to treatment failure

Secondary: Time to treatment failure

Secondary: Time-matched change from baseline to Day 1 in QTcF (QT interval corrected by the Fridericia formula) at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time-matched change from baseline to Day 1 in QTcF (QT interval corrected by the Fridericia formula) at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time-matched change from baseline in QTcF interval (QT interval corrected by the Fridericia formula) at the time of each participant’s maximum plasma concentration of nintedanib (BIBF 1120), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time-matched change from baseline in QTcF interval (QT interval corrected by the Fridericia formula) at the time of each participant’s maximum plasma concentration of nintedanib (BIBF 1120), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QTcF interval at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QTcF interval at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QTcF interval at the time of each patient’s maximum plasma concentration of BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QTcF interval at the time of each patient’s maximum plasma concentration of BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Average time-matched changes from baseline in QTcF interval over 1 h to 12 h after dosing on Days 1 and 15 of treatment cycle 1

Secondary: Average time-matched changes from baseline in QTcF interval over 1 h to 12 h after dosing on Days 1 and 15 of treatment cycle 1

Secondary: Time-matched changes from baseline to Day 15 in QT interval at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time-matched changes from baseline to Day 15 in QT interval at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time-matched changes from baseline to Day 1 in QT interval at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time-matched changes from baseline to Day 1 in QT interval at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration of nintedanib (BIBF 1120), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration of nintedanib (BIBF 1120), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in QT interval at the time of each patient’s maximum plasma concentration BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Averaged time-matched changes from baseline in QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) over 1 h to 12 h after dosing on Days 1 and 15 of treatment cycle 1

Secondary: Averaged time-matched changes from baseline in QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) over 1 h to 12 h after dosing on Days 1 and 15 of treatment cycle 1

Secondary: Time−matched heart rate (HR) changes from baseline to Day 15 at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time−matched heart rate (HR) changes from baseline to Day 15 at 0 hour (h), at 1 h, at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time−matched heart rate (HR) changes from baseline to Day 1 at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time−matched heart rate (HR) changes from baseline to Day 1 at 1 hour (h), at 2 h, at 3 h, at 4 h, at 5 h, at 6 h, at 7 h, at 10 h and at 12 h after dosing of nintedanib (BIBF 1120)

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum nintedanib (BIBF 1120) plasma concentration, calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum nintedanib (BIBF 1120) plasma concentration, calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum plasma concentration of BIBF 1202 (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum plasma concentration of BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Time−matched change from baseline in heart rate (HR) at the time of each patient’s maximum plasma concentration of BIBF 1202-glucuronide (a nintedanib (BIBF 1120) metabolite), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Averaged time−matched heart rate (HR) change from baseline over 1 to 12 hours, calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Averaged time−matched heart rate (HR) change from baseline over 1 to 12 hours, calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Frequency of patients with maximum time−matched QTcF interval change from baseline categorized by magnitude of change, calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Frequency of patients with maximum time−matched QTcF interval change from baseline categorized by magnitude of change, calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Frequency of patients with maximum time−matched QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) change from baseline categorized by magnitude of change, Days 1 and 15

Secondary: Frequency of patients with maximum time−matched QT interval (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) change from baseline categorized by magnitude of change, Days 1 and 15

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF ≤450 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF ≤450 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF >450 to 470 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF >450 to 470 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new onset of QTcF> 470 to 500 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new onset of QTcF> 470 to 500 milliseconds (ms), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF> 500 milliseconds (ms) (notable prolongation), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new (not present at any time pre-dose) onset of QTcF> 500 milliseconds (ms) (notable prolongation), calculated separately for Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new (not present at any time pre-dose) onset of QT (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) > 500 ms (notable prolongation), Days 1 and 15 of treatment cycle 1

Secondary: Number of participants with new (not present at any time pre-dose) onset of QT (electrocardiogram (ECG) interval from the beginning of the QRS complex to the end of the T wave) > 500 ms (notable prolongation), Days 1 and 15 of treatment cycle 1

Secondary: Absolute values at baseline (Day -1) and Day 1 and changes from baseline to Day 1 at each point in time in PR interval

Secondary: Absolute values at baseline (Day -1) and Day 1 and changes from baseline to Day 1 at each point in time in PR interval

Secondary: Absolute values at baseline (Day -1) and Day 15 and changes from baseline to Day 15 at each point in time in PR interval

Secondary: Absolute values at baseline (Day -1) and Day 15 and changes from baseline to Day 15 at each point in time in PR interval

Secondary: Absolute values at baseline (Day -1) and Day 1 and changes from baseline to Day 1 at each point in time in QRS interval

Secondary: Absolute values at baseline (Day -1) and Day 1 and changes from baseline to Day 1 at each point in time in QRS interval

Clinical Trial Results:
A randomised, open label, parallel group Phase II study comparing the efficacy and tolerability of BIBF 1120 versus sunitinib in previously untreated patients with Renal Cell Cancer