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Clinical Trial Results:
A multicentre, open label, Phase I/randomised Phase II study to evaluate safety, pharmacokinetics and efficacy of BIBF 1120 in comparison with sorafenib for advanced hepatocellular carcinoma patients

Summary
EudraCT number	2009-011925-14
Trial protocol	GB AT DE SK HU NL
Global end of trial date	12 Oct 2016

Results information
Results version number	v1
This version publication date	14 Oct 2017
First version publication date	14 Oct 2017
Other versions	v2

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

1199.37

ISRCTN number

US NCT number

NCT01004003

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, 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

28 Nov 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 Jul 2014

Global end of trial reached?

Yes

Global end of trial date

12 Oct 2016

Was the trial ended prematurely?

Main objective of the trial

Phase I part: To evaluate safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of nintedanib in patients with hepatocellular carcinoma (HCC). Phase II part: To evaluate the efficacy and safety of nintedanib in patients with HCC without prior systemic treatment compared with sorafenib.

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

22 Oct 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 18

Country: Number of subjects enrolled

Germany: 25

Country: Number of subjects enrolled

France: 11

Country: Number of subjects enrolled

Hungary: 1

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Poland: 13

Country: Number of subjects enrolled

Romania: 8

Country: Number of subjects enrolled

United Kingdom: 92

Worldwide total number of subjects

170

EEA total number of subjects

170

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

Screening details

All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be enrolled if any one of the specific entry criteria were violated.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Phase I is the uncontrolled dose escalation design and Phase II is the randomised, active controlled and parallel group design.

Are arms mutually exclusive

Yes

Phase 1 Group 1, 100mg Nintedanib Bid

Arm description

Oral administration of Nintedanib (BIBF 1120) 100 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the maximal tolerated dose (MTD). Group 1 patients had a baseline Child-Pugh score of 5 or 6, and AST (aspartate aminotransferase ) and ALT (alanine transaminase) ≤2 times the upper limit of normal (ULN).

Arm type

Experimental

Investigational medicinal product name

Nintedanib 100mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Nintedanib (BIBF 1120) 100 mg soft gelatine capsules twice daily (bid).

Phase I Group 1, 150mg Nintedanib Bid

Arm description

Oral administration of Nintedanib (BIBF 1120) 150 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 1 patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN).

Arm type

Experimental

Investigational medicinal product name

Nintedanib 150 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Nintedanib (BIBF 1120) 150 mg soft gelatine capsules twice daily (bid).

Phase I Group 1, 200mg Nintedanib Bid

Arm description

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 1 patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN).

Arm type

Experimental

Investigational medicinal product name

Nintedanib 200 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid).

Phase I Group 2, 50mg Nintedanib Bid

Arm description

Oral administration of Nintedanib (BIBF 1120) 50 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN.

Arm type

Experimental

Investigational medicinal product name

Nintedanib 50 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Nintedanib (BIBF 1120) 50 mg soft gelatine capsules twice daily (bid).

Phase I Group 2, 100mg Nintedanib Bid

Arm description

Oral administration of Nintedanib (BIBF 1120) 100 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN.

Arm type

Experimental

Investigational medicinal product name

Nintedanib 100mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Nintedanib (BIBF 1120) 100 mg soft gelatine capsules twice daily (bid).

Phase I Group 2, 150mg Nintedanib Bid

Arm description

Oral administration of Nintedanib (BIBF 1120) 150 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN.

Arm type

Experimental

Investigational medicinal product name

Nintedanib 150mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Nintedanib (BIBF 1120) 150 mg soft gelatine capsules twice daily (bid).

Phase I Group 2, 200mg Nintedanib Bid

Arm description

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN.

Arm type

Experimental

Investigational medicinal product name

Nintedanib 200mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid).

Phase II, 200 mg Nintedanib Bid

Arm description

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macrovascular invasion (MVI) and/or extra-hepatic spread (EHS). Patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN).

Arm type

Experimental

Investigational medicinal product name

Nintedanib 200mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid).

Phase II, 400 mg Sorafenib Bid

Arm description

Oral administration of Sorafenib 400 mg film coated tablets twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macrovascular invasion (MVI) and/or extra-hepatic spread (EHS). Patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN).

Arm type

Active comparator

Investigational medicinal product name

Sorafenib 400mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Oral administration of Sorafenib 400 mg film coated tablets twice daily (bid).

Number of subjects in period 1 ^[1]	Phase 1 Group 1, 100mg Nintedanib Bid	Phase I Group 1, 150mg Nintedanib Bid	Phase I Group 1, 200mg Nintedanib Bid	Phase I Group 2, 50mg Nintedanib Bid	Phase I Group 2, 100mg Nintedanib Bid	Phase I Group 2, 150mg Nintedanib Bid	Phase I Group 2, 200mg Nintedanib Bid	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Started	6	3	4	3	4	4	8	62	31
Completed	0	0	0	0	0	0	0	2	1
Not completed	6	3	4	3	4	4	8	60	30
Adverse event, non-fatal	4	2	3	3	2	2	7	21	6
Refused to continue taking trial med.	-	-	-	-	-	-	-	-	2
Unknown	-	-	-	-	-	1	-	-	-
Progressive disease	2	1	1	-	2	1	1	39	22

Notes
[1] - 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: Baseline characteristics are based on the patients who were randomised after successfully completing the screening period and received at least one of the trial medication.

Baseline characteristics

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Reporting group title

Phase 1 Group 1, 100mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 1, 150mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 1, 200mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 50mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 100mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 150mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 200mg Nintedanib Bid

Reporting group description

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN.

Reporting group title

Phase II, 200 mg Nintedanib Bid

Reporting group description

Reporting group title

Phase II, 400 mg Sorafenib Bid

Reporting group description

Reporting group values	Phase 1 Group 1, 100mg Nintedanib Bid	Phase I Group 1, 150mg Nintedanib Bid	Phase I Group 1, 200mg Nintedanib Bid	Phase I Group 2, 50mg Nintedanib Bid	Phase I Group 2, 100mg Nintedanib Bid	Phase I Group 2, 150mg Nintedanib Bid	Phase I Group 2, 200mg Nintedanib Bid	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid	Total
Number of subjects	6	3	4	3	4	4	8	62	31	125
Age categorical
Units: Subjects
Age Continuous
Treated set:Treated set which included all patients who received at least one single dose of trial medication.
Units: years
arithmetic mean (standard deviation)	69.7 ( 6.8 )	65 ( 7.8 )	66.5 ( 4 )	72.3 ( 11.7 )	56.3 ( 6.4 )	59.3 ( 13.9 )	57 ( 11 )	65.4 ( 10 )	63.1 ( 11.8 )	-
Gender, Male/Female
Units: Subjects
Female	1	1	0	0	0	1	2	14	5	24
Male	5	2	4	3	4	3	6	48	26	101

End points

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Reporting group title

Phase 1 Group 1, 100mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 1, 150mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 1, 200mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 50mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 100mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 150mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 200mg Nintedanib Bid

Reporting group description

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN.

Reporting group title

Phase II, 200 mg Nintedanib Bid

Reporting group description

Reporting group title

Phase II, 400 mg Sorafenib Bid

Reporting group description

Subject analysis set title

Group 1

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN). Intent to treat is actually Treated Set.

Subject analysis set title

Group 2

Subject analysis set type

Intention-to-treat

Subject analysis set description

Patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN. Intent to treat is actually Treated Set.

Primary: Maximum Tolerated Dose in Phase I

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End point title

Maximum Tolerated Dose in Phase I ^[1]

End point description

The MTD was defined as the highest dose studied for which the incidence of DLTs was 0/3 or less than 2/6 patients during the first treatment course. Treated set (TS): The set which included all patients who received at least one single dose of trial medication, including phase I patients from the dose escalation part that were not replaced for MTD determination.

End point type

Primary

End point timeframe

4 weeks

Notes
[1] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Group 1	Group 2
Number of subjects analysed	9 ^[2]	13 ^[3]
Units: mg bid	200	200

Notes
[2] - TS
[3] - TS

No statistical analyses for this end point

Primary: Time to Progression (TTP) in Phase II

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End point title

Time to Progression (TTP) in Phase II ^[4]

End point description

TTP according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 criteria based on central independent review. TTP RECIST 1.0 was defined as the time from randomisation to disease progression according to RECIST 1.0.

End point type

Primary

End point timeframe

From randomization until data cut-off (15 July 2014); Up to 1031 days

Notes
[4] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Number of subjects analysed	62 ^[5]	31 ^[6]
Units: months
median (inter-quartile range (Q1-Q3))	5.45 (2.69 to 9.2)	4.63 (2.79 to 20.4)

Notes
[5] - Treated set, only phase II participants.
[6] - Treated set, only phase II participants.

Statistical Analysis 1

Comparison groups

Phase II, 200 mg Nintedanib Bid v Phase II, 400 mg Sorafenib Bid

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[7]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.437

Confidence interval

level

95%

sides

2-sided

lower limit

0.805

upper limit

2.565

Notes
[7] - Hazard ratio from Cox proportional hazards model stratified by macroscopic vacular invasion, extrahepatic spread, or both present vs both absent. HR below 1 favors Nintedanib.

Secondary: Incidence of Dose Limiting Toxicity in Phase I

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End point title

Incidence of Dose Limiting Toxicity in Phase I ^[8]

End point description

Number of patients with dose limiting toxicity are presented

End point type

Secondary

End point timeframe

4 weeks

Notes
[8] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Phase 1 Group 1, 100mg Nintedanib Bid	Phase I Group 1, 150mg Nintedanib Bid	Phase I Group 1, 200mg Nintedanib Bid	Phase I Group 2, 50mg Nintedanib Bid	Phase I Group 2, 100mg Nintedanib Bid	Phase I Group 2, 150mg Nintedanib Bid	Phase I Group 2, 200mg Nintedanib Bid
Number of subjects analysed	3 ^[9]	3 ^[10]	3 ^[11]	3 ^[12]	4 ^[13]	3 ^[14]	3 ^[15]
Units: participants	0	0	0	0	0	0	0

Notes
[9] - TS (Phase I patients from the dose escalation part that were not replaced for MTD determination).
[10] - TS (Phase I patients from the dose escalation part that were not replaced for MTD determination).
[11] - TS (Phase I patients from the dose escalation part that were not replaced for MTD determination).
[12] - TS (Phase I patients from the dose escalation part that were not replaced for MTD determination).
[13] - TS (Phase I patients from the dose escalation part that were not replaced for MTD determination).
[14] - TS (Phase I patients from the dose escalation part that were not replaced for MTD determination).
[15] - TS (Phase I patients from the dose escalation part that were not replaced for MTD determination).

No statistical analyses for this end point

Secondary: Objective Tumour Response by RECIST

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End point title

Objective Tumour Response by RECIST ^[16]

End point description

Objective RECIST 1.0 tumour response was defined as Complete Response (CR) or Partial Response (PR) and was derived from the patient's best objective RECIST 1.0 response based on central independent review. 95% Confidence Interval presented below are computed by Clopper and Pearson method.

End point type

Secondary

End point timeframe

From randomization until data cut-off (15 July 2014); Up to 1031 days

Notes
[16] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Number of subjects analysed	62 ^[17]	31 ^[18]
Units: percentage of participants
number (confidence interval 95%)	1.6 (0 to 8.7)	6.5 (0.8 to 21.4)

Notes
[17] - Treated set, phase II participants only
[18] - Treated set, phase II participants only

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS) ^[19]

End point description

PFS by RECIST 1.0 was defined as the duration from date of randomisation to date of progression or death, whichever occurred earlier, based on central independent review.

End point type

Secondary

End point timeframe

From randomization until data cut-off (15 July 2014); Up to 1031 days

Notes
[19] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Number of subjects analysed	62 ^[20]	31 ^[21]
Units: months
median (inter-quartile range (Q1-Q3))	5.32 (2.69 to 9.2)	3.94 (2.33 to 7.36)

Notes
[20] - Treated set, only phase II participants
[21] - Treated set, only phase II participants

Statistical Analysis 1

Comparison groups

Phase II, 200 mg Nintedanib Bid v Phase II, 400 mg Sorafenib Bid

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[22]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.351

Confidence interval

level

95%

sides

2-sided

lower limit

0.779

upper limit

2.343

Notes
[22] - Hazard ratio from Cox proportional hazards model stratified by macroscopic vacular invasion, extrahepatic spread, or both present vs both absent. HR below 1 favors Nintedanib.

Secondary: Overall Survival

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End point title

Overall Survival ^[23]

End point description

Overall survival was defined as the duration from date of randomisation to the date of death.

End point type

Secondary

End point timeframe

From randomization until data cut-off (15 July 2014); Up to 1031 days

Notes
[23] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Number of subjects analysed	62 ^[24]	31 ^[25]
Units: months
median (inter-quartile range (Q1-Q3))	11.86 (6.6 to 25.46)	11.4 (6.51 to 17.25)

Notes
[24] - Treated set, only phase II participants
[25] - Treated set, only phase II participants

Statistical Analysis 1

Statistical analysis description

Hazard ratio from Cox proportional hazards model stratified by macroscopic vacular invasion, extrahepatic spread, or both present vs both absent.

Comparison groups

Phase II, 200 mg Nintedanib Bid v Phase II, 400 mg Sorafenib Bid

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.877

Confidence interval

level

95%

sides

2-sided

lower limit

0.522

upper limit

1.473

Notes
[26] - HR below 1 favors Nintedanib.

Adverse events

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Timeframe for reporting adverse events

From first administration of the trial drug and until 28 days after the last administration of nintedanib or sorafenib, up to 1289 days

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Phase 1 Group 1, 100mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 1, 150mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 1, 200mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 50mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 100mg Nintedanib Bid

Reporting group description

Reporting group title

Phase I Group 2, 200mg Nintedanib Bid

Reporting group description

Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN.

Reporting group title

Phase I Group 2, 150mg Nintedanib Bid

Reporting group description

Reporting group title

Phase II, 200 mg Nintedanib Bid

Reporting group description

Reporting group title

Phase II, 400 mg Sorafenib Bid

Reporting group description

Serious adverse events	Phase 1 Group 1, 100mg Nintedanib Bid	Phase I Group 1, 150mg Nintedanib Bid	Phase I Group 1, 200mg Nintedanib Bid	Phase I Group 2, 50mg Nintedanib Bid	Phase I Group 2, 100mg Nintedanib Bid	Phase I Group 2, 200mg Nintedanib Bid	Phase I Group 2, 150mg Nintedanib Bid	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 6 (50.00%)	1 / 3 (33.33%)	4 / 4 (100.00%)	3 / 3 (100.00%)	2 / 4 (50.00%)	4 / 8 (50.00%)	3 / 4 (75.00%)	34 / 62 (54.84%)	14 / 31 (45.16%)
number of deaths (all causes)	6	3	3	3	4	6	4	43	22
number of deaths resulting from adverse events	0	0	1	0	0	0	1	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
Lung adenocarcinoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	2 / 4 (50.00%)	2 / 62 (3.23%)	3 / 31 (9.68%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 2
Metastatic neoplasm
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Bleeding varicose vein
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Hepatectomy
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
Fatigue
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
Impaired healing
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hyperventilation
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory alkalosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Clavicle fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Nervous system disorders
Depressed level of consciousness
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	5 / 62 (8.06%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	3 / 62 (4.84%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic vein thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Glaucoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Macular fibrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 3 (66.67%)	1 / 4 (25.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric varices haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	2 / 4 (50.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal food impaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Varices oesophageal
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 8 (12.50%)	2 / 4 (50.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	1 / 1	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
Hepatic pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Stevens-Johnson syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrotic syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Biliary sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis B
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ludwig angina
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gout
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase 1 Group 1, 100mg Nintedanib Bid	Phase I Group 1, 150mg Nintedanib Bid	Phase I Group 1, 200mg Nintedanib Bid	Phase I Group 2, 50mg Nintedanib Bid	Phase I Group 2, 100mg Nintedanib Bid	Phase I Group 2, 200mg Nintedanib Bid	Phase I Group 2, 150mg Nintedanib Bid	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	7 / 8 (87.50%)	4 / 4 (100.00%)	61 / 62 (98.39%)	31 / 31 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	7 / 62 (11.29%)	3 / 31 (9.68%)
occurrences all number	0	0	1	0	1	0	0	8	3
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences all number	0	0	0	0	1	2	1	1	1
Intra-abdominal haematoma
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	3	2
Catheter site bruise
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0
Chest pain
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	2 / 31 (6.45%)
occurrences all number	1	0	1	0	0	1	0	1	2
Chills
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	3	0
Device difficult to use
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Fatigue
subjects affected / exposed	3 / 6 (50.00%)	0 / 3 (0.00%)	3 / 4 (75.00%)	2 / 3 (66.67%)	1 / 4 (25.00%)	5 / 8 (62.50%)	2 / 4 (50.00%)	32 / 62 (51.61%)	10 / 31 (32.26%)
occurrences all number	3	0	3	2	1	6	2	40	11
Feeling cold
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Gait disturbance
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	2	0	0	1	0	0	0	0	0
General physical health deterioration
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences all number	0	0	0	0	1	0	0	1	1
Impaired healing
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	1 / 6 (16.67%)	1 / 3 (33.33%)	3 / 4 (75.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	1	1	3	1	0	0	1	1	0
Injection site bruising
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Local swelling
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0
Malaise
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	2 / 31 (6.45%)
occurrences all number	0	0	0	1	0	0	0	1	2
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	3 / 31 (9.68%)
occurrences all number	0	0	0	0	0	0	0	0	4
Oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	4 / 62 (6.45%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	0	1	4	0
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 8 (25.00%)	1 / 4 (25.00%)	8 / 62 (12.90%)	1 / 31 (3.23%)
occurrences all number	0	0	0	1	0	2	1	8	1
Pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	1	3	0	0	0	0	1	0
Pyrexia
subjects affected / exposed	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	10 / 62 (16.13%)	3 / 31 (9.68%)
occurrences all number	2	0	1	0	0	0	0	14	4
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Seasonal allergy
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 4 (50.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	2 / 31 (6.45%)
occurrences all number	3	0	3	1	3	2	0	3	2
Dyspnoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	4 / 62 (6.45%)	1 / 31 (3.23%)
occurrences all number	0	0	2	1	0	1	0	5	1
Dyspnoea exertional
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	3	2
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	7 / 62 (11.29%)	3 / 31 (9.68%)
occurrences all number	0	0	0	1	1	0	2	9	4
Haemoptysis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	1	0	2	0
Hiccups
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Increased viscosity of bronchial secretion
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences all number	0	0	1	0	0	0	0	2	1
Productive cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0
Pulmonary oedema
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	2 / 62 (3.23%)	1 / 31 (3.23%)
occurrences all number	1	0	0	1	0	1	0	3	1
Depressed mood
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	5 / 62 (8.06%)	1 / 31 (3.23%)
occurrences all number	1	0	0	1	0	0	0	5	1
Insomnia
subjects affected / exposed	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	1 / 31 (3.23%)
occurrences all number	0	2	0	0	0	0	0	4	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	8 / 62 (12.90%)	3 / 31 (9.68%)
occurrences all number	0	1	0	0	0	0	1	9	3
Amylase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	2 / 4 (50.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	0	2	0	0	2	1	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)	11 / 62 (17.74%)	5 / 31 (16.13%)
occurrences all number	0	2	0	0	0	2	0	15	6
Blood albumin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	6 / 62 (9.68%)	2 / 31 (6.45%)
occurrences all number	0	3	0	0	1	0	0	7	2
Blood bilirubin increased
subjects affected / exposed	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)	8 / 62 (12.90%)	6 / 31 (19.35%)
occurrences all number	2	1	0	0	0	2	0	8	6
Blood potassium decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	6	0	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	4 / 62 (6.45%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	5	2
International normalised ratio increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Lipase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	1	2
Liver function test abnormal
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences all number	0	0	0	0	0	0	1	1	1
Platelet count decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	2 / 62 (3.23%)	2 / 31 (6.45%)
occurrences all number	0	1	0	0	0	0	1	2	2
Transaminases increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	1	2
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	8 / 62 (12.90%)	2 / 31 (6.45%)
occurrences all number	0	0	1	0	1	1	0	8	2
Injury, poisoning and procedural complications
Contrast media reaction
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Contusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Fall
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	3 / 62 (4.84%)	2 / 31 (6.45%)
occurrences all number	1	0	1	1	0	0	1	3	2
Sunburn
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Tooth fracture
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Nervous system disorders
Aphonia
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences all number	0	1	1	0	0	0	0	0	1
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	6 / 62 (9.68%)	3 / 31 (9.68%)
occurrences all number	0	0	0	0	0	1	1	11	3
Dizziness postural
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Dysaesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Dysgeusia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	4 / 62 (6.45%)	3 / 31 (9.68%)
occurrences all number	0	0	2	0	2	1	0	4	3
Dyskinesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Encephalopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Headache
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	8 / 62 (12.90%)	5 / 31 (16.13%)
occurrences all number	0	0	0	0	0	0	1	14	5
Lethargy
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	5 / 62 (8.06%)	8 / 31 (25.81%)
occurrences all number	0	0	1	0	2	0	0	5	8
Memory impairment
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0
Paraesthesia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Sensory disturbance
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Sensory loss
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0
Transient ischaemic attack
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Tremor
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	5 / 62 (8.06%)	1 / 31 (3.23%)
occurrences all number	0	0	0	0	0	0	0	11	1
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	4 / 31 (12.90%)
occurrences all number	0	0	0	0	0	0	0	2	6
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Deafness
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Eye disorders
Eye discharge
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	2	2
Abdominal distension
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 4 (75.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences all number	1	0	3	0	1	1	0	1	1
Abdominal pain
subjects affected / exposed	3 / 6 (50.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	3 / 8 (37.50%)	0 / 4 (0.00%)	15 / 62 (24.19%)	9 / 31 (29.03%)
occurrences all number	6	2	2	1	2	3	0	21	11
Abdominal pain lower
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	3	0
Abdominal pain upper
subjects affected / exposed	1 / 6 (16.67%)	1 / 3 (33.33%)	2 / 4 (50.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)	16 / 62 (25.81%)	4 / 31 (12.90%)
occurrences all number	1	1	3	1	3	3	0	20	5
Abdominal tenderness
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	1	0	1	0	0	0	1	0
Anorectal varices
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Ascites
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	3 / 62 (4.84%)	2 / 31 (6.45%)
occurrences all number	0	1	1	0	0	1	1	3	2
Constipation
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	2 / 4 (50.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	9 / 62 (14.52%)	6 / 31 (19.35%)
occurrences all number	1	0	4	1	0	1	0	12	9
Diarrhoea
subjects affected / exposed	2 / 6 (33.33%)	2 / 3 (66.67%)	3 / 4 (75.00%)	3 / 3 (100.00%)	2 / 4 (50.00%)	5 / 8 (62.50%)	3 / 4 (75.00%)	43 / 62 (69.35%)	21 / 31 (67.74%)
occurrences all number	8	3	7	6	3	14	6	98	44
Dry mouth
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	2 / 62 (3.23%)	3 / 31 (9.68%)
occurrences all number	0	0	0	0	0	1	0	2	5
Duodenal ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Dyspepsia
subjects affected / exposed	1 / 6 (16.67%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences all number	1	3	0	0	1	1	0	1	1
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	3 / 31 (9.68%)
occurrences all number	0	0	0	0	0	0	0	2	3
Flatulence
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	4 / 62 (6.45%)	1 / 31 (3.23%)
occurrences all number	0	0	0	0	0	0	0	4	1
Gastritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	1	2
Gastrointestinal disorder
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Gingival bleeding
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	1 / 62 (1.61%)	3 / 31 (9.68%)
occurrences all number	0	0	0	0	0	1	1	1	3
Haematemesis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 8 (25.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	2	0	1	0
Haematochezia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0
Melaena
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	1	0	4	0
Mouth ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	0	2
Nausea
subjects affected / exposed	1 / 6 (16.67%)	3 / 3 (100.00%)	3 / 4 (75.00%)	2 / 3 (66.67%)	1 / 4 (25.00%)	7 / 8 (87.50%)	3 / 4 (75.00%)	29 / 62 (46.77%)	9 / 31 (29.03%)
occurrences all number	2	5	8	2	1	8	3	51	14
Oral pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	0	2
Rectal haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	1	1	0	1	0
Retching
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0
Stomatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	3 / 31 (9.68%)
occurrences all number	0	0	0	0	0	0	0	2	3
Tooth loss
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Toothache
subjects affected / exposed	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	2	1	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	2 / 6 (33.33%)	3 / 3 (100.00%)	3 / 4 (75.00%)	2 / 3 (66.67%)	2 / 4 (50.00%)	5 / 8 (62.50%)	1 / 4 (25.00%)	23 / 62 (37.10%)	9 / 31 (29.03%)
occurrences all number	5	8	15	2	2	14	1	65	15
Hepatobiliary disorders
Drug-induced liver injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences all number	0	0	0	0	0	1	0	0	2
Hepatic haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Hepatic pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	2	0
Jaundice
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences all number	0	1	1	0	0	0	0	2	0
Portal vein thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	0	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	11 / 31 (35.48%)
occurrences all number	1	0	0	0	0	0	0	3	11
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	0	3
Dry skin
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	4 / 62 (6.45%)	5 / 31 (16.13%)
occurrences all number	0	0	0	0	0	0	0	5	5
Erythema
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	3 / 31 (9.68%)
occurrences all number	0	0	0	0	0	0	0	3	3
Hyperhidrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	2	2
Hyperkeratosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	0	2
Night sweats
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	11 / 31 (35.48%)
occurrences all number	0	0	0	0	1	1	0	1	18
Pruritus
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	2 / 4 (50.00%)	9 / 62 (14.52%)	3 / 31 (9.68%)
occurrences all number	2	0	1	0	0	0	2	9	4
Rash
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	6 / 62 (9.68%)	7 / 31 (22.58%)
occurrences all number	1	0	1	0	0	0	1	6	8
Skin reaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	3 / 31 (9.68%)
occurrences all number	0	0	0	0	0	0	0	1	4
Renal and urinary disorders
Chromaturia
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	1	0	1	0	0	0	0	1	0
Oliguria
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences all number	0	0	0	0	0	0	1	1	1
Renal failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Renal failure acute
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences all number	0	0	1	0	0	0	0	0	1
Urinary incontinence
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	1 / 31 (3.23%)
occurrences all number	1	0	0	0	0	0	0	1	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	4 / 62 (6.45%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	4	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	4 / 62 (6.45%)	2 / 31 (6.45%)
occurrences all number	1	0	3	2	0	0	0	7	2
Back pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	1 / 8 (12.50%)	1 / 4 (25.00%)	6 / 62 (9.68%)	3 / 31 (9.68%)
occurrences all number	0	1	1	2	0	1	1	6	4
Flank pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	1 / 31 (3.23%)
occurrences all number	0	1	0	0	0	0	0	0	1
Groin pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0
Joint swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	1 / 31 (3.23%)
occurrences all number	0	0	1	0	0	0	0	2	1
Muscle spasms
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	3 / 31 (9.68%)
occurrences all number	2	0	0	0	0	0	0	3	4
Musculoskeletal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	7 / 62 (11.29%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	7	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	1 / 31 (3.23%)
occurrences all number	0	1	1	1	0	0	0	3	1
Pain in extremity
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	3 / 62 (4.84%)	2 / 31 (6.45%)
occurrences all number	1	0	0	0	0	0	0	3	2
Pain in jaw
subjects affected / exposed	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0
Pathological fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Spinal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0
Infections and infestations
Influenza
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	0	0	3	0	0	0	0	1	0
Lower respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	4 / 62 (6.45%)	3 / 31 (9.68%)
occurrences all number	0	0	3	0	0	2	0	11	3
Nasopharyngitis
subjects affected / exposed	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	6 / 62 (9.68%)	0 / 31 (0.00%)
occurrences all number	1	1	3	1	0	0	0	8	0
Oral candidiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 8 (12.50%)	0 / 4 (0.00%)	4 / 62 (6.45%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	1	0	4	3
Tooth abscess
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	2 / 62 (3.23%)	3 / 31 (9.68%)
occurrences all number	2	2	0	0	1	0	2	2	4
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 4 (75.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	5 / 8 (62.50%)	2 / 4 (50.00%)	23 / 62 (37.10%)	13 / 31 (41.94%)
occurrences all number	1	0	6	0	3	5	2	27	15
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	1	0	0	2	0
Hyperuricaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 62 (1.61%)	0 / 31 (0.00%)
occurrences all number	1	0	0	0	0	0	1	1	0
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	2 / 31 (6.45%)
occurrences all number	0	0	1	0	0	0	0	0	2
Hypokalaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	1 / 4 (25.00%)	1 / 62 (1.61%)	2 / 31 (6.45%)
occurrences all number	1	0	0	0	0	0	1	1	5
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	2 / 62 (3.23%)	2 / 31 (6.45%)
occurrences all number	0	0	0	0	0	0	0	2	2
Malnutrition
subjects affected / exposed	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 8 (0.00%)	0 / 4 (0.00%)	0 / 62 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0

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Were there any global substantial amendments to the protocol? Yes

29 Apr 2010

The EudraCT number was corrected. The Trial Clinical Monitor was changed.

29 Apr 2011

1) Only patients with liver function in Group 1 (Child-Pugh A and both AST and ALT ≤2x ULN) were eligible for the Phase II part. 2) The Phase II dose for Group 1 patients was available. 3) Choi criteria were replaced by mRECIST for HCC criteria to more accurately reflect disease stabilisation and progression in this indication. 4) Stratification factors were specified. 5)Sampling for plasma protein binding of nintedanib was added because plasma protein concentrations can alter in patients with hepatic impairment. 5) The definition of MTD was updated. 6) The Trial Clinical Monitor was changed. 7) The recommended dose for Phase II (MTD) was identified, and an extension cohort of 11 to 15 Group 2 patients was added to further study the safety of patients from Group 2. 8) The randomisation procedure and analysis set was modified. 9) There was a change in the PK methods (12 instead of 24 hours). 10) The interim safety analysis was performed in Group 1 patients only. 11) Lipase, amylase and phosphate were added to the safety laboratory examinations.

25 Jan 2012

1) The wording for AE reporting was updated, was a requirement from the German health authority (BfArM) for a protocol submitted in any country. 2) The Food and Drug Administration drug-induced liver injury guidelines were implemented.3) Continuous HBV testing was added for patients with positive HBV DNA at baseline

25 Jul 2012

1) The restart criteria following interruption of study medication in Phase II due to AST/ALT/ALKP elevation were corrected. 2) Inclusion criterion 7 was clarified. 3) In sites participating in the Phase I MTD extension cohort, at least 6 patients with Child-Pugh B (7) in the MTD extension cohort for Group 2 had to be included. 4) The planned interim analysis was changed to the primary analysis, to clarify when the primary analysis was to be conducted. Justification for conducting the primary analysis after at least 80% of patients had a TTP event was added. 5) The interim analysis was not performed because the primary analysis was performed instead. 6) The criteria for defining the end of the whole trial were changed from as soon as the last patient has completed his/her last visit, to as soon as at least 50% of the patients have had an overall survival event or the last patient has completed his/her first follow-up visit for overall survival, whichever occurred last. This change was made because overall survival events of at least 50% of patients were considered to provide enough information to estimate the Kaplan-Meier curves, and ensured that all patients were off treatment and not in follow-up for disease progression

04 Dec 2013

1) Selected secondary and explorative endpoints were modified because PK parameters are considered further endpoints, and safety is summarised separately from secondary endpoints. 2) Selected text was deleted that should have been deleted in Amendment 2. 3) Selected text was revised that was unclear in Amendment 3. 4) An administrative change was made.

31 Mar 2014

1) The timing of the primary analysis was brought forward slightly because there were an unexpectedly high number of patients censored for TTP events due to early death, lost to follow-up or other treatment. The number of events for overall survival had already been reached. Therefore, the primary analysis was done after approximately 80% of patients (instead of at least 80% of patients) had reached the primary endpoint. 2) Minor corrections were made to 2 of the footnotes to the flow chart for the Phase II part

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 Trial Results:
A multicentre, open label, Phase I/randomised Phase II study to evaluate safety, pharmacokinetics and efficacy of BIBF 1120 in comparison with sorafenib for advanced hepatocellular carcinoma patients

Trial information

Trial information

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Subject disposition

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Baseline characteristics

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End points

Primary: Maximum Tolerated Dose in Phase I

Primary: Maximum Tolerated Dose in Phase I

Primary: Time to Progression (TTP) in Phase II

Primary: Time to Progression (TTP) in Phase II

Secondary: Incidence of Dose Limiting Toxicity in Phase I

Secondary: Incidence of Dose Limiting Toxicity in Phase I

Secondary: Objective Tumour Response by RECIST

Secondary: Objective Tumour Response by RECIST

Secondary: Progression Free Survival (PFS)

Secondary: Progression Free Survival (PFS)

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Secondary: Overall Survival

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Clinical trials

Clinical Trial Results: A multicentre, open label, Phase I/randomised Phase II study to evaluate safety, pharmacokinetics and efficacy of BIBF 1120 in comparison with sorafenib for advanced hepatocellular carcinoma patients

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum Tolerated Dose in Phase I

Primary: Maximum Tolerated Dose in Phase I

Primary: Time to Progression (TTP) in Phase II

Primary: Time to Progression (TTP) in Phase II

Secondary: Incidence of Dose Limiting Toxicity in Phase I

Secondary: Incidence of Dose Limiting Toxicity in Phase I

Secondary: Objective Tumour Response by RECIST

Secondary: Objective Tumour Response by RECIST

Secondary: Progression Free Survival (PFS)

Secondary: Progression Free Survival (PFS)

Secondary: Overall Survival

Secondary: Overall Survival

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A multicentre, open label, Phase I/randomised Phase II study to evaluate safety, pharmacokinetics and efficacy of BIBF 1120 in comparison with sorafenib for advanced hepatocellular carcinoma patients