A Phase I / II Trial of Nintedanib in Asian Hepatocellular Carcinoma Patients

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00987935
• Collaborator: (none)
• Enrollment: 134
• Locations: 16
• Arms: 2
• Duration (Months): 75
• Patients Per Site: 8.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is to evaluate the safety, appropriate dose, and efficacy of BIBF 1120 in liver cancer patients

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Sorafenib; Drug: BIBF 1120	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 134 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open Label, Phase I/Randomized II Study to Evaluate Safety, Pharmacokinetics and Efficacy of BIBF 1120 in Comparison With Sorafenib for Advanced Hepatocellular Carcinoma Patients in Asia.
• Study Start Date: Oct 1, 2009
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nintedanib (BIBF 1120) Phase I dose escalation and phase II using dose determined in phase I	Drug: BIBF 1120; Twice daily
Active Comparator: Sorafenib Twice daily dosing in phase II	Drug: Sorafenib; 400 mg twice daily

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose in Phase I [4 weeks]

   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.

2. Time to Progression (TTP) in Phase II [From randomization until data cut-off (28 Sep 2012); Up to 77 weeks]

   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.

Secondary Outcome Measures

1. Time to Progression (TTP) in Phase II (Follow-up Analyses) [From randomization until disease progression or data cut-off (16 Jul 2014); Up to 171 weeks]

   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.

2. Incidence and Intensity of Adverse Events (AEs) Reported as the Number of Patients With AEs According to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Throughout the Treatment Period. [AEs with an onset during therapy with study treatment or within 28 days after discontinuation of study treatment (up to 1066 days)]

   Incidence and worst intensity (severity) of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

3. Incidence of Dose Limiting Toxicity in Phase I [4 weeks]

   Number of patients with dose limiting toxicity are presented

4. Objective Tumour Response by RECIST [From randomization until data cut-off (16 July 2014); Up to 171 weeks]

   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.

5. Progression Free Survival (PFS) [From randomization until data cut-off (16 July 2014); Up to 171 weeks]

   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.

6. Overall Survival [From randomization until data cut-off (16 July 2014); Up to 171 weeks]

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

7. AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of Nintedanib [Day1, Day15 and Day 16]

   AUC0-12,ss,norm (area under the plasma concentration-time curve between 0 and 12 hours at steady state, normalised values) of Nintedanib Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.

8. AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of BIBF 1202 (Metabolite of Nintedanib) [Day1, Day15 and Day 16]

   AUC0-12,ss,norm (area under the plasma concentration-time curve between 0 and 12 hours at steady state, normalised values) of BIBF 1202 (metabolite of Nintedanib). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.

9. AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of BIBF 1202 Glucuronide (Metabolite of Nintedanib) [Day1, Day15 and Day 16]

   AUC0-12,ss,norm of BIBF 1202 glucuronide (Metabolite of Nintedanib): Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.

10. Cmax,ss,Norm (Maximum Concentration of the Nintedanib in Plasma at Steady State, Normalised Values) [Day1, Day15 and Day 16]

    Cmax,ss,norm (maximum concentration of the Nintedanib in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.

11. Cmax,ss,Norm (Maximum Concentration of the BIBF 1202 in Plasma at Steady State, Normalised Values) [Day1, Day15 and Day 16]

    Cmax,ss,norm (maximum concentration of the BIBF 1202 in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.

12. Cmax,ss,Norm (Maximum Concentration of the BIBF 1202 Glucuronide in Plasma at Steady State, Normalised Values) [Day1, Day15 and Day 16]

    Cmax,ss,norm (maximum concentration of the BIBF 1202 glucuronide in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.

13. fe0-12,ss (Fraction Excreted in Urine Between 0 and 12 Hours at Steady State) for Nintedanib [0 to 4 hours (h), 4 to 12 h, and 12 to 24 h after nintedanib]

    fe0-12,ss (fraction excreted in urine between 0 and 12 hours at steady state) for Nintedanib. The reported value corresponds to the percentage of administered dose.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

1. Hepatocellular carcinoma, either histologically/cytologically confirmed or clinically diagnosed, which is not amenable to curative surgery or loco-regional therapy

2. Age 18 years or older

3. Eastern Cooperative Group performance score of 2 or less

4. Child-Pugh score of 7 or less

5. Written informed consent in accordance with International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) and local legislation

Exclusion criteria:

1. Prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (for phase II)

2. More than one line of prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (for phase I)

3. Uncontrolled or refractory ascites to adequate medical therapy

4. Bilirubin greater than 1.5 times upper limit of normal

5. Aspartate amino transferase or alanine amino transferase greater than 5 times upper limit of normal

6. Absolute neutrophil count less than 1500/microliter

7. Platelet count less than 75000/microliter

8. Hemoglobin less than 9 g/dL

9. Serum creatinine greater than 1.5 times upper limit of normal

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	1199.39.82001 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
2	1199.39.82002 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
3	1199.39.82003 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
4	1199.39.82004 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
5	1199.39.82005 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
6	1199.39.82006 Boehringer Ingelheim Investigational Site	Seoul		Korea, Republic of
7	1199.39.88606 Boehringer Ingelheim Investigational Site	Changhua		Taiwan
8	1199.39.88609 Boehringer Ingelheim Investigational Site	Kaohsiung		Taiwan
9	1199.39.88610 Boehringer Ingelheim Investigational Site	Kaohsiung		Taiwan
10	1199.39.88605 Boehringer Ingelheim Investigational Site	Taichung		Taiwan
11	1199.39.88608 Boehringer Ingelheim Investigational Site	Tainan City		Taiwan
12	1199.39.88602 Boehringer Ingelheim Investigational Site	Tainan		Taiwan
13	1199.39.88601 Boehringer Ingelheim Investigational Site	Taipei		Taiwan
14	1199.39.88603 Boehringer Ingelheim Investigational Site	Taipei		Taiwan
15	1199.39.88604 Boehringer Ingelheim Investigational Site	Taoyuan County		Taiwan
16	1199.39.88607 Boehringer Ingelheim Investigational Site	Yunlin County		Taiwan

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00987935
• Other Study ID Numbers: 1199.39
• First Posted: Oct 1, 2009
• Last Update Posted: Mar 10, 2016
• Last Verified: Feb 1, 2016

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Sorafenib; Nintedanib

Study Results

Participant Flow

Recruitment Details	The trial consisted of 2 Phases. Patients were stratified into 1 of 2 groups according to their aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and Child-Pugh score at baseline.
Pre-assignment Detail	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). Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT >2 to ≤5 times ULN

Arm/Group Title	Phase I Group I, 100 mg Nintedanib Bid	Phase I Group 1, 150 mg Nintedanib Bid	Phase I Group 1, 200 mg Nintedanib Bid	Phase I Group 2, 50 mg Nintedanib Bid	Phase I Group 2, 100 mg Nintedanib Bid	Phase I Group 2, 150 mg Nintedanib Bid	Phase I Group 2, 200 mg Nintedanib Bid	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Arm/Group 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) and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).
Period Title: Overall Study
STARTED	4	3	3	3	7	3	16	63	32
COMPLETED	0	0	0	0	0	0	1	1	0
NOT COMPLETED	4	3	3	3	7	3	15	62	32

Baseline Characteristics

Arm/Group Title	Phase I Group I, 100 mg Nintedanib Bid	Phase I Group 1, 150 mg Nintedanib Bid	Phase I Group 1, 200 mg Nintedanib Bid	Phase I Group 2, 50 mg Nintedanib Bid	Phase I Group 2, 100 mg Nintedanib Bid	Phase I Group 2, 150 mg Nintedanib Bid	Phase I Group 2, 200 mg Nintedanib Bid	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid	Total
Arm/Group 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) and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	Total of all reporting groups
Overall Participants	4	3	3	3	7	3	16	63	32	134
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.5 (14.5)	55.7 (4.2)	47.7 (6.8)	64.3 (15.3)	62.3 (11.1)	68.7 (10.1)	56.1 (11.7)	58.2 (12.6)	61.2 (11.5)	58.6 (12.3)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%	3 18.8%	6 9.5%	6 18.8%	16 11.9%
Male	4 100%	3 100%	3 100%	3 100%	7 100%	2 66.7%	13 81.3%	57 90.5%	26 81.3%	118 88.1%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose in Phase I
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.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Treated set (Patients from the dose escalation part that were not replaced for MTD determination)

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)
Measure Participants	9	15
Number [mg]	200	200

2. Primary Outcome

Title	Time to Progression (TTP) in Phase II
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.
Time Frame	From randomization until data cut-off (28 Sep 2012); Up to 77 weeks

Outcome Measure Data

Analysis Population Description

Treated set, only phase II participants.

Arm/Group Title	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Arm/Group Description	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).
Measure Participants	63	32
Median (Inter-Quartile Range) [months]	2.73	3.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1, Group 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.357
	Confidence Interval	(2-Sided) 95%; 0.802 to 2.296
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

3. Secondary Outcome

Title	Time to Progression (TTP) in Phase II (Follow-up Analyses)
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.
Time Frame	From randomization until disease progression or data cut-off (16 Jul 2014); Up to 171 weeks

Outcome Measure Data

Analysis Population Description

Treated set, Only phase II participants

Arm/Group Title	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Arm/Group Description	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).
Measure Participants	63	32
Median (Inter-Quartile Range) [months]	2.76	3.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1, Group 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.213
	Confidence Interval	(2-Sided) 95%; 0.730 to 2.014
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

4. Secondary Outcome

Title	Incidence and Intensity of Adverse Events (AEs) Reported as the Number of Patients With AEs According to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Throughout the Treatment Period.
Description	Incidence and worst intensity (severity) of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
Time Frame	AEs with an onset during therapy with study treatment or within 28 days after discontinuation of study treatment (up to 1066 days)

Outcome Measure Data

Analysis Population Description

Treated set

Arm/Group Title	Phase I Group I, 100 mg Nintedanib Bid	Phase I Group 1, 150 mg Nintedanib Bid	Phase I Group 1, 200 mg Nintedanib Bid	Phase I Group 2, 50 mg Nintedanib Bid	Phase I Group 2, 100 mg Nintedanib Bid	Phase I Group 2, 150 mg Nintedanib Bid	Phase I Group 2, 200 mg Nintedanib Bid	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Arm/Group 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) and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).
Measure Participants	4	3	3	3	7	3	16	63	32
Grade 1	0 0%	0 0%	1 33.3%	0 0%	1 14.3%	0 0%	1 6.3%	12 19%	1 3.1%
Grade 2	2 50%	2 66.7%	1 33.3%	0 0%	0 0%	1 33.3%	4 25%	15 23.8%	4 12.5%
Grade 3	2 50%	1 33.3%	1 33.3%	1 33.3%	3 42.9%	2 66.7%	5 31.3%	17 27%	18 56.3%
Grade 4	0 0%	0 0%	0 0%	2 66.7%	1 14.3%	0 0%	1 6.3%	8 12.7%	5 15.6%
Grade 5	0 0%	0 0%	0 0%	0 0%	2 28.6%	0 0%	5 31.3%	10 15.9%	4 12.5%

5. Secondary Outcome

Title	Incidence of Dose Limiting Toxicity in Phase I
Description	Number of patients with dose limiting toxicity are presented
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

Treated set (Phase I patients from the dose escalation part that were not replaced for MTD determination).

Arm/Group Title	Phase I Group 1, 100 mg Nintedanib Bid	Phase I Group 1, 150 mg Nintedanib Bid	Phase I Group 1, 200 mg Nintedanib Bid	Phase I Group 2, 50 mg Nintedanib Bid	Phase I Group 2, 100 mg Nintedanib Bid	Phase I Group 2, 150 mg Nintedanib Bid	Phase I Group 2, 200 mg Nintedanib Bid
Arm/Group 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) and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	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 and pharmacokinetics (PK) of nintedanib.	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.
Measure Participants	3	3	3	3	6	3	3
Number [participants]	0 0%	0 0%	0 0%	0 0%	1 14.3%	0 0%	0 0%

6. Secondary Outcome

Title	Objective Tumour Response by RECIST
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.
Time Frame	From randomization until data cut-off (16 July 2014); Up to 171 weeks

Outcome Measure Data

Analysis Population Description

Treated set, only phase II participants.

Arm/Group Title	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Arm/Group Description	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).
Measure Participants	63	32
Number (95% Confidence Interval) [percentage of participants]	6.3 157.5%	3.1 103.3%

7. Secondary Outcome

Title	Progression Free Survival (PFS)
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.
Time Frame	From randomization until data cut-off (16 July 2014); Up to 171 weeks

Outcome Measure Data

Analysis Population Description

Treated set, only phase II participants.

Arm/Group Title	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Arm/Group Description	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).
Measure Participants	63	32
Median (Inter-Quartile Range) [months]	2.66	3.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1, Group 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.186
	Confidence Interval	(2-Sided) 95%; 0.728 to 1.932
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

8. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the duration from date of randomisation to the date of death.
Time Frame	From randomization until data cut-off (16 July 2014); Up to 171 weeks

Outcome Measure Data

Analysis Population Description

Treated set, include only phase II participants

Arm/Group Title	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid
Arm/Group Description	Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).
Measure Participants	63	32
Median (Inter-Quartile Range) [months]	10.18	10.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1, Group 2
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.940
	Confidence Interval	(2-Sided) 95%; 0.593 to 1.489
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

9. Secondary Outcome

Title	AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of Nintedanib
Description	AUC0-12,ss,norm (area under the plasma concentration-time curve between 0 and 12 hours at steady state, normalised values) of Nintedanib Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame	Day1, Day15 and Day 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PK set was a subset of the treated set and included all patients who received at least one dose of trial medication and for whom at least one PK observation was available.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)	Phase I Group 2 treatment consists of nintedanib, 50, 100, 150 or 200 mg twice daily:
Measure Participants	20	20
Geometric Mean (Geometric Coefficient of Variation) [(ng*h/mL)/mg]	1.97 (97.1)	3.82 (64.1)

10. Secondary Outcome

Title	AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of BIBF 1202 (Metabolite of Nintedanib)
Description	AUC0-12,ss,norm (area under the plasma concentration-time curve between 0 and 12 hours at steady state, normalised values) of BIBF 1202 (metabolite of Nintedanib). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame	Day1, Day15 and Day 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PK set was a subset of the treated set and included all patients who received at least one dose of trial medication and for whom at least one PK observation was available.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)	Phase I Group 2 treatment consists of nintedanib, 50, 100, 150 or 200 mg twice daily:
Measure Participants	20	20
Geometric Mean (Geometric Coefficient of Variation) [(ng*h/mL)/mg]	3.50 (157)	8.95 (114)

11. Secondary Outcome

Title	AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of BIBF 1202 Glucuronide (Metabolite of Nintedanib)
Description	AUC0-12,ss,norm of BIBF 1202 glucuronide (Metabolite of Nintedanib): Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame	Day1, Day15 and Day 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PK set was a subset of the treated set and included all patients who received at least one dose of trial medication and for whom at least one PK observation was available.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)	Phase I Group 2 treatment consists of nintedanib, 50, 100, 150 or 200 mg twice daily:
Measure Participants	20	20
Geometric Mean (Geometric Coefficient of Variation) [(ng*h/mL)/mg]	16.9 (144)	45.0 (124)

12. Secondary Outcome

Title	Cmax,ss,Norm (Maximum Concentration of the Nintedanib in Plasma at Steady State, Normalised Values)
Description	Cmax,ss,norm (maximum concentration of the Nintedanib in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame	Day1, Day15 and Day 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PK set was a subset of the treated set and included all patients who received at least one dose of trial medication and for whom at least one PK observation was available.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)	Phase I Group 2 treatment consists of nintedanib, 50, 100, 150 or 200 mg twice daily:
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [(ng/mL)/mg]	0.348 (98.8)	0.630 (68.9)

13. Secondary Outcome

Title	Cmax,ss,Norm (Maximum Concentration of the BIBF 1202 in Plasma at Steady State, Normalised Values)
Description	Cmax,ss,norm (maximum concentration of the BIBF 1202 in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame	Day1, Day15 and Day 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PK set was a subset of the treated set and included all patients who received at least one dose of trial medication and for whom at least one PK observation was available.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)	Phase I Group 2 treatment consists of nintedanib, 50, 100, 150 or 200 mg twice daily:
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [(ng/mL)/mg]	0.519 (148)	1.01 (118)

14. Secondary Outcome

Title	Cmax,ss,Norm (Maximum Concentration of the BIBF 1202 Glucuronide in Plasma at Steady State, Normalised Values)
Description	Cmax,ss,norm (maximum concentration of the BIBF 1202 glucuronide in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame	Day1, Day15 and Day 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PK set was a subset of the treated set and included all patients who received at least one dose of trial medication and for whom at least one PK observation was available.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)	Phase I Group 2 treatment consists of nintedanib, 50, 100, 150 or 200 mg twice daily:
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [(ng/mL)/mg]	1.56 (139)	3.48 (139)

15. Secondary Outcome

Title	fe0-12,ss (Fraction Excreted in Urine Between 0 and 12 Hours at Steady State) for Nintedanib
Description	fe0-12,ss (fraction excreted in urine between 0 and 12 hours at steady state) for Nintedanib. The reported value corresponds to the percentage of administered dose.
Time Frame	0 to 4 hours (h), 4 to 12 h, and 12 to 24 h after nintedanib

Outcome Measure Data

Analysis Population Description

Pharmacokinetic set (PKS): The PK set was a subset of the treated set and included all patients who received at least one dose of trial medication and for whom at least one PK observation was available.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Patients treated with nintedanib belonging to Group1 from the 2 phases, Phase I Group 1 treatment consists of nintedanib, 100, 150 or 200 mg twice daily (bid) Phase II treatment consists of Nintedanib 200 mg twice daily (bid)	Phase I Group 2 treatment consists of nintedanib, 50, 100, 150 or 200 mg twice daily:
Measure Participants	22	23
Geometric Mean (Geometric Coefficient of Variation) [percentage]	0.227 (94.6)	0.286 (46.0)

Adverse Events

Time Frame	AEs with an onset during therapy with study treatment or within 28 days after discontinuation of study treatment (up to 1066 days)
Arm/Group Title	Phase I Group I Nintedanib, 100 mg Bid		Phase I Group I Nintedanib, 150 mg Bid		Phase I Group I Nintedanib, 200 mg Bid		Phase I Group II Nintedanib, 50 mg Bid		Phase I Group II Nintedanib, 100 mg Bid		Phase I Group II Nintedanib, 150 mg Bid		Phase I Group II Nintedanib, 200 mg Bid		Phase II Nintedanib, 200 mg Bid		Phase II Sorafenib, 400 mg Bid
Arm/Group Description	Oral administration of Nintedanib (BIBF 1120) 100 mg soft gelatine capsules twice daily (bid) for the Group I patients during Phase I		Oral administration of Nintedanib (BIBF 1120) 150 mg soft gelatine capsules twice daily (bid) for the Group I patients during Phase I		Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid) for the Group I patients during Phase I		Oral administration of Nintedanib (BIBF 1120) 50 mg soft gelatine capsules twice daily (bid) for the Group II patients during Phase I		Oral administration of Nintedanib (BIBF 1120) 100 mg soft gelatine capsules twice daily (bid) for the Group II patients during Phase I		Oral administration of Nintedanib (BIBF 1120) 150 mg soft gelatine capsules twice daily (bid) for the Group II patients during Phase I		Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid) for the Group II patients during Phase I		Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid) during Phase II		Oral administration of Sorafenib 400 mg film coated tablets twice daily (bid) during Phase II
All Cause Mortality
	Phase I Group I Nintedanib, 100 mg Bid		Phase I Group I Nintedanib, 150 mg Bid		Phase I Group I Nintedanib, 200 mg Bid		Phase I Group II Nintedanib, 50 mg Bid		Phase I Group II Nintedanib, 100 mg Bid		Phase I Group II Nintedanib, 150 mg Bid		Phase I Group II Nintedanib, 200 mg Bid		Phase II Nintedanib, 200 mg Bid		Phase II Sorafenib, 400 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I Group I Nintedanib, 100 mg Bid		Phase I Group I Nintedanib, 150 mg Bid		Phase I Group I Nintedanib, 200 mg Bid		Phase I Group II Nintedanib, 50 mg Bid		Phase I Group II Nintedanib, 100 mg Bid		Phase I Group II Nintedanib, 150 mg Bid		Phase I Group II Nintedanib, 200 mg Bid		Phase II Nintedanib, 200 mg Bid		Phase II Sorafenib, 400 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/4 (50%)		1/3 (33.3%)		0/3 (0%)		3/3 (100%)		4/7 (57.1%)		1/3 (33.3%)		10/16 (62.5%)		29/63 (46%)		18/32 (56.3%)
Blood and lymphatic system disorders
Haemorrhagic anaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Thrombocytopenia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Cardiac disorders
Acute coronary syndrome	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Acute myocardial infarction	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Gastrointestinal disorders
Abdominal distension	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Abdominal pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		1/32 (3.1%)
Anal fistula	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Ascites	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		0/32 (0%)
Diarrhoea	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		0/32 (0%)
Food poisoning	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Gastric haemorrhage	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Gastric perforation	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Gastric ulcer	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		0/32 (0%)
Gastroduodenitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Gastrointestinal haemorrhage	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Haematochezia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Haemorrhoids	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Nausea	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Oesophageal varices haemorrhage	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Pancreatitis acute	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Upper gastrointestinal haemorrhage	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		3/63 (4.8%)		1/32 (3.1%)
Vomiting	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
General disorders
Asthenia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		2/32 (6.3%)
Chest pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Disease progression	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Fatigue	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Malaise	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Pyrexia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		4/63 (6.3%)		3/32 (9.4%)
Hepatobiliary disorders
Cholecystitis acute	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Hepatic failure	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		2/32 (6.3%)
Hepatic function abnormal	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		2/16 (12.5%)		0/63 (0%)		2/32 (6.3%)
Hepatitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Hyperbilirubinaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Infections and infestations
Biliary tract infection	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Cellulitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Peritonitis bacterial	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Pneumonia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Sepsis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		0/32 (0%)
Septic shock	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Upper respiratory tract infection	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Injury, poisoning and procedural complications
Eye injury	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Investigations
Aspartate aminotransferase increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		1/32 (3.1%)
Blood bilirubin increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		2/16 (12.5%)		1/63 (1.6%)		1/32 (3.1%)
Blood creatinine increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Blood urea increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Hyperkalaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Hypoglycaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		0/32 (0%)
Hyponatraemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Musculoskeletal chest pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Pathological fracture	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		0/32 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic cancer metastatic	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Hepatocellular carcinoma	1/4 (25%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		2/7 (28.6%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Malignant neoplasm progression	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		6/63 (9.5%)		2/32 (6.3%)
Metastases to central nervous system	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		1/32 (3.1%)
Metastatic pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Nasal sinus cancer	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Tumour associated fever	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Tumour haemorrhage	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Tumour rupture	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Nervous system disorders
Cognitive disorder	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Headache	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Hemiparesis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Hepatic encephalopathy	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Sciatica	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Psychiatric disorders
Anxiety	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Renal and urinary disorders
Renal failure	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Renal failure chronic	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		0/32 (0%)
Pleural effusion	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Pneumonia aspiration	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Pneumonitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Pulmonary embolism	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Respiratory failure	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Vascular disorders
Visceral arterial ischaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Phase I Group I Nintedanib, 100 mg Bid		Phase I Group I Nintedanib, 150 mg Bid		Phase I Group I Nintedanib, 200 mg Bid		Phase I Group II Nintedanib, 50 mg Bid		Phase I Group II Nintedanib, 100 mg Bid		Phase I Group II Nintedanib, 150 mg Bid		Phase I Group II Nintedanib, 200 mg Bid		Phase II Nintedanib, 200 mg Bid		Phase II Sorafenib, 400 mg Bid
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		7/7 (100%)		3/3 (100%)		16/16 (100%)		61/63 (96.8%)		32/32 (100%)
Blood and lymphatic system disorders
Anaemia	1/4 (25%)		0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		1/7 (14.3%)		1/3 (33.3%)		3/16 (18.8%)		12/63 (19%)		5/32 (15.6%)
Leukocytosis	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Leukopenia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		2/16 (12.5%)		4/63 (6.3%)		0/32 (0%)
Neutropenia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		2/3 (66.7%)		1/16 (6.3%)		4/63 (6.3%)		1/32 (3.1%)
Thrombocytopenia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		1/3 (33.3%)		4/16 (25%)		11/63 (17.5%)		7/32 (21.9%)
Cardiac disorders
Tachycardia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Ear and labyrinth disorders
Tinnitus	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		2/32 (6.3%)
Endocrine disorders
Hypothyroidism	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		2/32 (6.3%)
Eye disorders
Eye discharge	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Orbital oedema	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		3/63 (4.8%)		1/32 (3.1%)
Abdominal distension	1/4 (25%)		1/3 (33.3%)		2/3 (66.7%)		2/3 (66.7%)		3/7 (42.9%)		0/3 (0%)		3/16 (18.8%)		18/63 (28.6%)		3/32 (9.4%)
Abdominal pain	0/4 (0%)		2/3 (66.7%)		2/3 (66.7%)		2/3 (66.7%)		1/7 (14.3%)		1/3 (33.3%)		2/16 (12.5%)		11/63 (17.5%)		10/32 (31.3%)
Abdominal pain upper	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		4/16 (25%)		14/63 (22.2%)		11/32 (34.4%)
Abdominal tenderness	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Ascites	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		2/16 (12.5%)		12/63 (19%)		3/32 (9.4%)
Constipation	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		13/63 (20.6%)		7/32 (21.9%)
Diarrhoea	2/4 (50%)		1/3 (33.3%)		0/3 (0%)		2/3 (66.7%)		5/7 (71.4%)		3/3 (100%)		6/16 (37.5%)		28/63 (44.4%)		18/32 (56.3%)
Dry mouth	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		2/16 (12.5%)		0/63 (0%)		1/32 (3.1%)
Duodenal ulcer	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		2/32 (6.3%)
Duodenitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Dyspepsia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		5/63 (7.9%)		1/32 (3.1%)
Gastric ulcer	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		1/3 (33.3%)		1/16 (6.3%)		2/63 (3.2%)		2/32 (6.3%)
Gastritis	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		4/63 (6.3%)		1/32 (3.1%)
Gastrointestinal disorder	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Gastrointestinal haemorrhage	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		1/32 (3.1%)
Gastrooesophageal reflux disease	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		4/16 (25%)		5/63 (7.9%)		0/32 (0%)
Haematochezia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		2/32 (6.3%)
Haemorrhoids	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		3/63 (4.8%)		2/32 (6.3%)
Irritable bowel syndrome	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Mouth haemorrhage	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Mouth ulceration	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		2/32 (6.3%)
Nausea	2/4 (50%)		1/3 (33.3%)		1/3 (33.3%)		2/3 (66.7%)		2/7 (28.6%)		2/3 (66.7%)		7/16 (43.8%)		19/63 (30.2%)		4/32 (12.5%)
Plicated tongue	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Portal hypertensive gastropathy	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		1/32 (3.1%)
Stomatitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		3/32 (9.4%)
Upper gastrointestinal haemorrhage	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Vomiting	1/4 (25%)		1/3 (33.3%)		1/3 (33.3%)		1/3 (33.3%)		1/7 (14.3%)		1/3 (33.3%)		5/16 (31.3%)		19/63 (30.2%)		5/32 (15.6%)
General disorders
Asthenia	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		7/63 (11.1%)		3/32 (9.4%)
Chest pain	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		1/16 (6.3%)		2/63 (3.2%)		4/32 (12.5%)
Chills	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		0/32 (0%)
Fatigue	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		1/3 (33.3%)		3/7 (42.9%)		1/3 (33.3%)		5/16 (31.3%)		14/63 (22.2%)		4/32 (12.5%)
Influenza like illness	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		2/63 (3.2%)		0/32 (0%)
Malaise	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		4/63 (6.3%)		2/32 (6.3%)
Mucosal inflammation	0/4 (0%)		2/3 (66.7%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		2/16 (12.5%)		2/63 (3.2%)		2/32 (6.3%)
Oedema	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		1/16 (6.3%)		4/63 (6.3%)		3/32 (9.4%)
Oedema peripheral	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)		1/3 (33.3%)		4/16 (25%)		11/63 (17.5%)		4/32 (12.5%)
Pyrexia	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		4/16 (25%)		12/63 (19%)		6/32 (18.8%)
Tenderness	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Hepatobiliary disorders
Hepatic function abnormal	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		4/63 (6.3%)		1/32 (3.1%)
Hepatomegaly	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		0/32 (0%)
Immune system disorders
Hypersensitivity	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Infections and infestations
Herpes zoster	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		2/32 (6.3%)
Nasopharyngitis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		5/63 (7.9%)		1/32 (3.1%)
Pneumonia	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		1/32 (3.1%)
Upper respiratory tract infection	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		2/16 (12.5%)		5/63 (7.9%)		0/32 (0%)
Injury, poisoning and procedural complications
Wound	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		1/63 (1.6%)		1/32 (3.1%)
Investigations
Activated partial thromboplastin time prolonged	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Alanine aminotransferase increased	1/4 (25%)		2/3 (66.7%)		2/3 (66.7%)		0/3 (0%)		1/7 (14.3%)		1/3 (33.3%)		2/16 (12.5%)		7/63 (11.1%)		7/32 (21.9%)
Aspartate aminotransferase increased	1/4 (25%)		2/3 (66.7%)		2/3 (66.7%)		0/3 (0%)		2/7 (28.6%)		0/3 (0%)		4/16 (25%)		9/63 (14.3%)		10/32 (31.3%)
Blood alkaline phosphatase increased	0/4 (0%)		2/3 (66.7%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		2/32 (6.3%)
Blood bilirubin increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		2/7 (28.6%)		1/3 (33.3%)		2/16 (12.5%)		6/63 (9.5%)		3/32 (9.4%)
Blood creatine phosphokinase increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		2/32 (6.3%)
Blood creatinine increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		2/32 (6.3%)
Blood lactate dehydrogenase increased	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Blood potassium increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Electrocardiogram QT prolonged	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)		1/3 (33.3%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Gamma-glutamyltransferase increased	0/4 (0%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Haematocrit increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Haemoglobin increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
International normalised ratio increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		2/32 (6.3%)
Lipase increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		3/63 (4.8%)		2/32 (6.3%)
Protein total decreased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Prothrombin time prolonged	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Red blood cell count increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Weight decreased	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		4/63 (6.3%)		1/32 (3.1%)
Metabolism and nutrition disorders
Decreased appetite	1/4 (25%)		1/3 (33.3%)		0/3 (0%)		3/3 (100%)		2/7 (28.6%)		1/3 (33.3%)		8/16 (50%)		25/63 (39.7%)		8/32 (25%)
Hypercalcaemia	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Hyperglycaemia	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		2/63 (3.2%)		0/32 (0%)
Hyperkalaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)		0/3 (0%)		1/16 (6.3%)		5/63 (7.9%)		1/32 (3.1%)
Hypernatraemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Hyperuricaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		2/16 (12.5%)		1/63 (1.6%)		1/32 (3.1%)
Hypoalbuminaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		2/3 (66.7%)		1/7 (14.3%)		0/3 (0%)		3/16 (18.8%)		4/63 (6.3%)		6/32 (18.8%)
Hypoglycaemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Hypokalaemia	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		2/16 (12.5%)		3/63 (4.8%)		2/32 (6.3%)
Hyponatraemia	0/4 (0%)		0/3 (0%)		0/3 (0%)		3/3 (100%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		2/32 (6.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		2/32 (6.3%)
Back pain	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		2/3 (66.7%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		8/63 (12.7%)		0/32 (0%)
Bone pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		3/32 (9.4%)
Musculoskeletal pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		4/63 (6.3%)		1/32 (3.1%)
Musculoskeletal stiffness	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Myalgia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		3/63 (4.8%)		0/32 (0%)
Neck pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Nervous system disorders
Altered state of consciousness	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Dizziness	2/4 (50%)		1/3 (33.3%)		1/3 (33.3%)		2/3 (66.7%)		1/7 (14.3%)		0/3 (0%)		3/16 (18.8%)		9/63 (14.3%)		6/32 (18.8%)
Encephalopathy	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Headache	1/4 (25%)		1/3 (33.3%)		1/3 (33.3%)		2/3 (66.7%)		1/7 (14.3%)		0/3 (0%)		1/16 (6.3%)		3/63 (4.8%)		3/32 (9.4%)
Hepatic encephalopathy	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		3/32 (9.4%)
Hypoaesthesia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		1/32 (3.1%)
Lethargy	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Psychiatric disorders
Delirium	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		2/32 (6.3%)
Depression	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Insomnia	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		2/7 (28.6%)		3/3 (100%)		0/16 (0%)		9/63 (14.3%)		4/32 (12.5%)
Renal and urinary disorders
Dysuria	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Haematuria	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		1/32 (3.1%)
Micturition urgency	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Pollakiuria	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		1/32 (3.1%)
Proteinuria	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		1/16 (6.3%)		5/63 (7.9%)		1/32 (3.1%)
Renal failure acute	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		0/32 (0%)
Urinary retention	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		0/32 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)		0/3 (0%)		1/3 (33.3%)		1/3 (33.3%)		1/7 (14.3%)		0/3 (0%)		1/16 (6.3%)		18/63 (28.6%)		11/32 (34.4%)
Dysphonia	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		3/32 (9.4%)
Dyspnoea	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		5/63 (7.9%)		3/32 (9.4%)
Epistaxis	0/4 (0%)		0/3 (0%)		0/3 (0%)		2/3 (66.7%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		3/32 (9.4%)
Haemoptysis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		0/63 (0%)		1/32 (3.1%)
Hiccups	1/4 (25%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		3/63 (4.8%)		2/32 (6.3%)
Oropharyngeal pain	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		1/16 (6.3%)		5/63 (7.9%)		4/32 (12.5%)
Pleural effusion	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		3/32 (9.4%)
Pneumonia aspiration	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Productive cough	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		1/7 (14.3%)		0/3 (0%)		1/16 (6.3%)		1/63 (1.6%)		3/32 (9.4%)
Rhinorrhoea	1/4 (25%)		0/3 (0%)		0/3 (0%)		2/3 (66.7%)		1/7 (14.3%)		0/3 (0%)		1/16 (6.3%)		2/63 (3.2%)		1/32 (3.1%)
Sputum increased	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Skin and subcutaneous tissue disorders
Alopecia	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		5/32 (15.6%)
Decubitus ulcer	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		0/32 (0%)
Dry skin	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		0/7 (0%)		1/3 (33.3%)		2/16 (12.5%)		1/63 (1.6%)		0/32 (0%)
Ecchymosis	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		1/63 (1.6%)		2/32 (6.3%)
Palmar-plantar erythrodysaesthesia syndrome	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		4/63 (6.3%)		17/32 (53.1%)
Pruritus	0/4 (0%)		0/3 (0%)		0/3 (0%)		1/3 (33.3%)		1/7 (14.3%)		0/3 (0%)		1/16 (6.3%)		10/63 (15.9%)		3/32 (9.4%)
Rash	1/4 (25%)		2/3 (66.7%)		1/3 (33.3%)		1/3 (33.3%)		1/7 (14.3%)		0/3 (0%)		5/16 (31.3%)		10/63 (15.9%)		9/32 (28.1%)
Skin exfoliation	0/4 (0%)		1/3 (33.3%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Skin lesion	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		1/3 (33.3%)		0/16 (0%)		0/63 (0%)		0/32 (0%)
Skin reaction	0/4 (0%)		0/3 (0%)		0/3 (0%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		0/16 (0%)		2/63 (3.2%)		5/32 (15.6%)
Vascular disorders
Hypertension	1/4 (25%)		1/3 (33.3%)		1/3 (33.3%)		0/3 (0%)		0/7 (0%)		0/3 (0%)		3/16 (18.8%)		10/63 (15.9%)		7/32 (21.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights