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Clinical Trial Results:
An Open-Label, Multicenter, Randomized, Phase 1b/2 Study of Golvatinib (E7050) in Combination with Sorafenib versus Sorafenib Alone as First Line Therapy in Patients with Hepatocellular Carcinoma

Summary
EudraCT number	2011-000752-41
Trial protocol	ES BE GB IT
Global end of trial date	23 Jun 2015

Results information
Results version number	v1(current)
This version publication date	10 Jun 2021
First version publication date	10 Jun 2021
Other versions

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

E7050-701

ISRCTN number

US NCT number

NCT01271504

WHO universal trial number (UTN)

Sponsor organisation name

Eisai Inc.

Sponsor organisation address

155 Tice Boulevard, Woodcliff Lake, United States, 07677

Public contact

Eisai Medical Information, Eisai Inc., +1 888-274-2378, esi_oncmedinfo@eisai.com

Scientific contact

Eisai Medical Information, Eisai Inc., +1 888-274-2378, esi_oncmedinfo@eisai.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

23 Jun 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Jun 2015

Global end of trial reached?

Yes

Global end of trial date

23 Jun 2015

Was the trial ended prematurely?

Main objective of the trial

The purpose for Phase Ib was to determine the maximum-tolerated dose (MTD)/recommended Phase 2 dose (RP2D) and characterize the pharmacokinetics (PK) of golvatinib (E7050) when administered in combination with sorafenib in subjects with locally advanced or metastatic hepatocellular carcinoma (HCC) and for Phase 2 was to evaluate the safety and tolerability of golvatinib (E7050) when administered in combination with sorafenib as compared with sorafenib alone in subjects with locally advanced or metastatic HCC.

Protection of trial subjects

This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008). - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312. - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Jul 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Ukraine: 14

Country: Number of subjects enrolled

United States: 32

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

United Kingdom: 19

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Italy: 10

Worldwide total number of subjects

102

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects took part in the study at 23 investigative sites in Belgium, Italy, Spain, the Ukraine, the United Kingdom and the United States from 19 July 2011 to 23 June 2015.

Screening details

A total of 102 subjects were enrolled and randomized in this study, out of which, 15 subjects were enrolled in Phase 1b of study, of which 14 received study drug, and 87 subjects were enrolled in Phase 2 of study, of which 84 subjects received the study drug.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg

Arm description

Subjects received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400milligram (mg), tablet, orally, twice daily in 28-days treatment cycles until the occurrence of progressive disease (PD), unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).

Arm type

Experimental

Investigational medicinal product name

Golvatinib

Investigational medicinal product code

E7050

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Golvatinib 200 mg, tablet, orally, once daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).

Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg

Arm description

Subjects received golvatinib 300 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).

Arm type

Experimental

Investigational medicinal product name

Golvatinib

Investigational medicinal product code

E7050

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Golvatinib 300 mg, tablet, orally, once daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 513 Days).

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Phase 2: Golvatinib 200 mg + Sorafenib 400 mg

Arm description

Subjects received golvatinib 200 mg, tablet, orally, once daily in combination with sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).

Arm type

Experimental

Investigational medicinal product name

Golvatinib

Investigational medicinal product code

E7050

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Phase 2: Sorafenib 400 mg

Arm description

Subjects received sorafenib 400 mg, tablet, orally, twice daily in 28-days treatment cycles until the occurrence of PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first (Up to 705 Days).

Arm type

Experimental

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Started	7	7	42	42
Completed	0	0	0	0
Not completed	7	7	42	42
Consent withdrawn by subject	-	-	1	-
Death	7	6	32	32
Administrative reasons	-	-	6	5
Lost to follow-up	-	1	3	1
Consent withdrawn by subject	-	-	-	2
Protocol deviation	-	-	-	2

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: The number of subjects in the Baseline period are those who received study treatment.

Baseline characteristics

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Reporting group title

Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 2: Golvatinib 200 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 2: Sorafenib 400 mg

Reporting group description

Reporting group values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg	Total
Number of subjects	7	7	42	42	98
Age categorical
Units: subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	52.9 ± 15.68	68.1 ± 9.56	63.2 ± 9.31	65.8 ± 8.02	-
Gender categorical
Units: Subjects
Female	1	2	10	12	25
Male	6	5	32	30	73
Ethnicity
Units: Subjects
Hispanic or Latino	0	2	1	5	8
Not Hispanic or Latino	7	5	36	36	84
Unknown or Not Reported	0	0	5	1	6
Race
Units: Subjects
American Indian or Alaska Native	0	2	0	0	2
Black or African American	0	0	4	1	5
White	7	5	37	37	86
Unknown or Not Reported	0	0	1	3	4
Asian	0	0	0	1	1

End points

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Reporting group title

Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 2: Golvatinib 200 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 2: Sorafenib 400 mg

Reporting group description

Primary: Phase 1b: Number of Subjects Who Experienced Any Dose Limiting Toxicity (DLT)

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End point title

Phase 1b: Number of Subjects Who Experienced Any Dose Limiting Toxicity (DLT) ^[1] ^[2]

End point description

DLTs were defined as clinically significant adverse events (AEs) (non-hematological, hematological and other events) occurring less than or equal to (<=) 28 days after commencing study treatment and considered to be at least possibly or probably related to study drug by the Investigator. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v.4.0). Safety analysis set included all subjects enrolled and randomized into the Phase 1b of this study, except those who dropped out of the study prior to receiving any study drug, or were without any safety assessment after first dose of study drug.

End point type

Primary

End point timeframe

Cycle 1 (Cycle length is 28 days)

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 descriptive data was planned to be analyzed for this end point.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	7
Units: subject	1	2

No statistical analyses for this end point

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7

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End point title

Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7 ^[3] ^[4]

End point description

Pharmacokinetic (PK) analysis set was defined as all subjects in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

End point type

Primary

End point timeframe

Day -7: 0-72 hours post-dose

Notes
[3] - 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 descriptive data was planned to be analyzed for this end point.
[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: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	6
Units: nanograms per milliliter (ng/mL)
arithmetic mean (standard deviation)	1330 ± 858	2320 ± 2720

No statistical analyses for this end point

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

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End point title

Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1 ^[5] ^[6]

End point description

PK analysis set was defined as all subjects in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

End point type

Primary

End point timeframe

Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Notes
[5] - 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 descriptive data was planned to be analyzed for this end point.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	6
Units: ng/mL
arithmetic mean (standard deviation)	1820 ± 750	2820 ± 3170

No statistical analyses for this end point

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

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End point title

Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1 ^[7] ^[8]

End point description

PK analysis set was defined as all subjects in the safety population who had sufficient concentration data to derive one or more of the PK parameters. Here, overall number analyzed “N” were the subjects who were evaluable for the outcome measure.

End point type

Primary

End point timeframe

Cycle 1 Day 28: 0-24 hours post-dose

Notes
[7] - 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 descriptive data was planned to be analyzed for this end point.
[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: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	4
Units: ng/mL
arithmetic mean (standard deviation)	2140 ± 757	4570 ± 3610

No statistical analyses for this end point

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7

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End point title

Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7 ^[9] ^[10]

End point description

PK analysis set was defined as all subjects in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

End point type

Primary

End point timeframe

Day -7: 0-72 hours post-dose

Notes
[9] - 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 descriptive data was planned to be analyzed for this end point.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	6
Units: hour
arithmetic mean (full range (min-max))	2 (1.03 to 24.3)	2.38 (1 to 4)

No statistical analyses for this end point

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

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End point title

Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1 ^[11] ^[12]

End point description

PK analysis set was defined as all subjects in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

End point type

Primary

End point timeframe

Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Notes
[11] - 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 descriptive data was planned to be analyzed for this end point.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	4
Units: hour
median (full range (min-max))	3 (2 to 23.8)	3.53 (2 to 24)

No statistical analyses for this end point

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

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End point title

Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1 ^[13] ^[14]

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 28: 0-24 hours post-dose

Notes
[13] - 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 descriptive data was planned to be analyzed for this end point.
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	4
Units: hour
median (full range (min-max))	2.98 (1.08 to 4.03)	5.01 (0.833 to 23.5)

No statistical analyses for this end point

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7

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End point title

Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7 ^[15] ^[16]

End point description

PK analysis set was defined as all subjects in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

End point type

Primary

End point timeframe

Day -7: 0-72 hours post-dose

Notes
[15] - 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 descriptive data was planned to be analyzed for this end point.
[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: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	6
Units: nanogramhour per milliliter(ngh/mL)
arithmetic mean (standard deviation)	30400 ± 18900	47200 ± 37500

No statistical analyses for this end point

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

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End point title

Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1 ^[17] ^[18]

End point description

PK analysis set was defined as all subjects in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

End point type

Primary

End point timeframe

Cycle 1 Day 1: 0-24 hours post-dose (Cycle length is 28 days)

Notes
[17] - 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 descriptive data was planned to be analyzed for this end point.
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 1b arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	6
Units: ng*h/mL
arithmetic mean (standard deviation)	24000 ± 14300	36800 ± 38000

No statistical analyses for this end point

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

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End point title

End point description

End point type

Primary

End point timeframe

Cycle 1 Day 28: 0-24 hours post-dose (Cycle length is 28 days)

Notes
[19] - 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 descriptive data was planned to be analyzed for this end point.
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	4
Units: ng*h/mL
arithmetic mean (standard deviation)	35300 ± 16700	68700 ± 72500

No statistical analyses for this end point

Primary: Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7

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End point title

Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7 ^[21] ^[22]

End point description

PK analysis set was defined as all subjects in the safety population who had sufficient concentration data to derive one or more of the PK parameters.

End point type

Primary

End point timeframe

Day -7: 0-72 hours post-dose

Notes
[21] - 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 descriptive data was planned to be analyzed for this end point.
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg
Number of subjects analysed	7	6
Units: hour
arithmetic mean (standard deviation)	38.1 ± 6.82	35.9 ± 11.7

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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End point title

Phase 2: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) ^[23] ^[24]

End point description

Safety analysis set included all subjects enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.

End point type

Primary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Notes
[23] - 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 descriptive data was planned to be analyzed for this end point.
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	42
Units: subjects
TEAEs	42	40
SAEs	20	17

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With AEs by Severity Grades

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End point title

Phase 2: Number of Subjects With AEs by Severity Grades ^[25] ^[26]

End point description

AE severity was graded using CTCAE version 4.0, where Grade 1 = mild, Grade 2 = moderate, Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death related to the AE. All AEs graded as 4 or 5 were considered to be serious. Higher grade indicates more severe condition. Safety analysis set included all subjects enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug. Here, overall number analyzed are those subjects who were evaluable for this outcome measure.

End point type

Primary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Notes
[25] - 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 descriptive data was planned to be analyzed for this end point.
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	40
Units: subjects
Any AE: Grade 1	0	2
Any AE: Grade 2	4	6
Any AE: Grade 3	24	25
Any AE: Grade 4	6	5
Any AE: Grade 5	8	2

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Adverse Events Related to Vital Signs

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End point title

Phase 2: Number of Subjects With Adverse Events Related to Vital Signs ^[27] ^[28]

End point description

Number of subjects are reported with AEs related to Vital signs including body temperature, respiratory rate, heart rate, height, and weight. Safety analysis set included all subjects enrolled and randomized to treatment in the Phase 2 of this study, except for those who dropped out prior to receiving any study drug, or were without any safety assessment following the first dose of study drug.

End point type

Primary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Notes
[27] - 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 descriptive data was planned to be analyzed for this end point.
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	42
Units: subjects	2	0

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Clinically Significant Change From Baseline in Blood Pressure Including Systolic and Diastolic Blood Pressures

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End point title

Phase 2: Number of Subjects With Clinically Significant Change From Baseline in Blood Pressure Including Systolic and Diastolic Blood Pressures ^[29] ^[30]

End point description

End point type

Primary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Notes
[29] - 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 descriptive data was planned to be analyzed for this end point.
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	42
Units: subjects	0	0

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)

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End point title

Phase 2: Number of Subjects With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ^[31] ^[32]

End point description

Number of subjects with worst shifts post baseline in ECOG-PS levels were reported. ECOG had 6 levels (0-5). Level 0 is best status (fully active, able to carry on all pre-disease performance without restriction);Level 1: mildly restricted (Restricted in physically strenuous activity but ambulatory ad able to carry out work of a light/sedentary nature, e.g. light house work, office work);Level 2: more restricted (Ambulatory and capable of selfcare but unable to carry out any work activities;up and about more than 50% of waking hours); Level 3: restricted (Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours);Level 4: highly restricted (completely disabled; cannot carry on any selfcare; totally confined to bed/chair) and Level 5:death. Safety analysis set:all subjects enrolled and randomized to treatment in Phase 2 of study, except who dropped out prior to receiving study drug/were without any safety assessment following first dose of study drug.

End point type

Primary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Notes
[31] - 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 descriptive data was planned to be analyzed for this end point.
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	42
Units: Subjects
ECOG PS Level change from 0 to 1	7	4
ECOG PS Level change from 0 to 2	3	7
ECOG PS Level change from 0 to 3	3	0
ECOG PS Level change from 1 to 2	4	6
ECOG PS Level change from 0 to 4	0	1
ECOG PS Level change from 1 to 3	0	5

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values

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End point title

Phase 2: Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values ^[33] ^[34]

End point description

End point type

Primary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Notes
[33] - 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 descriptive data was planned to be analyzed for this end point.
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	42
Units: subjects	0	0

No statistical analyses for this end point

Primary: Phase 2: Number of Subjects With Markedly Abnormal Change From Baseline in Electrocardiograms (ECGs) Parameters

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End point title

Phase 2: Number of Subjects With Markedly Abnormal Change From Baseline in Electrocardiograms (ECGs) Parameters ^[35] ^[36]

End point description

End point type

Primary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Notes
[35] - 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 descriptive data was planned to be analyzed for this end point.
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	42
Units: subjects	0	0

No statistical analyses for this end point

Secondary: Phase 2: Time to Progression (TTP)

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End point title

Phase 2: Time to Progression (TTP) ^[37]

End point description

TTP was defined as the time from the date of randomization until the date of PD of such subject’s disease based on independent assessments according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. PD was defined as at least a 20% increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. TTP was estimated and analyzed using Kaplan-Meier (K-M) method. Modified Intent-to-Treat (MITT) set included all subjects randomized in the applicable study arm, except a subject who dropped out of such arm prior to receiving any comparator or investigative drug. Here ‘N’ (Overall number of subjects analyzed) signifies subjects with events (PD).

End point type

Secondary

End point timeframe

From the date of randomization until the date of PD (up to approximately 3 years 11 months)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	31	36
Units: weeks
median (confidence interval 95%)	10.29 (8.57 to 17.14)	16.00 (8.57 to 23.29)

Statistical analysis 1

Comparison groups

Phase 2: Golvatinib 200 mg + Sorafenib 400 mg v Phase 2: Sorafenib 400 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.56

upper limit

1.5

Secondary: Phase 2: Progression Free Survival (PFS)

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End point title

Phase 2: Progression Free Survival (PFS) ^[38]

End point description

PFS was defined as the time from the date of randomization of a subject until (1) the date of first documented progression (2) the date of such subject's death due to any cause based on independent assessments according to RECIST v. 1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. PFS was estimated and analyzed using KM method. MITT analysis set included all subjects randomized in the applicable study arm, except a subject who dropped out of such arm prior to receiving any comparator or investigative drug. Here ‘N’ (Overall number of subjects analyzed) signifies subjects with events (PD or/and death).

End point type

Secondary

End point timeframe

From the date of randomization until the earlier of the following two events: the date of PD or the date of death (Up to approximately 3 years 11 months)

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	32	37
Units: weeks
median (confidence interval 95%)	10.29 (8.14 to 17.14)	15.57 (8.57 to 23.14)

Statistical Analysis 1

Comparison groups

Phase 2: Golvatinib 200 mg + Sorafenib 400 mg v Phase 2: Sorafenib 400 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.5

Secondary: Phase 2: Percentage of Subjects With PFS at Week 12

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End point title

Phase 2: Percentage of Subjects With PFS at Week 12 ^[39]

End point description

The PFS rate at week 12 was defined as the percentage of subjects who were still alive without disease progression at 12 weeks from the date of randomization. PFS was defined as the time from the date of randomization of a subject until (1) the date of first documented progression (2) the date of such subject’s death due to any cause based on independent assessments according to RECIST v. 1.1. PD was defined as at least a 20% increase or 5 mm increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions. MITT analysis set included all subjects randomized in the applicable study arm, except a subject who dropped out of such arm prior to receiving any comparator or investigative drug. Here ‘N’ (overall number of subjects analyzed) signifies subjects with events (PD or/and death).

End point type

Secondary

End point timeframe

At 12 weeks

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	32	37
Units: percentage of subject
number (not applicable)	47.4	57.5

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[40]

End point description

OS was defined as the time from the date of randomization until the date of death. Subjects were censored at the date of last known alive. OS was analyzed using K-M method. MITT analysis set included all subjects randomized in the applicable study arm, except a subject who dropped out of such arm prior to receiving any comparator or investigative drug.

End point type

Secondary

End point timeframe

From the date of randomization until the date of death (Up to approximately 3 years 11 months)

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	42
Units: weeks
median (confidence interval 95%)	27.86 (20.86 to 67.71)	37.71 (23.29 to 57.00)

Statistical Analysis 1

Comparison groups

Phase 2: Sorafenib 400 mg v Phase 2: Golvatinib 200 mg + Sorafenib 400 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.99

Confidence interval

level

95%

sides

2-sided

lower limit

0.6

upper limit

1.62

Secondary: Phase 2: Percentage of Subjects With Overall Response

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End point title

Phase 2: Percentage of Subjects With Overall Response ^[41]

End point description

Overall response rate was defined as percentage of subjects with best confirmed response (CR) or partial response (PR) assessed by investigator per RECIST v1.1. A confirmatory scan was required after no less than 4 weeks and no later than 8 weeks, starting on the date that the response was first recorded. CR was defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<)10 mm. PR was defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. MITT analysis set included all subjects randomized in the applicable study arm, except a subject who dropped out of such arm prior to receiving any comparator or investigative drug.

End point type

Secondary

End point timeframe

From the date of randomization until disease progression or death (Up to approximately 3 years 11 months)

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This outcome measure was planned to be assessed only for subjects treated in Phase 2 arm.

End point values	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Number of subjects analysed	42	42
Units: percentage of subject
number (confidence interval 95%)	4.8 (0.0 to 11.2)	4.8 (-1.7 to 11.2)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to 30 days after last dose of study drug (up to approximately 3 years 11 months)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 2: Golvatinib 200 mg + Sorafenib 400 mg

Reporting group description

Reporting group title

Phase 2: Sorafenib 400 mg

Reporting group description

Serious adverse events	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 7 (57.14%)	3 / 7 (42.86%)	20 / 42 (47.62%)	17 / 42 (40.48%)
number of deaths (all causes)	7	6	32	32
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma Gastric
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant Neoplasm Progression
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Vascular disorders
Aneurysm Ruptured
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Hypertensive Crisis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
General Physical Health Deterioration
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema Peripheral
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional State
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Transaminases Increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Spinal Compression Fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac Arrest
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Encephalopathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic Stroke
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Metabolic Encephalopathy
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile Neutropenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Distension
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	3 / 42 (7.14%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular Perforation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal Varices Haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis Acute
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic Failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver Disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis Acneiform
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis Psoriasiform
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Palmar-Plantar Erythrodysaesthesia Syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephropathy Toxic
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal Failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Renal Impairment
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia Urinary Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infected Skin Ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infective Exacerbation Of Chronic Obstructive Airways Disease
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver Abscess
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Scrotal Abscess
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	3 / 42 (7.14%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Septic Shock
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Phase 1b: Golvatinib 200 mg + Sorafenib 400 mg	Phase 1b: Golvatinib 300 mg + Sorafenib 400 mg	Phase 2: Golvatinib 200 mg + Sorafenib 400 mg	Phase 2: Sorafenib 400 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	6 / 7 (85.71%)	40 / 42 (95.24%)	40 / 42 (95.24%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Keratoacanthoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	7	0	1
Paraneoplastic syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Deep vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Flushing
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	0	0	2
Hot flush
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Hypertension
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	8 / 42 (19.05%)	9 / 42 (21.43%)
occurrences all number	0	1	13	12
Hypotension
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	0	0	2	2
Orthostatic hypotension
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1	0	1
Pallor
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Vascular insufficiency
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	12 / 42 (28.57%)	12 / 42 (28.57%)
occurrences all number	2	0	17	19
Chest Pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Chills
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	1	0	0	1
Early satiety
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Face oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Facial pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Fatigue
subjects affected / exposed	1 / 7 (14.29%)	4 / 7 (57.14%)	13 / 42 (30.95%)	12 / 42 (28.57%)
occurrences all number	1	6	21	13
Generalised Oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Hypothermia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	2	0
Influenza like illness
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Injection site haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Localised oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Malaise
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	2 / 42 (4.76%)
occurrences all number	0	0	1	2
Mucosal Inflammation
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	3 / 42 (7.14%)	3 / 42 (7.14%)
occurrences all number	1	1	4	3
Oedema
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	1	0	2
Oedema Peripheral
subjects affected / exposed	2 / 7 (28.57%)	3 / 7 (42.86%)	5 / 42 (11.90%)	3 / 42 (7.14%)
occurrences all number	8	6	15	6
Pain
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	2	0	0	2
Pyrexia
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	3 / 42 (7.14%)	6 / 42 (14.29%)
occurrences all number	4	1	3	10
Thirst
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Vessel Puncture Site Bruise
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Xerosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Immune system disorders
Drug Hypersensitivity
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Reproductive system and breast disorders
Erectile dysfunction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Genital lesion
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Nipple pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	3	0
Prostatic obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Testicular pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Testicular swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	4
Vaginal Haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	3	0	0
Vaginal Polyp
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Vulvovaginal Discomfort
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Cough
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	3 / 42 (7.14%)	4 / 42 (9.52%)
occurrences all number	0	0	3	4
Dysphonia
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	1 / 42 (2.38%)	5 / 42 (11.90%)
occurrences all number	1	1	1	5
Dyspnoea
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	7 / 42 (16.67%)
occurrences all number	1	0	1	7
Dyspnoea Exertional
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 42 (0.00%)
occurrences all number	0	0	2	0
Epistaxis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 42 (4.76%)	4 / 42 (9.52%)
occurrences all number	1	0	2	4
Haemoptysis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	0	0	2	1
Hiccups
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	1	0	0	1
Nasal dryness
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 42 (2.38%)	1 / 42 (2.38%)
occurrences all number	0	1	1	1
Paranasal sinus hypersecretion
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Pneumonitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Productive cough
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Pulmonary oedema
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Throat tightness
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Anxiety
subjects affected / exposed	3 / 7 (42.86%)	0 / 7 (0.00%)	1 / 42 (2.38%)	2 / 42 (4.76%)
occurrences all number	3	0	1	2
Confusional state
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Depressed mood
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Depression
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	0	0	2	1
Insomnia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	5 / 42 (11.90%)	2 / 42 (4.76%)
occurrences all number	0	0	5	2
Investigations
Alanine Aminotransferase Increased
subjects affected / exposed	1 / 7 (14.29%)	4 / 7 (57.14%)	7 / 42 (16.67%)	8 / 42 (19.05%)
occurrences all number	1	15	12	11
Ammonia Increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 42 (2.38%)	1 / 42 (2.38%)
occurrences all number	0	1	1	1
Amylase Increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	4 / 42 (9.52%)
occurrences all number	2	0	6	7
Aspartate Aminotransferase Increased
subjects affected / exposed	2 / 7 (28.57%)	5 / 7 (71.43%)	11 / 42 (26.19%)	13 / 42 (30.95%)
occurrences all number	3	22	17	20
Bacterial test positive
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Blood Bilirubin Increased
subjects affected / exposed	3 / 7 (42.86%)	1 / 7 (14.29%)	3 / 42 (7.14%)	5 / 42 (11.90%)
occurrences all number	4	2	4	11
Blood Creatinine Increased
subjects affected / exposed	3 / 7 (42.86%)	2 / 7 (28.57%)	1 / 42 (2.38%)	2 / 42 (4.76%)
occurrences all number	4	5	1	2
Blood Lactate Dehydrogenase Increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	2 / 42 (4.76%)
occurrences all number	1	0	1	2
Blood Thyroid Stimulating Hormone Increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	2	0	0
Blood albumin decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Blood urine present
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Body temperature increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Breath sounds abnormal
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	2
Globulins increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Heart Rate Increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	2	0	0
Hepatitis C Virus Test Positive
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Lipase Increased
subjects affected / exposed	1 / 7 (14.29%)	3 / 7 (42.86%)	1 / 42 (2.38%)	7 / 42 (16.67%)
occurrences all number	9	3	8	16
Liver Palpable Subcostal
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Oxygen saturation decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Platelet Count Decreased
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	2	0	0
Protein urine present
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	1 / 42 (2.38%)
occurrences all number	0	0	1	1
Serum ferritin increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Thyroxine increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Transaminases increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	2 / 42 (4.76%)
occurrences all number	0	0	1	2
Urine analysis abnormal
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Weight Decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	6 / 42 (14.29%)	3 / 42 (7.14%)
occurrences all number	0	0	7	3
Blood Alkaline Phosphatase Increased
subjects affected / exposed	3 / 7 (42.86%)	4 / 7 (57.14%)	6 / 42 (14.29%)	11 / 42 (26.19%)
occurrences all number	6	15	10	11
Blood potassium increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	2
Eye Contusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Fall
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	1	0	0	1
Spinal compression fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Subcutaneous haematoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Wound
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	2
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Cardiac failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Sinus tachycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Nervous system disorders
Aphonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Balance disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Dementia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Dizziness
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	1	1	0	2
Dysgeusia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	4 / 42 (9.52%)	3 / 42 (7.14%)
occurrences all number	1	0	4	3
Headache
subjects affected / exposed	0 / 7 (0.00%)	3 / 7 (42.86%)	8 / 42 (19.05%)	4 / 42 (9.52%)
occurrences all number	0	3	17	5
Hepatic Encephalopathy
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	3 / 42 (7.14%)
occurrences all number	1	7	0	5
Lethargy
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	3 / 42 (7.14%)	2 / 42 (4.76%)
occurrences all number	0	0	4	2
Memory Impairment
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	1	0	1	0
Mental impairment
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Monoparesis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Neuropathy Peripheral
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Paraesthesia
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	2 / 42 (4.76%)	0 / 42 (0.00%)
occurrences all number	1	1	2	0
Restless Legs Syndrome
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Somnolence
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Syncope
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 7 (14.29%)	3 / 7 (42.86%)	6 / 42 (14.29%)	3 / 42 (7.14%)
occurrences all number	3	19	8	8
Anaemia Macrocytic
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Lymphadenopathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Lymphopenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1	0	5
Neutropenia
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	1 / 42 (2.38%)	1 / 42 (2.38%)
occurrences all number	4	5	3	1
Thrombocytopenia
subjects affected / exposed	1 / 7 (14.29%)	3 / 7 (42.86%)	4 / 42 (9.52%)	4 / 42 (9.52%)
occurrences all number	2	14	4	8
Leukopenia
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	5	0	0
Ear and labyrinth disorders
Ear pruritus
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
External ear inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Eye disorders
Dry Eye
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	2 / 42 (4.76%)	0 / 42 (0.00%)
occurrences all number	0	1	2	0
Eye pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Vision Blurred
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Gastrointestinal disorders
Abdominal Discomfort
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 42 (2.38%)	3 / 42 (7.14%)
occurrences all number	0	1	1	3
Abdominal Pain
subjects affected / exposed	2 / 7 (28.57%)	5 / 7 (71.43%)	8 / 42 (19.05%)	7 / 42 (16.67%)
occurrences all number	5	10	8	9
Abdominal Pain Lower
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Abdominal Pain Upper
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	8 / 42 (19.05%)	5 / 42 (11.90%)
occurrences all number	0	1	9	8
Abdominal distension
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	0	0	2	2
Abdominal hernia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Anal Fissure
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Anorectal Discomfort
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Ascites
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	8 / 42 (19.05%)	5 / 42 (11.90%)
occurrences all number	0	0	12	10
Constipation
subjects affected / exposed	3 / 7 (42.86%)	1 / 7 (14.29%)	7 / 42 (16.67%)	5 / 42 (11.90%)
occurrences all number	3	1	7	6
Diarrhoea
subjects affected / exposed	2 / 7 (28.57%)	6 / 7 (85.71%)	26 / 42 (61.90%)	22 / 42 (52.38%)
occurrences all number	6	30	43	41
Dry Mouth
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	3 / 42 (7.14%)	3 / 42 (7.14%)
occurrences all number	1	1	3	4
Dysphagia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 42 (2.38%)	2 / 42 (4.76%)
occurrences all number	0	1	1	2
Enterocolitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Faecal incontinence
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Faeces soft
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Food poisoning
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	2	0
Gastric ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Gastritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Gastrooesophageal Reflux Disease
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	2	1	0
Glossitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Haemorrhoids
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	0	0	2	1
Hypoaesthesia Oral
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Lip blister
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Malabsorption
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Melaena
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Nausea
subjects affected / exposed	6 / 7 (85.71%)	5 / 7 (71.43%)	15 / 42 (35.71%)	12 / 42 (28.57%)
occurrences all number	6	19	22	16
Rectal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	2
Retching
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	2	1	0
Stomatitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	6 / 42 (14.29%)	4 / 42 (9.52%)
occurrences all number	1	0	7	6
Toothache
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Varices oesophageal
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Vomiting
subjects affected / exposed	2 / 7 (28.57%)	5 / 7 (71.43%)	14 / 42 (33.33%)	7 / 42 (16.67%)
occurrences all number	9	14	20	10
Dyspepsia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	5 / 42 (11.90%)	2 / 42 (4.76%)
occurrences all number	1	0	5	2
Flatulence
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	1	0	1	0
Gastric hypomotility
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Hepatic cirrhosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Hepatic function abnormal
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	2
Hepatic pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Hepatotoxicity
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Hyperbilirubinaemia
subjects affected / exposed	1 / 7 (14.29%)	4 / 7 (57.14%)	5 / 42 (11.90%)	6 / 42 (14.29%)
occurrences all number	11	10	8	8
Jaundice
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Liver disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Liver tenderness
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Portal vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	8 / 42 (19.05%)	2 / 42 (4.76%)
occurrences all number	1	0	10	2
Blister
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	4 / 42 (9.52%)
occurrences all number	0	0	0	4
Decubitus ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Dermatitis acneiform
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	3	0	0	0
Dermatitis psoriasiform
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	2	0	0
Diabetic ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Dry skin
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 42 (4.76%)	2 / 42 (4.76%)
occurrences all number	1	0	2	3
Erythema
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	3 / 42 (7.14%)	1 / 42 (2.38%)
occurrences all number	0	0	3	1
Hyperhidrosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Hyperkeratosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	3 / 42 (7.14%)
occurrences all number	0	0	0	3
Night sweats
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Pain of skin
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	4 / 42 (9.52%)
occurrences all number	0	0	0	5
Palmar-Plantar Erythrodysaesthesia Syndrome
subjects affected / exposed	2 / 7 (28.57%)	3 / 7 (42.86%)	15 / 42 (35.71%)	9 / 42 (21.43%)
occurrences all number	5	14	31	16
Plantar erythema
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	0	0	2
Pruritus
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	9 / 42 (21.43%)	3 / 42 (7.14%)
occurrences all number	1	2	10	3
Rash
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	13 / 42 (30.95%)	9 / 42 (21.43%)
occurrences all number	0	1	19	13
Rash erythematous
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Rash generalised
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	1	1	0
Rash maculo-papular
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	2 / 42 (4.76%)	0 / 42 (0.00%)
occurrences all number	1	4	2	0
Skin exfoliation
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	0	0	5
Skin fissures
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Skin irritation
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Skin toxicity
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Skin ulcer
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	1 / 42 (2.38%)
occurrences all number	0	0	1	1
Urticaria
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	1	0	1	0
Dermatitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	0	0	2	1
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Nephrolithiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Nocturia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Pollakiuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	2 / 42 (4.76%)
occurrences all number	0	0	2	2
Polyuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Proteinuria
subjects affected / exposed	2 / 7 (28.57%)	2 / 7 (28.57%)	1 / 42 (2.38%)	2 / 42 (4.76%)
occurrences all number	9	5	1	3
Renal Failure Chronic
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1	0	1
Renal failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Renal failure acute
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	0	0	2
Urinary Incontinence
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	1	0	1
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Hypothyroidism
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	0	0	2
Arthropathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Axillary mass
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Back Pain
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	3 / 42 (7.14%)	7 / 42 (16.67%)
occurrences all number	5	2	3	7
Bone Pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Bursitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Groin pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Joint swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Muscle Spasms
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	3 / 42 (7.14%)	1 / 42 (2.38%)
occurrences all number	1	1	3	1
Muscular Weakness
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 42 (0.00%)	2 / 42 (4.76%)
occurrences all number	0	5	0	2
Musculoskeletal Chest Pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	5 / 42 (11.90%)
occurrences all number	0	0	1	7
Musculoskeletal Pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	1	0	1	0
Musculoskeletal discomfort
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Myalgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Myositis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	2	0
Neck Pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	1	0	0
Pain In Extremity
subjects affected / exposed	2 / 7 (28.57%)	0 / 7 (0.00%)	2 / 42 (4.76%)	5 / 42 (11.90%)
occurrences all number	2	0	3	8
Spinal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Tenosynovitis stenosans
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Infections and infestations
Acid fast bacilli infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Bronchitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 42 (0.00%)
occurrences all number	1	0	2	0
Cellulitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	2
Cystitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Fungal Skin Infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Gastroenteritis Viral
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Influenza
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Localised infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Nasopharyngitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	1	0	0	0
Oesophageal Candidiasis
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	1	0	2	1
Oral candidiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	0	0	2	1
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	1	1	0
Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Tooth abscess
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Upper Respiratory Tract Infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	1 / 42 (2.38%)	1 / 42 (2.38%)
occurrences all number	0	1	1	1
Urinary Tract Infection
subjects affected / exposed	2 / 7 (28.57%)	1 / 7 (14.29%)	2 / 42 (4.76%)	6 / 42 (14.29%)
occurrences all number	2	1	3	8
Viral diarrhoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Decreased Appetite
subjects affected / exposed	1 / 7 (14.29%)	3 / 7 (42.86%)	13 / 42 (30.95%)	15 / 42 (35.71%)
occurrences all number	1	5	19	19
Dehydration
subjects affected / exposed	0 / 7 (0.00%)	2 / 7 (28.57%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	6	0	1
Gout
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
Hyperglycaemia
subjects affected / exposed	1 / 7 (14.29%)	2 / 7 (28.57%)	2 / 42 (4.76%)	1 / 42 (2.38%)
occurrences all number	1	4	2	1
Hyperkalaemia
subjects affected / exposed	1 / 7 (14.29%)	4 / 7 (57.14%)	1 / 42 (2.38%)	3 / 42 (7.14%)
occurrences all number	2	8	1	3
Hyperlipasaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	2 / 42 (4.76%)	0 / 42 (0.00%)
occurrences all number	0	0	2	0
Hypermagnesaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	1	0	0	1
Hyperuricaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Hypervolaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Hypoalbuminaemia
subjects affected / exposed	3 / 7 (42.86%)	4 / 7 (57.14%)	1 / 42 (2.38%)	3 / 42 (7.14%)
occurrences all number	7	28	1	6
Hypocalcaemia
subjects affected / exposed	3 / 7 (42.86%)	4 / 7 (57.14%)	3 / 42 (7.14%)	2 / 42 (4.76%)
occurrences all number	7	15	5	2
Hypokalaemia
subjects affected / exposed	1 / 7 (14.29%)	4 / 7 (57.14%)	3 / 42 (7.14%)	2 / 42 (4.76%)
occurrences all number	5	5	3	9
Hypomagnesaemia
subjects affected / exposed	2 / 7 (28.57%)	2 / 7 (28.57%)	2 / 42 (4.76%)	0 / 42 (0.00%)
occurrences all number	5	4	2	0
Hyponatraemia
subjects affected / exposed	2 / 7 (28.57%)	2 / 7 (28.57%)	2 / 42 (4.76%)	2 / 42 (4.76%)
occurrences all number	4	10	4	2
Hypophosphataemia
subjects affected / exposed	0 / 7 (0.00%)	3 / 7 (42.86%)	4 / 42 (9.52%)	0 / 42 (0.00%)
occurrences all number	0	3	5	0
Malnutrition
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	1 / 42 (2.38%)	0 / 42 (0.00%)
occurrences all number	0	0	1	0
Metabolic acidosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 7 (0.00%)	0 / 42 (0.00%)	1 / 42 (2.38%)
occurrences all number	0	0	0	1
hypoproteinaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0
Fluid Overload
subjects affected / exposed	0 / 7 (0.00%)	1 / 7 (14.29%)	0 / 42 (0.00%)	0 / 42 (0.00%)
occurrences all number	0	1	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Dec 2010

Amendment 1: The purpose of this amendment was mainly to change planned upper dose for the Phase Ib portion of the study was from 360 mg daily to 400 mg daily.

22 Feb 2011

Amendment 2: The purpose of this amendment was mainly to add additional PK sampling times, continuing treatment from sorafenib with or without golvatinib to golvatinib with or without sorafenib for subjects who were experiencing clinical benefit after 6 cycles, added efficacy endpoints and removed history of portal vein thrombosis as an exclusion criterion.

20 Jun 2011

Amendment 3: The purpose of this amendment was mainly to allow subjects on golvatinib who experienced nausea to take golvatinib with food and antiemetic therapy per local guidelines and Investigator practice and updated definition of an SAE to reflect new FDA guidelines.

13 Sep 2012

Amendment 4: The purpose of this amendment was mainly to add disease progression to Section 4.4.3 “Patient Withdrawal and provided the dose for the Phase 2 portion of the study.

05 Nov 2014

Amendment 5: The purpose of this amendment was mainly to remove the long-term overall survival follow-up.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: An Open-Label, Multicenter, Randomized, Phase 1b/2 Study of Golvatinib (E7050) in Combination with Sorafenib versus Sorafenib Alone as First Line Therapy in Patients with Hepatocellular Carcinoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Number of Subjects Who Experienced Any Dose Limiting Toxicity (DLT)

Primary: Phase 1b: Number of Subjects Who Experienced Any Dose Limiting Toxicity (DLT)

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day -7

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Primary: Phase 1b: Cmax: Maximum Observed Plasma Concentration for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day -7

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Primary: Phase 1b: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day -7

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 1 Cycle 1

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Primary: Phase 1b: AUCt: Area Under the Plasma Concentration-time Curve From Time 0 to Time t Over the Dosing Interval for Golvatinib When Administered in Combination With Sorafenib at Day 28 Cycle 1

Primary: Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7

Primary: Phase 1b: t1/2: Terminal Elimination Half-life for Golvatinib When Administered in Combination With Sorafenib at Day -7

Primary: Phase 2: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Primary: Phase 2: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Primary: Phase 2: Number of Subjects With AEs by Severity Grades

Primary: Phase 2: Number of Subjects With AEs by Severity Grades

Primary: Phase 2: Number of Subjects With Adverse Events Related to Vital Signs

Primary: Phase 2: Number of Subjects With Adverse Events Related to Vital Signs

Primary: Phase 2: Number of Subjects With Clinically Significant Change From Baseline in Blood Pressure Including Systolic and Diastolic Blood Pressures

Primary: Phase 2: Number of Subjects With Clinically Significant Change From Baseline in Blood Pressure Including Systolic and Diastolic Blood Pressures

Primary: Phase 2: Number of Subjects With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)

Primary: Phase 2: Number of Subjects With Worst Shifts Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG-PS)

Primary: Phase 2: Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values

Primary: Phase 2: Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values

Primary: Phase 2: Number of Subjects With Markedly Abnormal Change From Baseline in Electrocardiograms (ECGs) Parameters

Primary: Phase 2: Number of Subjects With Markedly Abnormal Change From Baseline in Electrocardiograms (ECGs) Parameters

Secondary: Phase 2: Time to Progression (TTP)

Secondary: Phase 2: Time to Progression (TTP)

Secondary: Phase 2: Progression Free Survival (PFS)

Secondary: Phase 2: Progression Free Survival (PFS)

Secondary: Phase 2: Percentage of Subjects With PFS at Week 12

Secondary: Phase 2: Percentage of Subjects With PFS at Week 12

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Percentage of Subjects With Overall Response

Secondary: Phase 2: Percentage of Subjects With Overall Response

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
An Open-Label, Multicenter, Randomized, Phase 1b/2 Study of Golvatinib (E7050) in Combination with Sorafenib versus Sorafenib Alone as First Line Therapy in Patients with Hepatocellular Carcinoma