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Clinical Trial Results:
Randomized, Double-Blind Phase 2 Study of Axitinib (AG 013736) With or Without Dose Titration in Patients with Metastatic Renal Cell Carcinoma

Summary
EudraCT number	2008-007786-23
Trial protocol	ES CZ DE
Global end of trial date	29 Feb 2016

Results information
Results version number	v1(current)
This version publication date	16 Mar 2017
First version publication date	16 Mar 2017
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

A4061046

ISRCTN number

US NCT number

NCT00835978

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 Est 42nd Street, New York, United States, 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.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

29 Feb 2016

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Feb 2016

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to prospectively evaluate the safety and efficacy of axitinib with and without dose titration in patients with metastatic renal cell carcinoma (mRCC)

Protection of trial subjects

The study was conducted in accordance with legal and regulatory requirements, as well as the ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki as amended by the 52nd World Medical Association (WMA) General Assembly in October 20001. Informed consent was obtained from each patient (or patient’s legally authorized representative) before the patient was admitted to the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

11 Sep 2009

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Czech Republic: 18

Country: Number of subjects enrolled

Germany: 12

Country: Number of subjects enrolled

Japan: 44

Country: Number of subjects enrolled

Russian Federation: 45

Country: Number of subjects enrolled

Spain: 4

Country: Number of subjects enrolled

United States: 90

Worldwide total number of subjects

213

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)

136

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 49 centers in Czech Republic, Germany, Japan, Russian Federation, Spain, and United States (US).

Screening details

Participants were enrolled in a 4-week lead-in period, during which they received axitinib 5 milligram (mg) twice a day (BID). After the lead-in period, participants meeting randomization criteria were then randomized to one of the two treatment arms. Participants, not meeting criteria, continued study without dose titration (non-randomized arm).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

The dose titration in the randomized arms (Arm A and B) was double-blinded. The interactive voice response system (IVRS) assigned study treatment on Cycle 2 Day 1. The IVRS maintained the blind.

Are arms mutually exclusive

Yes

Active Titration Arm

Arm description

Participants initially received axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator’s clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).

Arm type

Experimental

Investigational medicinal product name

Axitinib

Investigational medicinal product code

AG-013736

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Axitinib 5 mg twice a day (BID) + axitinib (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator’s clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).

Placebo Titration Arm

Arm description

Participants initially received axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator’s clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Axitinib 5mg BID + placebo (blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + placebo (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator’s clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + placebo [blinded therapy] 5 mg BID).

Non-randomized Arm

Arm description

Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.

Arm type

Experimental

Investigational medicinal product name

Axitinib

Investigational medicinal product code

AG-013736

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants not eligible for randomization received axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.

Discontinued Prior to Randomization

Arm description

Participants who discontinued before they were randomized to any of the treatment or non-randomized arms.

Arm type

Experimental

Investigational medicinal product name

Axitinib

Investigational medicinal product code

AG-013736

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Participants who discontinued before they were randomized to any of the treatment or non-randomized arms.

Number of subjects in period 1	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization
Started	56	56	91	10
Treated	56	56	91	10
Completed	0	0	0	0
Not completed	56	56	91	10
Consent withdrawn by subject	-	3	-	5
Adverse event, non-fatal	1	-	1	-
Death	33	40	49	4
Not Specified	5	1	8	-
Study terminated by sponsor	12	8	30	-
Lost to follow-up	3	4	2	1
Objective progression or relapse	2	-	1	-

Baseline characteristics

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Reporting group title

Active Titration Arm

Reporting group description

Reporting group title

Placebo Titration Arm

Reporting group description

Reporting group title

Non-randomized Arm

Reporting group description

Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.

Reporting group title

Discontinued Prior to Randomization

Reporting group description

Participants who discontinued before they were randomized to any of the treatment or non-randomized arms.

Reporting group values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization	Total
Number of subjects	56	56	91	10	213
Age Categorical
Units: Subjects
< 65 Years	38	38	54	6	136
>= 65 Years	18	18	37	4	77
Age Continuous
Units: Years
arithmetic mean (standard deviation)	59.7 ( 10.2 )	59.6 ( 10.5 )	62.9 ( 8.9 )	62.9 ( 7.5 )	-
Gender, Male/Female
Units: Subjects
Female	19	11	36	4	70
Male	37	45	55	6	143

Subject analysis set title

All Participants

Subject analysis set type

Per protocol

Subject analysis set description

All enrolled participants (randomized and non-randomized) who received at least one dose of study medication.

Subject analysis sets values	All Participants
Number of subjects	213
Age Categorical
Units: Subjects
< 65 Years
>= 65 Years
Age Continuous
Units: Years
arithmetic mean (standard deviation)	61.2 ( 9.7 )
Gender, Male/Female
Units: Subjects
Female
Male

End points

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Reporting group title

Active Titration Arm

Reporting group description

Reporting group title

Placebo Titration Arm

Reporting group description

Reporting group title

Non-randomized Arm

Reporting group description

Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.

Reporting group title

Discontinued Prior to Randomization

Reporting group description

Participants who discontinued before they were randomized to any of the treatment or non-randomized arms.

Subject analysis set title

All Participants

Subject analysis set type

Per protocol

Subject analysis set description

All enrolled participants (randomized and non-randomized) who received at least one dose of study medication.

Primary: Objective Response Rate (ORR) - Percentage of Participants With Objective Response

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End point title

Objective Response Rate (ORR) - Percentage of Participants With Objective Response ^[1]

End point description

ORR was defined as the proportion of participants with objective response based assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.0). CR was defined as complete disappearance of all target lesions and non-target disease. No new lesions. PR was defined as >=30% decrease on study under baseline of the sum of longest diameters of all target lesions. No unequivocal progression of non-target disease. No new lesions.

End point type

Primary

End point timeframe

Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Notes
[1] - 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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	All Participants
Number of subjects analysed	56	56	91	213
Units: Percentage of Participants
number (confidence interval 95%)	53.6 (39.7 to 67)	33.9 (21.8 to 47.8)	59.3 (48.5 to 69.5)	48.4 (41.5 to 55.3)

Objective Response Rate (ORR)

Statistical analysis description

ORR for the 2 treatment arms was compared with the Cochran-Mantel-Haenszel test stratified by ECOG performance status. The relative risk ratio estimator was used to contrast the treatment effects on the endpoint. Both a point estimate and a 2-sided 95% CI were calculated using a normal approximation.

Comparison groups

Active Titration Arm v Placebo Titration Arm

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0189 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Risk ratio (RR)

Point estimate

1.578

Confidence interval

level

95%

sides

2-sided

lower limit

1.017

upper limit

2.448

Notes
[2] - A priori defined threshold for statistical significance was: alpha=0.10 (one-sided)

Secondary: Progression-Free Survival (PFS)

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End point title

Progression-Free Survival (PFS) ^[3]

End point description

The time from first dose administration to first documentation of objective tumor progression or to death due to any cause. PFS in each arm was assessed using the Kaplan-Meier method and estimates of the PFS curves from the Kaplan-Meier method were presented.

End point type

Secondary

End point timeframe

Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks

Notes
[3] - 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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	All Participants
Number of subjects analysed	56	56	91	213
Units: Months
median (confidence interval 95%)	14.5 (9.2 to 24.5)	15.7 (8.3 to 19.4)	16.6 (11.2 to 22.5)	14.6 (11.5 to 17.5)

Progression-Free Survival (PFS)

Comparison groups

Active Titration Arm v Placebo Titration Arm

Number of subjects included in analysis

112

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2444

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.849

Confidence interval

level

95%

sides

2-sided

lower limit

0.535

upper limit

1.348

Secondary: Duration of Response (DR)

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End point title

Duration of Response (DR) ^[4]

End point description

DR was defined as the time from the first documentation of objective tumor response (complete response - CR or Partial response - PR) to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. The median values were estimated based on Kaplan-Meier method. 95% confidence interval was based on the Brookmeyer and Crowley method.

End point type

Secondary

End point timeframe

Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	30	19	54
Units: Months
median (confidence interval 95%)	9999 (10.8 to 9999)	21.2 (11.1 to 25.8)	23.3 (15.7 to 28.6)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS) ^[5]

End point description

OS was defined as the time from date of the first dose of the study medication to date of death due to any cause. For participants who did not die, their survival times were to be censored at the last date they were known to be alive.

End point type

Secondary

End point timeframe

Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	56	56	91
Units: Months
median (confidence interval 95%)	42.7 (24.7 to 9999)	30.4 (23.7 to 45)	41.6 (33 to 9999)

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Axitinib

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End point title

Maximum Observed Plasma Concentration (Cmax) of Axitinib ^[6]

End point description

Cmax for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.

End point type

Secondary

End point timeframe

Cycle 2 Day 15 (C2D15): pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Notes
[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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm
Number of subjects analysed	16	20
Units: ng/mL
geometric mean (confidence interval 95%)	31.74 (21.63 to 46.58)	23.05 (16.36 to 32.49)

No statistical analyses for this end point

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib,

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End point title

Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib, ^[7]

End point description

Tmax for steady-state axitinib was evaluated on Cycle 2 Day 15.

End point type

Secondary

End point timeframe

C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Notes
[7] - 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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm
Number of subjects analysed	16	20
Units: hrs
median (full range (min-max))	2.04 (1 to 6)	2 (0 to 6)

No statistical analyses for this end point

Secondary: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib

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End point title

Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib ^[8]

End point description

Area under the plasma concentration time-curve from zero to the last measurable concentration (AUClast). AUClast for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.

End point type

Secondary

End point timeframe

C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm
Number of subjects analysed	16	20
Units: ng.hr/mL
geometric mean (confidence interval 95%)	105.33 (70.16 to 158.14)	78.44 (54.53 to 112.82)

No statistical analyses for this end point

Secondary: Area Under the Curve From Time Zero to 24 hours[AUC(0-24)] for Axitinib

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End point title

Area Under the Curve From Time Zero to 24 hours[AUC(0-24)] for Axitinib ^[9]

End point description

Area under the plasma concentration time-curve from zero 24 hours[AUC(0-24). AUC(0-24) for steady-state axitinib was evaluated on Cycle 2 Day 15. Results were normalized to axitinib 7 mg dose for active titration arm and axitinib 5 mg dose for placebo titration arm.

End point type

Secondary

End point timeframe

C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Notes
[9] - 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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm
Number of subjects analysed	10	14
Units: ng.hr/mL
geometric mean (confidence interval 95%)	258.68 (150.47 to 444.72)	161.38 (102.09 to 255.12)

No statistical analyses for this end point

Secondary: Plasma Decay Half-Life (t1/2) for Axitinib

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End point title

Plasma Decay Half-Life (t1/2) for Axitinib ^[10]

End point description

Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. Plasma decay half life for steady-state axitinib was evaluated on Cycle 2 Day 15.

End point type

Secondary

End point timeframe

C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Notes
[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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm
Number of subjects analysed	10	14
Units: Hour
arithmetic mean (standard deviation)	2.48 ( 1.902 )	2.81 ( 1.685 )

No statistical analyses for this end point

Secondary: Apparent oral clearance (CL/F) of Axitinib

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End point title

Apparent oral clearance (CL/F) of Axitinib ^[11]

End point description

Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed (F). Clearance is defined as the volume of blood from which drug can be completely removed per unit of time. CL/F for steady-state axitinib was evaluated on Cycle 2 Day 15.

End point type

Secondary

End point timeframe

C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Notes
[11] - 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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm
Number of subjects analysed	10	14
Units: L/hr
geometric mean (confidence interval 95%)	54.15 (31.49 to 93.12)	61.93 (39.17 to 97.91)

No statistical analyses for this end point

Secondary: Apparent volume of distribution during the elimination phase (Vz/F) for Axitinib

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End point title

Apparent volume of distribution during the elimination phase (Vz/F) for Axitinib ^[12]

End point description

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vz/F is influenced by the fraction absorbed. Vz/F for steady-state axitinb was evaluated on Cycle 2 Day 15.

End point type

Secondary

End point timeframe

C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Notes
[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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm
Number of subjects analysed	10	14
Units: Litre
geometric mean (confidence interval 95%)	158.18 (98.38 to 254.34)	216.62 (145 to 323.6)

No statistical analyses for this end point

Secondary: Change from baseline in systolic blood pressure

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End point title

Change from baseline in systolic blood pressure ^[13]

End point description

Value at respective visit minus value at baseline

End point type

Secondary

End point timeframe

At screening (D-14 to D-1); lead-in period: Cycle 1 - Day 1 and Day 15; Cycle 2 - Day 1 and Day 15; Cycle 3 & subsequent cycles Day 1; end of study and follow-up 28 days after last dose.

Notes
[13] - 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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	56	56	91
Units: mmHg
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=52,51,73)	-4.3 ( 11.1 )	-2.9 ( 9.2 )	-1.8 ( 14.2 )
Cycle 1 Day 15 (n=56,56,91)	3.8 ( 12.2 )	4.1 ( 12.5 )	11.5 ( 18 )
Cycle 2 Day 1 (n=56,56,91)	1.9 ( 12.4 )	0.9 ( 13.6 )	9.9 ( 18.7 )
Cycle 2 Day 15 (n=55,55,86)	3.6 ( 13.8 )	2.7 ( 16.6 )	5.9 ( 20.3 )
Cycle 3 Day 1 (n=48,49,84)	3.5 ( 15.1 )	8.4 ( 15.4 )	5.2 ( 20.2 )
Cycle 4 Day 1 (n=45,48,79)	4.3 ( 12.7 )	3.5 ( 13 )	5.5 ( 18.2 )
End of treatment (n=35,44,51)	2.4 ( 17 )	1.7 ( 14 )	-2.8 ( 19 )
Follow-up (n=16,25,36)	-3.6 ( 16.9 )	-0.4 ( 16.3 )	-0.6 ( 16.7 )

No statistical analyses for this end point

Secondary: Change from baseline in diastolic blood pressure

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End point title

Change from baseline in diastolic blood pressure ^[14]

End point description

Value at respective visit minus value at baseline.

End point type

Secondary

End point timeframe

At screening (D-14 to D-1); lead-in period: Cycle 1 - Day 1 and Day 15; Cycle 2 - Day 1 and Day 15; Cycle 3 & subsequent cycles Day 1; end of study and follow-up 28 days after last dose.

Notes
[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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	56	56	91
Units: mmHg
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n=52,51,73)	-1.6 ( 8.2 )	-2.6 ( 7.4 )	0.5 ( 8.4 )
Cycle 1 Day 15 (n=56,56,91)	4.8 ( 8.5 )	3 ( 7.7 )	11.5 ( 10 )
Cycle 2 Day 1 (n=56,56,91)	4.2 ( 9 )	3.5 ( 8 )	10.5 ( 10.5 )
Cycle 2 Day 15 (n=55,55,86)	5.5 ( 10.5 )	4.4 ( 10.7 )	9.7 ( 11.3 )
Cycle 3 Day 1 (n=48,49,84)	6.6 ( 8.3 )	5.9 ( 9.3 )	9.1 ( 13.6 )
Cycle 4 Day 1 (n=45,48,79)	7.4 ( 8.2 )	4.6 ( 8.5 )	8.7 ( 11.8 )
End of treatment (n=35,44,51)	0.6 ( 10.8 )	3.5 ( 6.3 )	3 ( 10.5 )
Follow-up (n=16,25,36)	-4.5 ( 10.1 )	-1.3 ( 8.5 )	1.8 ( 9 )

No statistical analyses for this end point

Secondary: Comparison of Circulating Endothelial Cells (CECs) in blood: cluster of differentiation (CD)146+/CD105+ at baseline

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End point title

Comparison of Circulating Endothelial Cells (CECs) in blood: cluster of differentiation (CD)146+/CD105+ at baseline ^[15]

End point description

CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD146+/CD105+ CECs, CD146+/CD105+ mean fluorescence intensity (MFI) platelet derived growth factor receptor (PDGFR)-beta, CD146+/CD105+ MFI phospho-PDGFR (pPDGFR)-beta, CD146+/CD105+ phospho-Vascular endothelial growth factor receptor (pVEGFR), CD146+/CD105+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.

End point type

Secondary

End point timeframe

At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Notes
[15] - 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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	17	22	20
Units: Fluorescent Intensity Unit (FIU)
arithmetic mean (standard deviation)
Baseline CECs Count (n=17,22,20)	23584 ( 18213.1 )	28544 ( 27694.4 )	29663 ( 30651 )
Baseline MFI PDGFR-BETA (n=17,22,20)	346815 ( 179563 )	455238 ( 238157 )	327567 ( 167728 )
Baseline MFI pPDGFR-BETA (n=17,22,20)	401226 ( 195445 )	395509 ( 136933 )	397672 ( 193172 )
Baseline MFI pVEGFR (n=16,22,20)	456086 ( 290174 )	436197 ( 128225 )	398754 ( 188137 )
Baseline MFI VEGFR (n=16,22,20)	367799 ( 181320 )	473290 ( 228619 )	359092 ( 167706 )

No statistical analyses for this end point

Secondary: Comparison of the ratio of CECs in blood: CD146+/CD105+ at each time point to baseline

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End point title

Comparison of the ratio of CECs in blood: CD146+/CD105+ at each time point to baseline ^[16]

End point description

CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD146+/CD105+ CECs, CD146+/CD105+ MFI platelet derived growth factor receptor (PDGFR)-beta, CD146+/CD105+ MFI phospho-PDGFR (pPDGFR)-beta, CD146+/CD105+ phospho-VEGFR (pVEGFR), CD146+/CD105+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.

End point type

Secondary

End point timeframe

At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	17	22	20
Units: Ratio
arithmetic mean (standard deviation)
C1D15:C1D1 CECs Count (n=11,18,14)	2.3 ( 2.52 )	3.7 ( 6.92 )	2.2 ( 3.1 )
C2D15:C1D1 CECs Count (n=13,16,11)	1.3 ( 1.43 )	4.4 ( 9.27 )	1.3 ( 1.22 )
EOT:C1D1 CECs Count (n=7,9,4)	2.8 ( 4.81 )	8.9 ( 21.7 )	1.2 ( 1.5 )
C1D15:C1D1 MFI PDGFRBETA (n=11,17,13)	1.3 ( 1.03 )	1.5 ( 1.14 )	1.1 ( 0.73 )
C2D15:C1D1 MFI PDGFRBETA (n=13,16,11)	1.4 ( 1.24 )	1.1 ( 1.14 )	1.62 ( 1.62 )
EOT:C1D1 MFI PDGFRBETA (n=7,9,4)	1.5 ( 1.75 )	0.6 ( 0.52 )	1.2 ( 1.78 )
C1D15:C1D1 MFI pPDGFR-BETA (n=11,17,13)	1.1 ( 0.63 )	1.2 ( 0.77 )	1 ( 1.12 )
C2D15:C1D1 MFI pPDGFR-BETA (n=13,16,11)	1 ( 0.69 )	0.8 ( 0.45 )	1.2 ( 0.79 )
EOT:C1D1 MFI pPDGFRBETA (n=7,9,4)	0.8 ( 0.71 )	0.8 ( 0.93 )	1.9 ( 1.57 )
C1D15:C1D1 MFI pVEGFR (n=10,18,14)	1 ( 0.46 )	1.2 ( 0.88 )	1.2 ( 1 )
C2D15:C1D1 MFI pVEGFR (n=12,16,11)	1 ( 0.74 )	0.9 ( 0.82 )	1.2 ( 0.8 )
EOT:C1D1 MFI pVEGFR (n=7,9,4)	0.8 ( 0.53 )	1.3 ( 0.96 )	3 ( 1.16 )
C1D15:C1D1 MFI VEGFR (n=10,18,14)	1.4 ( 1.25 )	1.3 ( 0.94 )	1 ( 0.64 )
C2D15:C1D1 MFI VEGFR (n=12,16,11)	1.5 ( 1.48 )	1.3 ( 0.99 )	2.1 ( 1.72 )
EOT:C1D1 MFI VEGFR (n=7,9,4)	1.1 ( 1.03 )	0.7 ( 0.48 )	1.9 ( 1.63 )

No statistical analyses for this end point

Secondary: Circulating Endothelial Cells (CECs) in blood: CD31+/CD146+

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End point title

Circulating Endothelial Cells (CECs) in blood: CD31+/CD146+ ^[17]

End point description

CECs are noninvasive marker of vascular damage, remodeling, and dysfunction. Samples were collected and following proteins were analyzed: CD31+/CD146+ CECs, CD31+/CD146+ MFI PDGFR-beta, CD31+/CD146+ MFI pPDGFR-beta, CD31+/CD146+ pVEGFR, CD31+/CD146+ MFI VEGFR. The ratio of plasma levels of the biomarkers at the selected time point vs baseline is reported.

End point type

Secondary

End point timeframe

At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Notes
[17] - 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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	17	22	20
Units: Fluorescent Intensity Unit (FIU)
arithmetic mean (standard deviation)
Baseline CECs Count (n=17,22,20)	74668 ( 50558.9 )	76258 ( 46779.5 )	77437 ( 63419.4 )
Baseline MFI PDGFR-BETA (n=17,21,20)	333760 ( 164604 )	380886 ( 147261 )	442642 ( 267436 )
Baseline MFI pPDGFR-BETA (n=17,21,20)	380139 ( 205600 )	355441 ( 147046 )	383202 ( 211174 )
Baseline MFI pVEGFR (n=17,22,20)	385617 ( 203956 )	352644 ( 128803 )	380184 ( 173578 )
Baseline MFI VEGFR (n=17,22,20)	330333 ( 151710 )	401909 ( 165235 )	359097 ( 146943 )

No statistical analyses for this end point

Secondary: Comparison of ratio of CECs in blood: CD31+/CD146+ at each time point to baseline

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End point title

Comparison of ratio of CECs in blood: CD31+/CD146+ at each time point to baseline ^[18]

End point description

End point type

Secondary

End point timeframe

At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)

Notes
[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: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	17	22	20
Units: Ratio
arithmetic mean (standard deviation)
C1D15:C1D1 CECs Count (n=11,18,14)	2.7 ( 3.17 )	1.6 ( 2.32 )	1.5 ( 2.31 )
C2D15:C1D1 CECs Count (n=13,16,11)	1.4 ( 1.4 )	2.2 ( 3.91 )	2.5 ( 3.98 )
EOT:C1D1 CECs COUNT (n=7,9,4)	1.5 ( 1.95 )	1.4 ( 2.2 )	0.6 ( 0.71 )
C1D15:C1D1 MFI PDGFRBETA (n=11,15,13)	1.2 ( 0.74 )	1.3 ( 0.89 )	0.8 ( 0.51 )
C2D15:C1D1 MFI PDGFRBETA (n=13,14,11)	1.4 ( 1.36 )	1.1 ( 1.03 )	2.2 ( 2.64 )
EOT:C1D1 MFI PDGFRBETA (n=6,8,4)	1.2 ( 1.23 )	0.6 ( 0.51 )	1.7 ( 1.49 )
C1D15:C1D1 MFI pPDGFR-BETA (n=11,15,13)	1.2 ( 1.07 )	1.4 ( 0.81 )	1 ( 0.87 )
C2D15:C1D1 MFI pPDGFR-BETA (n=13,14,11)	1.2 ( 0.89 )	0.8 ( 0.38 )	1.1 ( 0.71 )
EOT:C1D1 MFI pPDGFRBETA (n=6,8,4)	0.7 ( 0.63 )	0.8 ( 0.91 )	3 ( 0.47 )
C1D15:C1D1 MFI pVEGFR (n=11,18,14)	1.1 ( 0.75 )	1.4 ( 0.74 )	1.2 ( 0.9 )
C2D15:C1D1 MFI pVEGFR (n=13,16,10)	1.2 ( 1 )	0.9 ( 0.68 )	1.3 ( 0.7 )
EOT:C1D1 MFI pVEGFR (n=7,9,4)	0.7 ( 0.59 )	1.1 ( 1.24 )	3.1 ( 0.95 )
C1D15:C1D1 MFI VEGFR (n=11,18,14)	1.3 ( 0.93 )	1.3 ( 0.9 )	1 ( 0.57 )
C2D15:C1D1 MFI VEGFR n=13,16,10)	1.5 ( 1.44 )	1.2 ( 0.96 )	2.1 ( 1.8 )
EOT:C1D1 MFI VEGFR (n=7,9,4)	1.2 ( 1.27 )	1.1 ( 0.9 )	1.5 ( 1.42 )

No statistical analyses for this end point

Secondary: ORR in Subgroups That Were Defined by Vascular endothelial growth factor A (VEGFA) or Vascular endothelial growth factor receptor 3 (VEGFR3) Polymorphisms

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End point title

ORR in Subgroups That Were Defined by Vascular endothelial growth factor A (VEGFA) or Vascular endothelial growth factor receptor 3 (VEGFR3) Polymorphisms ^[19]

End point description

ORR, defined as proportion of participants with CR or PR according to RECIST, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms.

End point type

Secondary

End point timeframe

Baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	49	49	79
Units: Percentage of participants
number (confidence interval 95%)
VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14)	85.7 (42.1 to 99.6)	22.2 (2.8 to 60)	42.9 (17.7 to 71.1)
VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41)	54.5 (32.2 to 75.6)	35 (15.4 to 59.2)	65.9 (49.4 to 79.9)
VEGFA/rs699947 Genotype: C/C (n = 14, 14, 24)	50 (23 to 77)	35.7 (12.8 to 64.9)	66.7 (44.7 to 84.4)
VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43)	59.1 (36.4 to 79.3)	39.1 (19.7 to 61.5)	67.4 (51.5 to 80.9)
VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29)	57.9 (33.5 to 79.7)	18.8 (4 to 45.6)	58.6 (38.9 to 76.5)
VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 7)	50 (1.3 to 98.7)	50 (6.8 to 93.2)	42.9 (9.9 to 81.6)
VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28)	81.3 (54.4 to 96)	53.3 (26.6 to 78.7)	60.7 (40.6 to 78.5)
VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35)	45.5 (24.4 to 67.8)	18.2 (5.2 to 40.3)	57.1 (39.4 to 73.7)
VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16)	40 (5.3 to 85.3)	33.3 (4.3 to 77.7)	75 (47.6 to 92.7)
VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 79)	58.3 (40.8 to 74.5)	30.8 (17 to 47.6)	64.3 (51.9 to 75.4)
VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9)	50 (11.8 to 88.2)	50 (6.8 to 93.2)	44.4 (13.7 to 78.8)
VEGFR3/rs307826 Genotype: G/G (n = 1, 0, 0)	100 (2.5 to 100)	0 (0 to 0)	0 (0 to 0)
VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 79)	55.6 (38.1 to 72.1)	28.9 (15.4 to 45.9)	65.2 (52.8 to 76.3)
VEGFR3/rs307821 Genotype: G/T (n = 6, 5, 10)	66.7 (22.3 to 95.7)	60 (14.7 to 94.7)	40 (12.2 to 73.8)
VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0)	100 (2.5 to 100)	0 (0 to 0)	0 (0 to 0)

No statistical analyses for this end point

Secondary: PFS in Subgroups That Were Defined by Vascular endothelial growth factor A (VEGFA) or Vascular endothelial growth factor receptor 3 (VEGFR3) Polymorphisms

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End point title

PFS in Subgroups That Were Defined by Vascular endothelial growth factor A (VEGFA) or Vascular endothelial growth factor receptor 3 (VEGFR3) Polymorphisms ^[20]

End point description

PFS, defined as the time from randomization to first documentation of objective tumor progression or to death due to any cause, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms. Estimates of the PFS curves from the Kaplan-Meier method were presented.

End point type

Secondary

End point timeframe

Baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No statistical analyses have been specified for this end point. No inferential statistical analysis was done.

End point values	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Number of subjects analysed	43	43	79
Units: Months
median (confidence interval 95%)
VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14)	9999 (1.74 to 9999)	11.5 (7.33 to 9999)	7.33 (5.06 to 13.83)
VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41)	11.07 (3.02 to 17.44)	9.67 (1.91 to 16.59)	16.59 (10.97 to 9999)
VEGFA/rs699947 Genotype: C/C (n = 14, 14, 41)	18.74 (1.84 to 9999)	24.64 (4.01 to 9999)	25.13 (8.28 to 30.45)
VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43)	14.62 (7.39 to 9999)	19.42 (5.81 to 27.63)	25.13 (11.47 to 30.45)
VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29)	12.78 (1.84 to 9999)	8.34 (1.91 to 16.59)	13.9 (8.28 to 22.54)
VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 29)	9999 (1.74 to 9999)	10.04 (3.58 to 9999)	8.57 (1.74 to 9999)
VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28)	17.44 (12.78 to 9999)	19.42 (5.35 to 9999)	22.54 (8.08 to 9999)
VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35)	9.18 (1.84 to 9999)	8.31 (3.58 to 16.52)	13.83 (5.62 to 16.59)
VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16)	11.07 (1.84 to 9999)	15.67 (1.91 to 27.63)	9999 (8.57 to 9999)
VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 70)	13.73 (8.28 to 24.47)	15.67 (8.21 to 22.17)	16.56 (10.28 to 25.13)
VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9)	16.52 (1.18 to 9999)	7.93 (1.84 to 11.86)	16.26 (2.66 to 30.45)
VEGFR3/rs307826 Genotype: G/G (n = 0, 0, 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)
VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 69)	12.78 (7.39 to 24.47)	15.67 (8.21 to 23.95)	16.59 (10.28 to 28.52)
VEGFR3/rs307821 Genotype: G/T (n = 36, 38, 10)	24.8 (1.18 to 9999)	8.34 (1.84 to 11.86)	13.86 (2.66 to 30.45)
VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0)	0 (0 to 0)	0 (0 to 0)	0 (0 to 0)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

3 years

Adverse event reporting additional description

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Active Titration Arm

Reporting group description

Participants initially received axitinib 5 mg twice a day (BID) + axitinib(blinded therapy) 2 mg BID. After at least 2 consecutive weeks, participants satisfying the dose titration criteria had their dose level increased by one additional dose level, to axitinib 5 mg BID + axitinib (blinded therapy) 5 mg BID, unless otherwise contraindicated per the investigator’s clinical judgment. The maximum total daily dose was 10 mg BID (axitinib 5mg BID + axitinib [blinded therapy] 5 mg BID).

Reporting group title

Non-randomized Arm

Reporting group description

Participants not eligible for randomization were assigned to receive axitinib 5 mg BID or a reduced dose per the dose modification guideline. Dose titration was not permitted in this treatment arm.

Reporting group title

Placebo Titration Arm

Reporting group description

Reporting group title

Discontinued Prior to Randomization

Reporting group description

Participants who were discontinued prior to randomization to either treatment or non-randomization arms.

Serious adverse events	Active Titration Arm	Non-randomized Arm	Placebo Titration Arm	Discontinued Prior to Randomization
Total subjects affected by serious adverse events
subjects affected / exposed	25 / 56 (44.64%)	39 / 91 (42.86%)	14 / 56 (25.00%)	2 / 10 (20.00%)
number of deaths (all causes)	4	0	1	0
number of deaths resulting from adverse events	3	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Breast cancer
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (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
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Hypertension
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	0 / 56 (0.00%)	1 / 10 (10.00%)
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
Hypotension
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Orthostatic hypotension
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Surgical and medical procedures
Incisional hernia repair
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
General disorders and administration site conditions
Disease progression
subjects affected / exposed	1 / 56 (1.79%)	6 / 91 (6.59%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 6	0 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 56 (1.79%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic prolapse
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (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
Dyspnoea
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Pleural effusion
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Pulmonary hypertension
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Pulmonary oedema
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Hypercapnia
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Pulmonary embolism
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Blood sodium decreased
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Injury, poisoning and procedural complications
Lumbar vertebral fracture
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Overdose
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Postoperative hernia
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Postoperative wound complication
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Road traffic accident
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Cervical vertebral fracture
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Incisional hernia
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative ileus
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Cardiac disorders
Myocardial ischaemia
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (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
Acute myocardial infarction
subjects affected / exposed	1 / 56 (1.79%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 56 (0.00%)	2 / 91 (2.20%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diastolic dysfunction
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Myocardial infarction
subjects affected / exposed	4 / 56 (7.14%)	2 / 91 (2.20%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Cardiac failure
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Coronary artery disease
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Nervous system disorders
Cerebrovascular insufficiency
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (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
Syncope
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Headache
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Somnolence
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Cerebrovascular accident
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (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
Monoparesis
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 56 (0.00%)	3 / 91 (3.30%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	2 / 56 (3.57%)	1 / 91 (1.10%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	3 / 3	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 56 (3.57%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 56 (5.36%)	1 / 91 (1.10%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (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
Abdominal distension
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Abdominal pain
subjects affected / exposed	1 / 56 (1.79%)	1 / 91 (1.10%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Ascites
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	2 / 56 (3.57%)	0 / 10 (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 / 0	0 / 0
Crohn’s disease
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Enterocolitis
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal hypomotility
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Ileus
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Intestinal obstruction
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Small intestinal obstruction
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis chronic
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Cholelithiasis
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (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
Renal and urinary disorders
Renal colic
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postrenal failure
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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 / 56 (0.00%)	0 / 91 (0.00%)	0 / 56 (0.00%)	1 / 10 (10.00%)
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
Acute kidney injury
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Urinary retention
subjects affected / exposed	0 / 56 (0.00%)	2 / 91 (2.20%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	2 / 56 (3.57%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Pain in extremity
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Infections and infestations
Cystitis
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	0 / 56 (0.00%)	0 / 10 (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
Pneumonia
subjects affected / exposed	3 / 56 (5.36%)	1 / 91 (1.10%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	0 / 10 (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
Infection
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Lung infection
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Osteomyelitis
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Postoperative wound infection
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Gingivitis
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	5 / 56 (8.93%)	3 / 91 (3.30%)	0 / 56 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	3 / 7	1 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 56 (1.79%)	2 / 91 (2.20%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 1	4 / 4	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	0 / 56 (0.00%)	1 / 10 (10.00%)
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
Hypokalaemia
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	0 / 10 (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
Hyponatraemia
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 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: 5%

Non-serious adverse events	Active Titration Arm	Non-randomized Arm	Placebo Titration Arm	Discontinued Prior to Randomization
Total subjects affected by non serious adverse events
subjects affected / exposed	55 / 56 (98.21%)	91 / 91 (100.00%)	51 / 56 (91.07%)	9 / 10 (90.00%)
Vascular disorders
Hypertension
subjects affected / exposed	35 / 56 (62.50%)	76 / 91 (83.52%)	24 / 56 (42.86%)	5 / 10 (50.00%)
occurrences all number	67	167	75	12
Hypotension
subjects affected / exposed	0 / 56 (0.00%)	9 / 91 (9.89%)	8 / 56 (14.29%)	0 / 10 (0.00%)
occurrences all number	0	10	11	0
Surgical and medical procedures
Tooth extraction
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	0	1	3	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	6 / 56 (10.71%)	6 / 91 (6.59%)	5 / 56 (8.93%)	0 / 10 (0.00%)
occurrences all number	9	11	7	0
Fatigue
subjects affected / exposed	27 / 56 (48.21%)	49 / 91 (53.85%)	26 / 56 (46.43%)	4 / 10 (40.00%)
occurrences all number	74	127	66	7
General physical health deterioration
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	0 / 56 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1
Mucosal inflammation
subjects affected / exposed	12 / 56 (21.43%)	13 / 91 (14.29%)	8 / 56 (14.29%)	0 / 10 (0.00%)
occurrences all number	21	39	21	0
Chest pain
subjects affected / exposed	5 / 56 (8.93%)	6 / 91 (6.59%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	8	6	2	0
Chills
subjects affected / exposed	4 / 56 (7.14%)	5 / 91 (5.49%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences all number	4	5	1	0
Oedema peripheral
subjects affected / exposed	4 / 56 (7.14%)	14 / 91 (15.38%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	11	29	3	0
Pain
subjects affected / exposed	4 / 56 (7.14%)	6 / 91 (6.59%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	5	9	3	0
Pyrexia
subjects affected / exposed	6 / 56 (10.71%)	4 / 91 (4.40%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	8	4	4	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 56 (12.50%)	19 / 91 (20.88%)	8 / 56 (14.29%)	0 / 10 (0.00%)
occurrences all number	8	25	13	0
Dysphonia
subjects affected / exposed	18 / 56 (32.14%)	44 / 91 (48.35%)	20 / 56 (35.71%)	3 / 10 (30.00%)
occurrences all number	27	74	20	3
Dyspnoea
subjects affected / exposed	6 / 56 (10.71%)	27 / 91 (29.67%)	8 / 56 (14.29%)	1 / 10 (10.00%)
occurrences all number	15	36	11	3
Epistaxis
subjects affected / exposed	4 / 56 (7.14%)	12 / 91 (13.19%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	5	24	3	0
Oropharyngeal pain
subjects affected / exposed	4 / 56 (7.14%)	8 / 91 (8.79%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	5	9	2	0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 56 (1.79%)	0 / 91 (0.00%)	1 / 56 (1.79%)	2 / 10 (20.00%)
occurrences all number	1	0	1	2
Insomnia
subjects affected / exposed	3 / 56 (5.36%)	8 / 91 (8.79%)	4 / 56 (7.14%)	1 / 10 (10.00%)
occurrences all number	4	10	4	1
Anxiety
subjects affected / exposed	3 / 56 (5.36%)	7 / 91 (7.69%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	4	10	3	0
Depression
subjects affected / exposed	4 / 56 (7.14%)	6 / 91 (6.59%)	4 / 56 (7.14%)	0 / 10 (0.00%)
occurrences all number	5	8	4	0
Delirium
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	0 / 56 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	6 / 56 (10.71%)	12 / 91 (13.19%)	9 / 56 (16.07%)	0 / 10 (0.00%)
occurrences all number	10	36	21	0
Aspartate aminotransferase increased
subjects affected / exposed	6 / 56 (10.71%)	12 / 91 (13.19%)	10 / 56 (17.86%)	0 / 10 (0.00%)
occurrences all number	10	36	23	0
Blood creatinine increased
subjects affected / exposed	4 / 56 (7.14%)	14 / 91 (15.38%)	8 / 56 (14.29%)	1 / 10 (10.00%)
occurrences all number	10	31	17	1
Blood glucose increased
subjects affected / exposed	4 / 56 (7.14%)	10 / 91 (10.99%)	7 / 56 (12.50%)	2 / 10 (20.00%)
occurrences all number	24	23	17	3
Fibrin D dimer increased
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	1 / 10 (10.00%)
occurrences all number	0	0	2	1
Weight decreased
subjects affected / exposed	16 / 56 (28.57%)	25 / 91 (27.47%)	12 / 56 (21.43%)	1 / 10 (10.00%)
occurrences all number	53	88	22	1
Blood alkaline phosphatase increased
subjects affected / exposed	4 / 56 (7.14%)	6 / 91 (6.59%)	4 / 56 (7.14%)	2 / 10 (20.00%)
occurrences all number	4	12	5	2
Blood glucose decreased
subjects affected / exposed	3 / 56 (5.36%)	1 / 91 (1.10%)	5 / 56 (8.93%)	0 / 10 (0.00%)
occurrences all number	10	1	7	0
Blood potassium increased
subjects affected / exposed	4 / 56 (7.14%)	4 / 91 (4.40%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	30	5	17	0
Blood triglycerides increased
subjects affected / exposed	2 / 56 (3.57%)	5 / 91 (5.49%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	3	17	3	0
Haemoglobin decreased
subjects affected / exposed	1 / 56 (1.79%)	5 / 91 (5.49%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences all number	1	14	6	0
Blood albumin decreased
subjects affected / exposed	1 / 56 (1.79%)	1 / 91 (1.10%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	1	8	4	0
Blood sodium decreased
subjects affected / exposed	2 / 56 (3.57%)	1 / 91 (1.10%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	4	2	5	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	8 / 56 (14.29%)	9 / 91 (9.89%)	7 / 56 (12.50%)	0 / 10 (0.00%)
occurrences all number	34	15	10	0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	1 / 56 (1.79%)	2 / 10 (20.00%)
occurrences all number	0	0	0	2
Nervous system disorders
Dysgeusia
subjects affected / exposed	9 / 56 (16.07%)	21 / 91 (23.08%)	5 / 56 (8.93%)	1 / 10 (10.00%)
occurrences all number	15	31	10	1
Dyskinesia
subjects affected / exposed	0 / 56 (0.00%)	0 / 91 (0.00%)	0 / 56 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1
Headache
subjects affected / exposed	9 / 56 (16.07%)	27 / 91 (29.67%)	15 / 56 (26.79%)	0 / 10 (0.00%)
occurrences all number	18	53	25	0
Hypoaesthesia
subjects affected / exposed	2 / 56 (3.57%)	4 / 91 (4.40%)	0 / 56 (0.00%)	1 / 10 (10.00%)
occurrences all number	2	5	0	1
Paraesthesia
subjects affected / exposed	5 / 56 (8.93%)	3 / 91 (3.30%)	3 / 56 (5.36%)	1 / 10 (10.00%)
occurrences all number	8	3	4	1
Transient ischaemic attack
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	1
Dizziness
subjects affected / exposed	8 / 56 (14.29%)	14 / 91 (15.38%)	10 / 56 (17.86%)	1 / 10 (10.00%)
occurrences all number	14	53	16	1
Peripheral sensory neuropathy
subjects affected / exposed	4 / 56 (7.14%)	3 / 91 (3.30%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences all number	6	4	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 56 (8.93%)	9 / 91 (9.89%)	4 / 56 (7.14%)	1 / 10 (10.00%)
occurrences all number	5	13	6	1
Lymphopenia
subjects affected / exposed	0 / 56 (0.00%)	2 / 91 (2.20%)	0 / 56 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1
Thrombocytopenia
subjects affected / exposed	5 / 56 (8.93%)	15 / 91 (16.48%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	8	22	5	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 56 (0.00%)	4 / 91 (4.40%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	0	4	4	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	9 / 56 (16.07%)	11 / 91 (12.09%)	9 / 56 (16.07%)	1 / 10 (10.00%)
occurrences all number	26	17	10	1
Abdominal pain upper
subjects affected / exposed	6 / 56 (10.71%)	11 / 91 (12.09%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	9	14	2	0
Constipation
subjects affected / exposed	11 / 56 (19.64%)	27 / 91 (29.67%)	7 / 56 (12.50%)	3 / 10 (30.00%)
occurrences all number	15	43	11	4
Diarrhoea
subjects affected / exposed	34 / 56 (60.71%)	58 / 91 (63.74%)	35 / 56 (62.50%)	1 / 10 (10.00%)
occurrences all number	232	236	97	1
Dry Mouth
subjects affected / exposed	7 / 56 (12.50%)	7 / 91 (7.69%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	9	8	2	0
Dyspepsia
subjects affected / exposed	7 / 56 (12.50%)	18 / 91 (19.78%)	5 / 56 (8.93%)	0 / 10 (0.00%)
occurrences all number	10	24	5	0
Dysphagia
subjects affected / exposed	0 / 56 (0.00%)	2 / 91 (2.20%)	2 / 56 (3.57%)	1 / 10 (10.00%)
occurrences all number	0	3	2	1
Flatulence
subjects affected / exposed	7 / 56 (12.50%)	4 / 91 (4.40%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	7	7	3	0
Haemorrhoids
subjects affected / exposed	2 / 56 (3.57%)	4 / 91 (4.40%)	1 / 56 (1.79%)	1 / 10 (10.00%)
occurrences all number	2	8	1	1
Nausea
subjects affected / exposed	24 / 56 (42.86%)	33 / 91 (36.26%)	19 / 56 (33.93%)	2 / 10 (20.00%)
occurrences all number	70	66	57	4
Stomatitis
subjects affected / exposed	10 / 56 (17.86%)	17 / 91 (18.68%)	4 / 56 (7.14%)	0 / 10 (0.00%)
occurrences all number	18	26	4	0
Vomiting
subjects affected / exposed	18 / 56 (32.14%)	25 / 91 (27.47%)	12 / 56 (21.43%)	2 / 10 (20.00%)
occurrences all number	35	44	37	2
Abdominal discomfort
subjects affected / exposed	2 / 56 (3.57%)	6 / 91 (6.59%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	9	2	0
Abdominal distension
subjects affected / exposed	1 / 56 (1.79%)	3 / 91 (3.30%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	1	5	3	0
Gastritis
subjects affected / exposed	3 / 56 (5.36%)	9 / 91 (9.89%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	3	13	3	0
Toothache
subjects affected / exposed	1 / 56 (1.79%)	5 / 91 (5.49%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	1	16	5	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 56 (3.57%)	6 / 91 (6.59%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	2	6	3	0
Proctalgia
subjects affected / exposed	2 / 56 (3.57%)	5 / 91 (5.49%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	7	0	0
Hepatobiliary disorders
Hepatic function abnormal
subjects affected / exposed	3 / 56 (5.36%)	5 / 91 (5.49%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences all number	4	9	1	0
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	7 / 56 (12.50%)	7 / 91 (7.69%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	7	8	3	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	18 / 56 (32.14%)	40 / 91 (43.96%)	10 / 56 (17.86%)	0 / 10 (0.00%)
occurrences all number	37	199	45	0
Pruritus
subjects affected / exposed	2 / 56 (3.57%)	13 / 91 (14.29%)	6 / 56 (10.71%)	0 / 10 (0.00%)
occurrences all number	7	16	9	0
Rash
subjects affected / exposed	5 / 56 (8.93%)	19 / 91 (20.88%)	8 / 56 (14.29%)	0 / 10 (0.00%)
occurrences all number	8	30	11	0
Alopecia
subjects affected / exposed	2 / 56 (3.57%)	14 / 91 (15.38%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	2	14	3	0
Erythema
subjects affected / exposed	1 / 56 (1.79%)	6 / 91 (6.59%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	1	6	2	0
Hyperkeratosis
subjects affected / exposed	2 / 56 (3.57%)	5 / 91 (5.49%)	4 / 56 (7.14%)	0 / 10 (0.00%)
occurrences all number	2	8	5	0
Renal and urinary disorders
Haemoglobinuria
subjects affected / exposed	2 / 56 (3.57%)	5 / 91 (5.49%)	3 / 56 (5.36%)	1 / 10 (10.00%)
occurrences all number	3	6	4	1
Proteinuria
subjects affected / exposed	12 / 56 (21.43%)	40 / 91 (43.96%)	12 / 56 (21.43%)	2 / 10 (20.00%)
occurrences all number	41	376	43	2
Dysuria
subjects affected / exposed	3 / 56 (5.36%)	3 / 91 (3.30%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences all number	5	5	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	18 / 56 (32.14%)	41 / 91 (45.05%)	13 / 56 (23.21%)	2 / 10 (20.00%)
occurrences all number	26	64	15	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	13 / 56 (23.21%)	17 / 91 (18.68%)	11 / 56 (19.64%)	0 / 10 (0.00%)
occurrences all number	23	33	53	0
Back pain
subjects affected / exposed	13 / 56 (23.21%)	17 / 91 (18.68%)	8 / 56 (14.29%)	0 / 10 (0.00%)
occurrences all number	32	28	12	0
Groin pain
subjects affected / exposed	0 / 56 (0.00%)	1 / 91 (1.10%)	0 / 56 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	1
Musculoskeletal pain
subjects affected / exposed	8 / 56 (14.29%)	15 / 91 (16.48%)	4 / 56 (7.14%)	0 / 10 (0.00%)
occurrences all number	8	17	6	0
Bone pain
subjects affected / exposed	3 / 56 (5.36%)	5 / 91 (5.49%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	3	7	2	0
Flank pain
subjects affected / exposed	1 / 56 (1.79%)	4 / 91 (4.40%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	1	4	3	0
Muscle spasms
subjects affected / exposed	3 / 56 (5.36%)	6 / 91 (6.59%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	4	23	3	0
Muscular weakness
subjects affected / exposed	3 / 56 (5.36%)	2 / 91 (2.20%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	4	2	2	0
Musculoskeletal chest pain
subjects affected / exposed	8 / 56 (14.29%)	15 / 91 (16.48%)	4 / 56 (7.14%)	0 / 10 (0.00%)
occurrences all number	8	17	6	0
Musculoskeletal stiffness
subjects affected / exposed	1 / 56 (1.79%)	3 / 91 (3.30%)	4 / 56 (7.14%)	0 / 10 (0.00%)
occurrences all number	1	4	13	0
Myalgia
subjects affected / exposed	4 / 56 (7.14%)	8 / 91 (8.79%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	6	17	34	0
Neck pain
subjects affected / exposed	4 / 56 (7.14%)	5 / 91 (5.49%)	4 / 56 (7.14%)	0 / 10 (0.00%)
occurrences all number	10	8	5	0
Pain in extremity
subjects affected / exposed	8 / 56 (14.29%)	23 / 91 (25.27%)	9 / 56 (16.07%)	2 / 10 (20.00%)
occurrences all number	11	26	13	4
Infections and infestations
Rhinitis
subjects affected / exposed	3 / 56 (5.36%)	4 / 91 (4.40%)	6 / 56 (10.71%)	0 / 10 (0.00%)
occurrences all number	7	5	6	0
Urinary tract infection
subjects affected / exposed	3 / 56 (5.36%)	10 / 91 (10.99%)	1 / 56 (1.79%)	1 / 10 (10.00%)
occurrences all number	6	20	1	1
Nasopharyngitis
subjects affected / exposed	4 / 56 (7.14%)	19 / 91 (20.88%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	8	37	6	0
Sinusitis
subjects affected / exposed	4 / 56 (7.14%)	2 / 91 (2.20%)	2 / 56 (3.57%)	0 / 10 (0.00%)
occurrences all number	8	2	3	0
Upper respiratory tract infection
subjects affected / exposed	4 / 56 (7.14%)	6 / 91 (6.59%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	6	6	4	0
Respiratory tract infection
subjects affected / exposed	2 / 56 (3.57%)	0 / 91 (0.00%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	2	0	3	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	21 / 56 (37.50%)	37 / 91 (40.66%)	16 / 56 (28.57%)	3 / 10 (30.00%)
occurrences all number	45	109	28	3
Dehydration
subjects affected / exposed	3 / 56 (5.36%)	5 / 91 (5.49%)	4 / 56 (7.14%)	0 / 10 (0.00%)
occurrences all number	3	8	6	0
Hyponatraemia
subjects affected / exposed	4 / 56 (7.14%)	4 / 91 (4.40%)	1 / 56 (1.79%)	1 / 10 (10.00%)
occurrences all number	6	9	2	1
Hyperglycaemia
subjects affected / exposed	4 / 56 (7.14%)	6 / 91 (6.59%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	4	8	7	0
Hyperkalaemia
subjects affected / exposed	6 / 56 (10.71%)	5 / 91 (5.49%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences all number	7	6	1	0
Hyperlipidaemia
subjects affected / exposed	0 / 56 (0.00%)	7 / 91 (7.69%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	12	0	0
Hyperuricaemia
subjects affected / exposed	1 / 56 (1.79%)	9 / 91 (9.89%)	0 / 56 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	17	0	0
Hypoalbuminaemia
subjects affected / exposed	3 / 56 (5.36%)	2 / 91 (2.20%)	1 / 56 (1.79%)	0 / 10 (0.00%)
occurrences all number	7	4	1	0
Hypoglycaemia
subjects affected / exposed	0 / 56 (0.00%)	2 / 91 (2.20%)	3 / 56 (5.36%)	0 / 10 (0.00%)
occurrences all number	0	2	3	0
Hypophosphataemia
subjects affected / exposed	2 / 56 (3.57%)	4 / 91 (4.40%)	2 / 56 (3.57%)	1 / 10 (10.00%)
occurrences all number	2	15	3	1

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Were there any global substantial amendments to the protocol? No

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: Randomized, Double-Blind Phase 2 Study of Axitinib (AG 013736) With or Without Dose Titration in Patients with Metastatic Renal Cell Carcinoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Objective Response Rate (ORR) - Percentage of Participants With Objective Response

Primary: Objective Response Rate (ORR) - Percentage of Participants With Objective Response

Secondary: Progression-Free Survival (PFS)

Secondary: Progression-Free Survival (PFS)

Secondary: Duration of Response (DR)

Secondary: Duration of Response (DR)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Maximum Observed Plasma Concentration (Cmax) of Axitinib

Secondary: Maximum Observed Plasma Concentration (Cmax) of Axitinib

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib,

Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib,

Secondary: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib

Secondary: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib

Secondary: Area Under the Curve From Time Zero to 24 hours[AUC(0-24)] for Axitinib

Secondary: Area Under the Curve From Time Zero to 24 hours[AUC(0-24)] for Axitinib

Secondary: Plasma Decay Half-Life (t1/2) for Axitinib

Secondary: Plasma Decay Half-Life (t1/2) for Axitinib

Secondary: Apparent oral clearance (CL/F) of Axitinib

Secondary: Apparent oral clearance (CL/F) of Axitinib

Secondary: Apparent volume of distribution during the elimination phase (Vz/F) for Axitinib

Secondary: Apparent volume of distribution during the elimination phase (Vz/F) for Axitinib

Secondary: Change from baseline in systolic blood pressure

Secondary: Change from baseline in systolic blood pressure

Secondary: Change from baseline in diastolic blood pressure

Secondary: Change from baseline in diastolic blood pressure

Secondary: Comparison of Circulating Endothelial Cells (CECs) in blood: cluster of differentiation (CD)146+/CD105+ at baseline

Secondary: Comparison of Circulating Endothelial Cells (CECs) in blood: cluster of differentiation (CD)146+/CD105+ at baseline

Secondary: Comparison of the ratio of CECs in blood: CD146+/CD105+ at each time point to baseline

Secondary: Comparison of the ratio of CECs in blood: CD146+/CD105+ at each time point to baseline

Secondary: Circulating Endothelial Cells (CECs) in blood: CD31+/CD146+

Secondary: Circulating Endothelial Cells (CECs) in blood: CD31+/CD146+

Secondary: Comparison of ratio of CECs in blood: CD31+/CD146+ at each time point to baseline

Secondary: Comparison of ratio of CECs in blood: CD31+/CD146+ at each time point to baseline

Secondary: ORR in Subgroups That Were Defined by Vascular endothelial growth factor A (VEGFA) or Vascular endothelial growth factor receptor 3 (VEGFR3) Polymorphisms

Secondary: ORR in Subgroups That Were Defined by Vascular endothelial growth factor A (VEGFA) or Vascular endothelial growth factor receptor 3 (VEGFR3) Polymorphisms

Secondary: PFS in Subgroups That Were Defined by Vascular endothelial growth factor A (VEGFA) or Vascular endothelial growth factor receptor 3 (VEGFR3) Polymorphisms

Secondary: PFS in Subgroups That Were Defined by Vascular endothelial growth factor A (VEGFA) or Vascular endothelial growth factor receptor 3 (VEGFR3) Polymorphisms

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
Randomized, Double-Blind Phase 2 Study of Axitinib (AG 013736) With or Without Dose Titration in Patients with Metastatic Renal Cell Carcinoma