Axitinib (AG-013736) With Or Without Dose Titration (Increase) In Patients With Kidney Cancer

Sponsor

Pfizer (Industry)

Overall Status

Completed

CT.gov ID

NCT00835978

Collaborator

(none)

213

Enrollment

Locations

Arms

Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Axitinib dose titration (giving a higher dose of the drug above its standard starting dose) among certain patients may improve the response to treatment.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Renal Cell	Drug: axitinib Drug: axitinib Drug: axitinib	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

213 participants

Allocation:

Randomized

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Randomized, Double-blind Phase 2 Study Of Axitinib (Ag-013736) With Or Without Dose Titration In Patients With Metastatic Renal Cell Carcinoma

Study Start Date :

Aug 1, 2009

Actual Primary Completion Date :

Oct 1, 2012

Actual Study Completion Date :

Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Other: A Randomized arm	Drug: axitinib axitinib 5mg BID (open-label) + axitinib dose titration (blinded)
Other: B Randomized arm	Drug: axitinib axitinib 5mg BID (open-label) + placebo dose titration (blinded)
Other: C Non-randomized arm	Drug: axitinib axitinib 5mg BID (open-label)

Arm

Intervention/Treatment

Other: A

Randomized arm

Drug: axitinib

axitinib 5mg BID (open-label) + axitinib dose titration (blinded)

Other: B

Randomized arm

Drug: axitinib

axitinib 5mg BID (open-label) + placebo dose titration (blinded)

Other: C

Non-randomized arm

Drug: axitinib

axitinib 5mg BID (open-label)

Outcome Measures

Primary Outcome Measures

Objective Response Rate (ORR) - Percentage of Participants With Objective Response [Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.]
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.

Secondary Outcome Measures

Progression-Free Survival (PFS) [Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.]
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.
Duration of Response (DR) [Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks]
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.
Overall Survival (OS) [Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.]
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.
Maximum Observed Plasma Concentration (Cmax) of Axitinib [Cycle 2 Day 15 (C2D15): pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose]
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.
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib, [C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose]
Tmax for steady-state axitinib was evaluated on Cycle 2 Day 15.
Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib [C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose]
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.
Area Under the Curve From Time Zero to 24 Hours[AUC(0-24)] for Axitinib [C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose]
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.
Plasma Decay Half-Life (t1/2) for Axitinib [C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose]
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.
Apparent Oral Clearance (CL/F) of Axitinib [C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose]
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.
Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib [C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose]
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.
Change From Baseline in Systolic Blood Pressure [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.]
Value at respective visit minus value at baseline
Change From Baseline in Diastolic Blood Pressure [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.]
Value at respective visit minus value at baseline.
Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline [At baseline - Beginning of the lead-in period (Cycle 1 Day 1)]
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.
Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline [At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)]
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.
Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+ [At baseline - Beginning of the lead-in period (Cycle 1 Day 1)]
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.
Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline [At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)]
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.
ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms [At baseline - Beginning of the lead-in period (Cycle 1 Day 1)]
ORR, defined as proportion of participants with CR or PR according to RECIST, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms.
PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms [At baseline - Beginning of the lead-in period (Cycle 1 Day 1)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

metastatic renal cell carcinoma (kidney cancer) with clear cell component
no prior systemic therapy (including no prior adjuvant or neoadjuvant)
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
Blood Pressure < or = 140/90mmHg

Exclusion Criteria:

brain/CNS metastasis
using more than 2 blood pressure medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	East Bay Medical Oncology/Hematology Medical Associates Inc.	Antioch	California	United States	94531
2	Comprehensive Blood and Cancer Center	Bakersfield	California	United States	93309
3	Bay Area Cancer Research Group, LLC	Pleasant Hill	California	United States	94523
4	Diablo Valley Oncology and Hematology Medical Group Inc	Pleasant Hill	California	United States	94523
5	East Bay Medical Oncology/Hematology Medical Associates Inc	Pleasant Hill	California	United States	94523
6	East Bay Medical Oncology/Hematology Medical Associates Inc	San Leandro	California	United States	94578
7	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
8	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
9	Investigational Drug Services, IUHSCC	Indianapolis	Indiana	United States	46202
10	IU Health University Hospital	Indianapolis	Indiana	United States	46202
11	University of Maryland Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
12	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231
13	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
14	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
15	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
16	Cancer and Hematology Centers of Western Michigan	Grand Rapids	Michigan	United States	49503
17	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110-1094
18	Washington University	Saint Louis	Missouri	United States	63110
19	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
20	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-7680
21	Nevada Cancer Institute	Las Vegas	Nevada	United States	89135
22	The University Hospital	Cincinnati	Ohio	United States	45219
23	University of Cincinnati	Cincinnati	Ohio	United States	45219
24	Cleveland Clinic	Cleveland	Ohio	United States	44195
25	The Ohio State University, James Cancer Hospital	Columbus	Ohio	United States	43210
26	JamesCare in Kenny	Columbus	Ohio	United States	43221
27	West Chester Hospital Medical Building	West Chester	Ohio	United States	45069
28	Oregon Health and Science University	Portland	Oregon	United States	97239
29	Texas Oncology, Sammons Cancer Center	Dallas	Texas	United States	75246
30	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030-4004
31	Virginia Mason Medical Center	Seattle	Washington	United States	98101
32	Masarykuv onkologicky ustav	Brno	CZE	Czechia	656 53
33	Fakultni nemocnice Olomouc Onkologicka klinika	Olomouc		Czechia	775 20
34	Fakultni nemocnice Na Bulovce	Praha 8		Czechia	180 81
35	Krajska zdravotni, a.s. - Masarykova nemocnice V Usti nad Labem, o.z.	Usti nad Labem		Czechia	401 13
36	Universitaetsklinikum Duesseldorf	Duesseldorf		Germany	40225
37	Klinikum der J. W. Goethe-Universitaet, Medizinische Klinik II	Frankfurt		Germany	60590
38	Medizinische Hochschule Hannover, Abt. Haematologie, Haemostaseologie & Onkologie	Hannover		Germany	30625
39	Eberhardt-Karls-Universitaet Tuebingen, Klinik fuer Urologie	Tuebingen		Germany	72076
40	Klinikum Weiden Klinik fuer Urologie, Andrologie und Kinderurologie	Weiden		Germany	92637
41	Nagoya University Hospital	Nagoya	Aichi	Japan	466-8560
42	Sapporo Medical University Hospital	Sapporo	Hokkaido	Japan	060-8543
43	Hokkaido University Hospital	Sapporo	Hokkaido	Japan	060-8638
44	Kobe University Hospital	Kobe	Hyogo	Japan	650-0017
45	Kinki University Hospital	Osakasayama	Osaka	Japan	589-8511
46	Hamamatsu University School of Medicine, University Hospital	Hamamatsu-City	Shizuoka	Japan	431-3192
47	National Cancer Center	Chuo-ku	Tokyo	Japan	104-0045
48	Japanese Foundation For Cancer Research Cancer Institute Hospital	Koto-ku	Tokyo	Japan	135-8550
49	Keio University Hospital	Shinjuku-ku	Tokyo	Japan	160-8582
50	Akita University Hospital	Akita		Japan	010-8543
51	Chiba Cancer Center	Chiba		Japan	260-8717
52	Kyushu University Hospital	Fukuoka		Japan	812-8582
53	Nagasaki University Hospital	Nagasaki		Japan	852-8501
54	Tokushima University Hospital	Tokushima		Japan	770-8503
55	Yamagata University Hospital	Yamagata		Japan	990-9585
56	Medical Radiology Research Center of the Minzdravsotsrazvitiya of Russia	Obninsk	Kaluga Region	Russian Federation	249036
57	State Healthcare Institution "Leningrad Regional Oncology Dispensary"	Poselok Kuzmolovskiy	Vsevolozhskiy Region, Leningradskaya Oblast	Russian Federation	188663
58	FSBSI "N.N. Blokhin Russian Cancer Research Center"	Moscow		Russian Federation	115478
59	FSBI"Russian Scientific Center of Roengenoradiology" of the MH of RF	Moscow		Russian Federation	117997
60	Saint-Petersburg's State Healthcare Institution 'City Clinical Oncology Dispensary'	Saint-Petersburg		Russian Federation	197022
61	Saint-Petersburg's State Healthcare Institution 'City Clinical Oncology Dispensary'	Saint-Petersburg		Russian Federation	198255
62	GBUZ "Samara Regional Clinical Oncology Dispensary"	Samara		Russian Federation	443031
63	Hospital de La Princesa	Madrid		Spain	28006
64	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
65	Hospital Universitario La Paz	Madrid		Spain	28046

Sponsors and Collaborators

Pfizer

Investigators

Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

To obtain contact information for a study center near you, click here.

Publications

None provided.

Responsible Party:

Pfizer

ClinicalTrials.gov Identifier:

NCT00835978

Other Study ID Numbers:

A4061046
2008-007786-23

First Posted:

Feb 4, 2009

Last Update Posted:

May 30, 2017

Last Verified:

Apr 1, 2017

Keywords provided by Pfizer

axitinib or AG-013736 dose titration (increase) renal cell carcinoma

kidney cancer

Additional relevant MeSH terms:

Carcinoma

Carcinoma, Renal Cell

Axitinib

Study Results

Participant Flow

Recruitment Details	This study was conducted at 49 centers in Czech Republic, Germany, Japan, Russian Federation, Spain, and the United States (US).
Pre-assignment Detail	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).

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization
Arm/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).	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).	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.	Participants who discontinued before they were randomized to any of the treatment or non-randomized arms.
Period Title: Overall Study
STARTED	56	56	91	10
Treated	56	56	91	10
COMPLETED	0	0	0	0
NOT COMPLETED	56	56	91	10

Baseline Characteristics

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	Discontinued Prior to Randomization	Total
Arm/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).	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).	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.	Participants who discontinued before they were randomized to any of the treatment or non-randomized arms.	Total of all reporting groups
Overall Participants	56	56	91	10	213
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.7 (10.2)	59.6 (10.5)	62.9 (8.9)	62.9 (7.5)	61.2 (9.7)
Age, Customized (Number) [Number]
< 65 Years	38 67.9%	38 67.9%	54 59.3%	6 60%	136 63.8%
>= 65 Years	18 32.1%	18 32.1%	37 40.7%	4 40%	77 36.2%
Sex: Female, Male (Count of Participants)
Female	19 33.9%	11 19.6%	36 39.6%	4 40%	70 32.9%
Male	37 66.1%	45 80.4%	55 60.4%	6 60%	143 67.1%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) - Percentage of Participants With Objective Response
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.
Time Frame	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Outcome Measure Data

Analysis Population Description
The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	All Participants
Arm/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).	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).	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.	All enrolled participants (randomized and non-randomized)
Measure Participants	56	56	91	213
Number (95% Confidence Interval) [Percentage of Participants]	53.6 95.7%	33.9 60.5%	59.3 65.2%	48.4 484%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Titration Arm, Placebo Titration Arm
	Comments	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.
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.0189
	Comments	A priori defined threshold for statistical significance was: alpha=0.10 (one-sided)
	Method	Cochran-Mantel-Haenszel
	Comments

Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.578
	Confidence Interval	(2-Sided) 95% 1.017 to 2.448
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
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.
Time Frame	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Outcome Measure Data

Analysis Population Description
The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm	All Participants
Arm/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).	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).	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.	All enrolled participants (randomized and non-randomized)
Measure Participants	56	56	91	213
Median (95% Confidence Interval) [Months]	14.5	15.7	16.6	14.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Titration Arm, Placebo Titration Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value	0.2444
	Comments
	Method	Log Rank
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.849
	Confidence Interval	(2-Sided) 95% 0.535 to 1.348
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Duration of Response (DR)
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.
Time Frame	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks

Outcome Measure Data

Analysis Population Description
Subset of Full Analysis (FA) and Safety Analysis (SA) patients who achieved confirmed complete or partial response. FA included all randomized patients and was based on randomized treatment assignment regardless of whether or not study drug was administered. SA included all non randomized patients who received at least one dose of study medication.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	30	19	54
Median (95% Confidence Interval) [Months]	NA	21.2	23.3

4. Secondary Outcome

Title	Overall Survival (OS)
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.
Time Frame	Baseline up to disease progression, death, or withdrawal; performed at baseline and repeated every 8 weeks for 24 weeks, then every 12 weeks.

Outcome Measure Data

Analysis Population Description
The Full Analysis (FA) population included all randomized participants who received study drug or different drug to which they were randomized. The Safety Analysis (SA) population included all non-randomized patients who received at least 1 dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm (FA Population)	Placebo Titration Arm (FA Population)	Non-randomized Arm (SA Population)
Arm/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).	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).	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.
Measure Participants	56	56	91
Median (95% Confidence Interval) [Months]	42.7	30.4	41.6

5. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Axitinib
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.
Time Frame	Cycle 2 Day 15 (C2D15): pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/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).	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).
Measure Participants	16	20
Geometric Mean (95% Confidence Interval) [ng/mL]	31.74	23.05

6. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) for Axitinib,
Description	Tmax for steady-state axitinib was evaluated on Cycle 2 Day 15.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/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).	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).
Measure Participants	16	20
Median (Full Range) [hrs]	2.04	2.00

7. Secondary Outcome

Title	Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for Axitinib
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.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/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).	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).
Measure Participants	16	20
Geometric Mean (95% Confidence Interval) [ng.hr/mL]	105.33	78.44

8. Secondary Outcome

Title	Area Under the Curve From Time Zero to 24 Hours[AUC(0-24)] for Axitinib
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.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/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).	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).
Measure Participants	16	20
Geometric Mean (95% Confidence Interval) [ng.hr/mL]	258.68	161.38

9. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) for Axitinib
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.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/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).	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).
Measure Participants	16	20
Mean (Standard Deviation) [hr]	2.48 (1.902)	2.81 (1.685)

10. Secondary Outcome

Title	Apparent Oral Clearance (CL/F) of Axitinib
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.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/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).	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).
Measure Participants	16	20
Geometric Mean (95% Confidence Interval) [L/hr]	54.15	61.93

11. Secondary Outcome

Title	Apparent Volume of Distribution During the Elimination Phase (Vz/F) for Axitinib
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.
Time Frame	C2D15: pre-dose, 0.5, 1, 2, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description
The pharmacokinetic (PK) population included all participants who were treated and had at least 1 concentration on 1 PK assessment day. The PK parameter analysis data set included all participants treated who had at least 1 estimated PK parameter of primary interest.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm
Arm/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).	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).
Measure Participants	16	20
Geometric Mean (95% Confidence Interval) [L]	158.18	216.62

12. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure
Description	Value at respective visit minus value at baseline
Time Frame	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.

Outcome Measure Data

Analysis Population Description
The SA population consists of all participatns who received at least one dose of study medication.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	56	56	91
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 (18.0)
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 (13.0)	5.5 (18.2)
End of treatment (n=35,44,51)	2.4 (17.0)	1.7 (14.0)	-2.8 (19.0)
Follow-up (n=16,25,36)	-3.6 (16.9)	-0.4 (16.3)	-0.6 (16.7)

13. Secondary Outcome

Title	Change From Baseline in Diastolic Blood Pressure
Description	Value at respective visit minus value at baseline.
Time Frame	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.

Outcome Measure Data

Analysis Population Description
The SA population consists of all participatns who received at least one dose of study medication.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	56	56	91
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)	3.0 (7.7)	11.5 (10.0)
Cycle 2 Day 1 (n=56,56,91)	4.2 (9.0)	3.5 (8.0)	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)	3.0 (10.5)
Follow-up (n=16,25,36)	-4.5 (10.1)	-1.3 (8.5)	1.8 (9.0)

14. Secondary Outcome

Title	Comparison of Circulating Endothelial Cells (CECs) in Blood: Cluster of Differentiation (CD)146+/CD105+ at Baseline
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.
Time Frame	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Outcome Measure Data

Analysis Population Description
The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	17	22	20
Baseline CECs Count (n=17,22,20)	23584 (18213.1)	28544 (27694.4)	29663 (30651.0)
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)

15. Secondary Outcome

Title	Comparison of the Ratio of CECs in Blood: CD146+/CD105+ at Each Time Point to Baseline
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.
Time Frame	At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)

Outcome Measure Data

Analysis Population Description
The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	17	22	20
C1D15:C1D1 CECs Count (n=11,18,14)	2.3 (2.52)	3.7 (6.92)	2.2 (3.10)
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 (21.70)	1.2 (1.50)
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)	2.2 (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)	1.0 (1.12)
C2D15:C1D1 MFI pPDGFR-BETA (n=13,16,11)	1.0 (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 (0.46)	1.2 (0.88)	1.2 (1.00)
C2D15:C1D1 MFI pVEGFR (n=12,16,11)	1.0 (0.74)	0.9 (0.82)	1.2 (0.80)
EOT:C1D1 MFI pVEGFR (n=7,9,4)	0.8 (0.53)	1.3 (0.96)	3.0 (1.16)
C1D15:C1D1 MFI VEGFR (n=10,18,14)	1.4 (1.25)	1.3 (0.94)	1.0 (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)

16. Secondary Outcome

Title	Circulating Endothelial Cells (CECs) in Blood: CD31+/CD146+
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.
Time Frame	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Outcome Measure Data

Analysis Population Description
The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	17	22	20
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)

17. Secondary Outcome

Title	Comparison of Ratio of CECs in Blood: CD31+/CD146+ at Each Time Point to Baseline
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.
Time Frame	At end of the lead-in period (Cycle 1 Day 15), Cycle 2 Day 15 and End of therapy (EOT)

Outcome Measure Data

Analysis Population Description
The Biomarker Analysis Set included participants receiving at least one dose of treatment, with a Cycle 1 Day 1 biomarker result for at least one biomarker.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	17	22	20
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 (1.38)	2.2 (3.91)	2.5 (3.98)
EOT:C1D1 CECs COUNT (n=7,9,4)	1.5 (1.95)	1.4 (2.66)	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 (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 (0.47)
C1D15:C1D1 MFI pVEGFR (n=11,18,14)	1.1 (0.75)	1.4 (0.74)	1.2 (0.90)
C2D15:C1D1 MFI pVEGFR (n=13,16,10)	1.2 (1.00)	0.9 (0.68)	1.3 (0.70)
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 (0.90)	1.0 (0.57)
C2D15:C1D1 MFI VEGFR n=13,16,10)	1.5 (1.44)	1.2 (0.96)	2.1 (1.80)
EOT:C1D1 MFI VEGFR (n=7,9,4)	1.2 (1.27)	1.1 (0.90)	1.5 (1.42)

18. Secondary Outcome

Title	ORR in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms
Description	ORR, defined as proportion of participants with CR or PR according to RECIST, in subgroups that were defined by VEGFA or VEGFR3 polymorphisms.
Time Frame	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Outcome Measure Data

Analysis Population Description
The Safety Analysis (SA) population consisted of all participants who received at least one dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	49	49	79
VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14)	85.7 153%	22.2 39.6%	42.9 47.1%
VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41)	54.5 97.3%	35.0 62.5%	65.9 72.4%
VEGFA/rs699947 Genotype: C/C (n = 14, 14, 24)	50.0 89.3%	35.7 63.8%	66.7 73.3%
VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43)	59.1 105.5%	39.1 69.8%	67.4 74.1%
VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29)	57.9 103.4%	18.8 33.6%	58.6 64.4%
VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 7)	50.0 89.3%	50.0 89.3%	42.9 47.1%
VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28)	81.3 145.2%	53.3 95.2%	60.7 66.7%
VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35)	45.5 81.3%	18.2 32.5%	57.1 62.7%
VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16)	40.0 71.4%	33.3 59.5%	75.0 82.4%
VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 79)	58.3 104.1%	30.8 55%	64.3 70.7%
VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9)	50.0 89.3%	50.0 89.3%	44.4 48.8%
VEGFR3/rs307826 Genotype: G/G (n = 1, 0, 0)	100.0 178.6%	0 0%	0 0%
VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 79)	55.6 99.3%	28.9 51.6%	65.2 71.6%
VEGFR3/rs307821 Genotype: G/T (n = 6, 5, 10)	66.7 119.1%	60.0 107.1%	40.0 44%
VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0)	100.0 178.6%	0 0%	0 0%

19. Secondary Outcome

Title	PFS in Subgroups That Were Defined by Vascular Endothelial Growth Factor A (VEGFA) or Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) Polymorphisms
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.
Time Frame	At baseline - Beginning of the lead-in period (Cycle 1 Day 1)

Outcome Measure Data

Analysis Population Description
The Safety Analysis (SA) population consisted of all participants who received at least one dose of study medication with treatment assignments designated according to actual study treatment received.

Arm/Group Title	Active Titration Arm	Placebo Titration Arm	Non-randomized Arm
Arm/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).	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).	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.
Measure Participants	43	43	79
VEGFA/rs699947 Genotype: A/A (n = 7, 9, 14)	NA	11.50	7.33
VEGFA/rs699947 Genotype: A/C (n = 22, 20, 41)	11.07	9.67	16.59
VEGFA/rs699947 Genotype: C/C (n = 14, 14, 41)	18.74	24.64	25.13
VEGFA/rs1570360 Genotype: G/G (n = 22, 23, 43)	14.62	19.42	25.13
VEGFA/rs1570360 Genotype: G/A (n = 19, 16, 29)	12.78	8.34	13.90
VEGFA/rs1570360 Genotype: A/A (n = 2, 4, 29)	NA	10.04	8.57
VEGFR3/rs448012 Genotype: G/G (n = 16, 15, 28)	17.44	19.42	22.54
VEGFR3/rs448012 Genotype: G/C (n = 22, 22, 35)	9.18	8.31	13.83
VEGFR3/rs448012 Genotype: C/C (n = 5, 6, 16)	11.07	15.67	NA
VEGFR3/rs307826 Genotype: A/A (n = 36, 39, 70)	13.73	15.67	16.56
VEGFR3/rs307826 Genotype: A/G (n = 6, 4, 9)	16.52	7.93	16.26
VEGFR3/rs307826 Genotype: G/G (n = 0, 0, 0)	NA	NA	NA
VEGFR3/rs307821 Genotype: G/G (n = 36, 38, 69)	12.78	15.67	16.59
VEGFR3/rs307821 Genotype: G/T (n = 36, 38, 10)	24.80	8.34	13.86
VEGFR3/rs307821 Genotype: T/T (n = 1, 0, 0)	NA	NA	NA

Adverse Events

	Active Titration Arm		Placebo Titration Arm		Non-randomized Arm		Discontinued Prior to Randomization
Time Frame	AEs were reported until follow up visit. Non-SAEs: up to 28 days post last dose or upon starting new anticancer treatment, whichever was first. SAEs: up to 28 days post last dose, irrespective of new anticancer treatment.
Adverse Event Reporting Description	The same event may be referred to as (serious and non-serious) AEs. 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.

Arm/Group Title	Active Titration Arm		Placebo Titration Arm		Non-randomized Arm		Discontinued Prior to Randomization
Arm/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).		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).		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.		Participants who were discontinued prior to randomization to either treatment or non-randomization arms.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Active Titration Arm		Placebo Titration Arm		Non-randomized Arm		Discontinued Prior to Randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/56 (44.6%)		14/56 (25%)		39/91 (42.9%)		2/10 (20%)
Blood and lymphatic system disorders
Neutropenia	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Anaemia	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Cardiac disorders
Myocardial ischaemia	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Acute myocardial infarction	1/56 (1.8%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Angina pectoris	0/56 (0%)		0/56 (0%)		2/91 (2.2%)		0/10 (0%)
Coronary artery stenosis	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Diastolic dysfunction	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Myocardial infarction	4/56 (7.1%)		0/56 (0%)		2/91 (2.2%)		0/10 (0%)
Acute coronary syndrome	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Atrial fibrillation	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Cardiac failure	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Coronary artery disease	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Ear and labyrinth disorders
Tinnitus	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Endocrine disorders
Hypothyroidism	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Eye disorders
Cataract	0/56 (0%)		0/56 (0%)		3/91 (3.3%)		0/10 (0%)
Gastrointestinal disorders
Diarrhoea	2/56 (3.6%)		1/56 (1.8%)		1/91 (1.1%)		0/10 (0%)
Nausea	2/56 (3.6%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Vomiting	3/56 (5.4%)		1/56 (1.8%)		1/91 (1.1%)		0/10 (0%)
Diverticulum intestinal haemorrhagic	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Abdominal distension	1/56 (1.8%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Abdominal pain	1/56 (1.8%)		1/56 (1.8%)		1/91 (1.1%)		0/10 (0%)
Abdominal pain upper	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Ascites	0/56 (0%)		2/56 (3.6%)		0/91 (0%)		0/10 (0%)
Crohn's disease	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Enterocolitis	0/56 (0%)		1/56 (1.8%)		1/91 (1.1%)		0/10 (0%)
Gastrointestinal hypomotility	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/1 (0%)
Ileus	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Intestinal obstruction	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Pancreatitis	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Small intestinal obstruction	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
General disorders
Disease progression	1/56 (1.8%)		1/56 (1.8%)		6/91 (6.6%)		0/10 (0%)
General physical health deterioration	1/56 (1.8%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Chest pain	1/56 (1.8%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Fatigue	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Pyrexia	0/56 (0%)		2/56 (3.6%)		1/91 (1.1%)		0/10 (0%)
Hepatobiliary disorders
Cholecystitis chronic	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Biliary colic	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Cholelithiasis	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Infections and infestations
Cystitis	1/56 (1.8%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Lung abscess	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Pneumonia	3/56 (5.4%)		2/56 (3.6%)		1/91 (1.1%)		0/10 (0%)
Appendicitis	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Infection	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Lung infection	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Osteomyelitis	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Peritonitis bacterial	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Postoperative wound infection	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Gingivitis	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Overdose	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Postoperative hernia	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Postoperative wound complication	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Road traffic accident	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Cervical vertebral fracture	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Incisional hernia	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Postoperative ileus	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Rib fracture	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Investigations
Blood creatinine increased	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Blood sodium decreased	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Metabolism and nutrition disorders
Dehydration	5/56 (8.9%)		0/56 (0%)		3/91 (3.3%)		1/10 (10%)
Decreased appetite	1/56 (1.8%)		1/56 (1.8%)		2/91 (2.2%)		0/10 (0%)
Hypercalcaemia	0/56 (0%)		0/56 (0%)		0/91 (0%)		1/10 (10%)
Hypokalaemia	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Hyponatraemia	0/56 (0%)		1/56 (1.8%)		1/91 (1.1%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/56 (3.6%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Haemarthrosis	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Pain in extremity	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Breast cancer	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Colon cancer	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Nervous system disorders
Cerebrovascular insufficiency	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Syncope	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Encephalopathy	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Headache	0/56 (0%)		1/56 (1.8%)		1/91 (1.1%)		0/10 (0%)
Presyncope	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Somnolence	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Cerebrovascular accident	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Monoparesis	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Transient ischaemic attack	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Psychiatric disorders
Delirium	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Renal and urinary disorders
Renal colic	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Postrenal failure	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Renal failure	0/56 (0%)		0/56 (0%)		0/91 (0%)		1/10 (10%)
Acute kidney injury	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Urinary retention	0/56 (0%)		0/56 (0%)		2/91 (2.2%)		0/10 (0%)
Reproductive system and breast disorders
Pelvic prolapse	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Dyspnoea	1/56 (1.8%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Cough	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		0/10 (0%)
Pleural effusion	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Pulmonary hypertension	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Pulmonary oedema	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Hypercapnia	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Pulmonary embolism	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Dermatitis	1/56 (1.8%)		0/56 (0%)		0/91 (0%)		0/10 (0%)
Surgical and medical procedures
Incisional hernia repair	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Vascular disorders
Circulatory collapse	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Hypertension	0/56 (0%)		1/56 (1.8%)		1/91 (1.1%)		0/10 (0%)
Hypertensive crisis	0/56 (0%)		0/56 (0%)		0/91 (0%)		1/10 (10%)
Hypotension	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Orthostatic hypotension	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Active Titration Arm		Placebo Titration Arm		Non-randomized Arm		Discontinued Prior to Randomization
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/56 (98.2%)		51/56 (91.1%)		91/91 (100%)		9/10 (90%)
Blood and lymphatic system disorders
Anaemia	5/56 (8.9%)		4/56 (7.1%)		9/91 (9.9%)		1/10 (10%)
Lymphopenia	0/56 (0%)		0/56 (0%)		2/91 (2.2%)		1/10 (10%)
Thrombocytopenia	5/56 (8.9%)		3/56 (5.4%)		15/91 (16.5%)		0/10 (0%)
Cardiac disorders
Sinus tachycardia	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		2/10 (20%)
Ear and labyrinth disorders
Tinnitus	0/56 (0%)		3/56 (5.4%)		4/91 (4.4%)		0/10 (0%)
Endocrine disorders
Hypothyroidism	18/56 (32.1%)		13/56 (23.2%)		41/91 (45.1%)		2/10 (20%)
Gastrointestinal disorders
Abdominal pain	9/56 (16.1%)		9/56 (16.1%)		11/91 (12.1%)		1/10 (10%)
Abdominal pain upper	6/56 (10.7%)		2/56 (3.6%)		11/91 (12.1%)		0/10 (0%)
Constipation	11/56 (19.6%)		7/56 (12.5%)		27/91 (29.7%)		3/10 (30%)
Diarrhoea	34/56 (60.7%)		35/56 (62.5%)		58/91 (63.7%)		1/10 (10%)
Dry Mouth	7/56 (12.5%)		2/56 (3.6%)		7/91 (7.7%)		0/10 (0%)
Dyspepsia	7/56 (12.5%)		5/56 (8.9%)		18/91 (19.8%)		0/10 (0%)
Flatulence	7/56 (12.5%)		3/56 (5.4%)		4/91 (4.4%)		0/10 (0%)
Haemorrhoids	2/56 (3.6%)		1/56 (1.8%)		4/91 (4.4%)		1/10 (10%)
Nausea	24/56 (42.9%)		19/56 (33.9%)		33/91 (36.3%)		2/10 (20%)
Stomatitis	10/56 (17.9%)		4/56 (7.1%)		17/91 (18.7%)		0/10 (0%)
Vomiting	18/56 (32.1%)		12/56 (21.4%)		25/91 (27.5%)		2/10 (20%)
Abdominal distension	1/56 (1.8%)		3/56 (5.4%)		3/91 (3.3%)		0/10 (0%)
Gastritis	3/56 (5.4%)		2/56 (3.6%)		9/91 (9.9%)		0/10 (0%)
Gastrooesophageal reflux disease	2/56 (3.6%)		3/56 (5.4%)		6/91 (6.6%)		0/10 (0%)
Abdominal discomfort	2/56 (3.6%)		0/56 (0%)		6/91 (6.6%)		0/10 (0%)
Dysphagia	0/56 (0%)		2/56 (3.6%)		2/91 (2.2%)		1/10 (10%)
Proctalgia	2/56 (3.6%)		0/56 (0%)		5/91 (5.5%)		0/10 (0%)
Toothache	1/56 (1.8%)		3/56 (5.4%)		5/91 (5.5%)		0/10 (0%)
General disorders
Asthenia	6/56 (10.7%)		5/56 (8.9%)		6/91 (6.6%)		0/10 (0%)
Fatigue	27/56 (48.2%)		26/56 (46.4%)		49/91 (53.8%)		4/10 (40%)
Mucosal inflammation	12/56 (21.4%)		8/56 (14.3%)		13/91 (14.3%)		0/10 (0%)
Oedema peripheral	4/56 (7.1%)		3/56 (5.4%)		14/91 (15.4%)		0/10 (0%)
Pain	4/56 (7.1%)		3/56 (5.4%)		6/91 (6.6%)		0/10 (0%)
Chest pain	5/56 (8.9%)		2/56 (3.6%)		6/91 (6.6%)		0/10 (0%)
Chills	4/56 (7.1%)		1/56 (1.8%)		5/91 (5.5%)		0/10 (0%)
General physical health deterioration	0/56 (0%)		0/56 (0%)		0/91 (0%)		1/10 (10%)
Pyrexia	6/56 (10.7%)		3/56 (5.4%)		4/91 (4.4%)		0/10 (0%)
Hepatobiliary disorders
Hepatic function abnormal	3/56 (5.4%)		1/56 (1.8%)		5/91 (5.5%)		0/10 (0%)
Infections and infestations
Rhinitis	3/56 (5.4%)		6/56 (10.7%)		4/91 (4.4%)		0/10 (0%)
Upper respiratory tract infection	4/56 (7.1%)		3/56 (5.4%)		6/91 (6.6%)		0/10 (0%)
Nasopharyngitis	4/56 (7.1%)		3/56 (5.4%)		19/91 (20.9%)		0/10 (0%)
Respiratory tract infection	2/56 (3.6%)		3/56 (5.4%)		0/91 (0%)		0/10 (0%)
Sinusitis	4/56 (7.1%)		2/56 (3.6%)		2/91 (2.2%)		0/10 (0%)
Urinary tract infection	3/56 (5.4%)		1/56 (1.8%)		10/91 (11%)		1/10 (10%)
Investigations
Alanine aminotransferase increased	6/56 (10.7%)		9/56 (16.1%)		12/91 (13.2%)		0/10 (0%)
Aspartate aminotransferase increased	6/56 (10.7%)		10/56 (17.9%)		12/91 (13.2%)		0/10 (0%)
Blood creatinine increased	4/56 (7.1%)		8/56 (14.3%)		14/91 (15.4%)		1/10 (10%)
Blood glucose increased	4/56 (7.1%)		7/56 (12.5%)		10/91 (11%)		2/10 (20%)
Fibrin D dimer increased	0/56 (0%)		1/56 (1.8%)		0/91 (0%)		1/10 (10%)
Weight decreased	16/56 (28.6%)		12/56 (21.4%)		25/91 (27.5%)		1/10 (10%)
Blood alkaline phosphatase increased	4/56 (7.1%)		4/56 (7.1%)		6/91 (6.6%)		2/10 (20%)
Blood glucose decreased	3/56 (5.4%)		5/56 (8.9%)		1/91 (1.1%)		0/10 (0%)
Blood potassium increased	4/56 (7.1%)		3/56 (5.4%)		4/91 (4.4%)		0/10 (0%)
Blood thyroid stimulating hormone increased	8/56 (14.3%)		7/56 (12.5%)		9/91 (9.9%)		0/10 (0%)
Blood albumin decreased	1/56 (1.8%)		3/56 (5.4%)		1/91 (1.1%)		0/10 (0%)
Blood sodium decreased	2/56 (3.6%)		3/56 (5.4%)		1/91 (1.1%)		0/10 (0%)
Blood triglycerides increased	2/56 (3.6%)		2/56 (3.6%)		5/91 (5.5%)		0/10 (0%)
Haemoglobin decreased	1/56 (1.8%)		1/56 (1.8%)		5/91 (5.5%)		0/10 (0%)
Metabolism and nutrition disorders
Decreased appetite	21/56 (37.5%)		16/56 (28.6%)		37/91 (40.7%)		3/10 (30%)
Hyponatraemia	4/56 (7.1%)		1/56 (1.8%)		4/91 (4.4%)		1/10 (10%)
Hyperkalaemia	6/56 (10.7%)		1/56 (1.8%)		5/91 (5.5%)		0/10 (0%)
Hyperlipidaemia	0/56 (0%)		0/56 (0%)		7/91 (7.7%)		0/10 (0%)
Hyperuricaemia	1/56 (1.8%)		0/56 (0%)		9/91 (9.9%)		0/10 (0%)
Hypoalbuminaemia	3/56 (5.4%)		1/56 (1.8%)		2/91 (2.2%)		0/10 (0%)
Hypophosphataemia	2/56 (3.6%)		2/56 (3.6%)		4/91 (4.4%)		1/10 (10%)
Dehydration	3/56 (5.4%)		4/56 (7.1%)		5/91 (5.5%)		0/10 (0%)
Hyperglycaemia	4/56 (7.1%)		3/56 (5.4%)		6/91 (6.6%)		0/10 (0%)
Hypoglycaemia	0/56 (0%)		3/56 (5.4%)		2/91 (2.2%)		0/10 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/56 (23.2%)		11/56 (19.6%)		17/91 (18.7%)		0/10 (0%)
Back pain	13/56 (23.2%)		8/56 (14.3%)		17/91 (18.7%)		0/10 (0%)
Groin pain	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		1/10 (10%)
Musculoskeletal pain	8/56 (14.3%)		4/56 (7.1%)		15/91 (16.5%)		0/10 (0%)
Bone pain	3/56 (5.4%)		2/56 (3.6%)		5/91 (5.5%)		0/10 (0%)
Muscular weakness	3/56 (5.4%)		2/56 (3.6%)		2/91 (2.2%)		0/10 (0%)
Musculoskeletal stiffness	1/56 (1.8%)		4/56 (7.1%)		3/91 (3.3%)		0/10 (0%)
Myalgia	4/56 (7.1%)		3/56 (5.4%)		8/91 (8.8%)		0/10 (0%)
Neck pain	4/56 (7.1%)		4/56 (7.1%)		5/91 (5.5%)		0/10 (0%)
Pain in extremity	8/56 (14.3%)		9/56 (16.1%)		23/91 (25.3%)		2/10 (20%)
Flank pain	1/56 (1.8%)		3/56 (5.4%)		4/91 (4.4%)		0/10 (0%)
Muscle spasms	3/56 (5.4%)		3/56 (5.4%)		6/91 (6.6%)		0/10 (0%)
Musculoskeletal chest pain	3/56 (5.4%)		3/56 (5.4%)		3/91 (3.3%)		0/10 (0%)
Nervous system disorders
Dysgeusia	9/56 (16.1%)		5/56 (8.9%)		21/91 (23.1%)		1/10 (10%)
Headache	9/56 (16.1%)		15/56 (26.8%)		27/91 (29.7%)		0/10 (0%)
Hypoaesthesia	2/56 (3.6%)		0/56 (0%)		4/91 (4.4%)		1/10 (10%)
Paraesthesia	5/56 (8.9%)		3/56 (5.4%)		3/91 (3.3%)		1/10 (10%)
Dizziness	8/56 (14.3%)		10/56 (17.9%)		14/91 (15.4%)		1/10 (10%)
Transient ischaemic attack	0/56 (0%)		0/56 (0%)		1/91 (1.1%)		1/10 (10%)
Dyskinesia	0/56 (0%)		0/56 (0%)		0/91 (0%)		1/10 (10%)
Peripheral sensory neuropathy	4/56 (7.1%)		1/56 (1.8%)		3/91 (3.3%)		0/10 (0%)
Psychiatric disorders
Confusional state	1/56 (1.8%)		1/56 (1.8%)		0/91 (0%)		2/10 (20%)
Insomnia	3/56 (5.4%)		4/56 (7.1%)		8/91 (8.8%)		1/10 (10%)
Anxiety	3/56 (5.4%)		3/56 (5.4%)		7/91 (7.7%)		0/10 (0%)
Delirium	0/56 (0%)		0/56 (0%)		0/91 (0%)		1/10 (10%)
Depression	4/56 (7.1%)		4/56 (7.1%)		6/91 (6.6%)		0/10 (0%)
Renal and urinary disorders
Haemoglobinuria	2/56 (3.6%)		3/56 (5.4%)		5/91 (5.5%)		1/10 (10%)
Proteinuria	12/56 (21.4%)		12/56 (21.4%)		40/91 (44%)		2/10 (20%)
Dysuria	3/56 (5.4%)		0/56 (0%)		3/91 (3.3%)		0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	7/56 (12.5%)		8/56 (14.3%)		19/91 (20.9%)		0/10 (0%)
Dysphonia	18/56 (32.1%)		20/56 (35.7%)		44/91 (48.4%)		3/10 (30%)
Dyspnoea	6/56 (10.7%)		8/56 (14.3%)		27/91 (29.7%)		1/10 (10%)
Epistaxis	4/56 (7.1%)		3/56 (5.4%)		12/91 (13.2%)		0/10 (0%)
Oropharyngeal pain	4/56 (7.1%)		2/56 (3.6%)		8/91 (8.8%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Dry skin	7/56 (12.5%)		3/56 (5.4%)		7/91 (7.7%)		0/10 (0%)
Palmar-plantar erythrodysaesthesia syndrome	18/56 (32.1%)		10/56 (17.9%)		40/91 (44%)		0/10 (0%)
Pruritus	2/56 (3.6%)		6/56 (10.7%)		13/91 (14.3%)		0/10 (0%)
Rash	5/56 (8.9%)		8/56 (14.3%)		19/91 (20.9%)		0/10 (0%)
Alopecia	2/56 (3.6%)		3/56 (5.4%)		14/91 (15.4%)		0/10 (0%)
Erythema	1/56 (1.8%)		2/56 (3.6%)		6/91 (6.6%)		0/10 (0%)
Hyperkeratosis	2/56 (3.6%)		4/56 (7.1%)		5/91 (5.5%)		0/10 (0%)
Surgical and medical procedures
Tooth extraction	0/56 (0%)		3/56 (5.4%)		1/91 (1.1%)		0/10 (0%)
Vascular disorders
Hypertension	35/56 (62.5%)		24/56 (42.9%)		76/91 (83.5%)		5/10 (50%)
Hypotension	0/56 (0%)		8/56 (14.3%)		9/91 (9.9%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.

Results Point of Contact

Name/Title	Pfizer ClinicalTrials.gov Call Center
Organization	Pfizer, Inc.
Phone	1-800-718-1021
Email	ClinicalTrials.gov_Inquiries@pfizer.com

Responsible Party:

Pfizer

ClinicalTrials.gov Identifier:

NCT00835978

Other Study ID Numbers:

A4061046
2008-007786-23

First Posted:

Feb 4, 2009

Last Update Posted:

May 30, 2017

Last Verified:

Apr 1, 2017

Axitinib (AG-013736) With Or Without Dose Titration (Increase) In Patients With Kidney Cancer

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Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

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Outcome Measure Data

Outcome Measure Data

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