A Study To Assess The Safety And Efficacy Of SU11248 In Patients With Gastrointestinal Stromal Tumor(GIST)

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00075218
• Collaborator: (none)
• Enrollment: 361
• Locations: 61
• Arms: 2
• Duration (Months): 53
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A study to assess the safety and efficacy of SU11248 in patients with gastrointestinal stromal tumor (GIST) whose disease has failed imatinib therapy or who were intolerant to imatinib treatment.

Condition or Disease	Intervention/Treatment	Phase
Gastrointestinal Stromal Tumor	Drug: Placebo; Drug: SU011248	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 361 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study Of SU011248 In The Treatment Of Patients With Imatinib Mesylate (Gleevec Tm, Glivec)-Resistant Or Intolerant Malignant Gastrointestinal Stromal Tumor
• Study Start Date: Dec 1, 2003
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: B	Drug: Placebo; 50 mg taken orally once a day. 6 week treatment cycle (Schedule 4/2) 4 weeks on study drug/2 weeks off study drug.
Active Comparator: A	Drug: SU011248; 50 mg taken orally once a day. 6 week treatment cycle (Schedule 4/2) 4 weeks on study drug/2 weeks off study drug.

Outcome Measures

Primary Outcome Measures

1. Time to Tumor Progression (TTP) as Assessed by Imaging Studies at End of Double-blind Treatment Phase [Day 28 of each 6-week cycle : duration of double-blind treatment phase]

   Time from randomization to first documentation of objective tumor progression based on the assessment of an independent, third-party imaging laboratory using RECIST (Response Evaluation Criteria in Solid Tumors).

2. Time to Tumor Progression (TTP) as Assessed in the Double-blind Treatment Phase at End of Study [Day 28 of each 6-week cycle : duration of double-blind treatment phase after Last Subject Last Visit (LSLV)]

   Time from randomization to first documentation of objective tumor progression based on the assessment of an independent, third-party imaging laboratory using RECIST (Response Evaluation Criteria in Solid Tumors).

Secondary Outcome Measures

1. Progression Free Survival (PFS) [Day 28 of each cycle : duration of double-blind treatment phase]

   Time from randomization to first documentation of objective tumor progression or to death due to any cause (on treatment or within 28 days of last dose).

2. Overall Survival Status of Subjects [clinic visit or telephone contact every 2 months for up to 3 years from the last dose of study drug]

   Number of subjects alive at end of study.

3. Overall Survival [clinic visit or telephone contact every 2 months for up to 3 years from the last dose of study drug]

   Time from date of randomization to date of death due to any cause.

4. Overall Survival Based on the Rank Preserving Structural Failure Time Method [clinic visit or telephone contact every 2 months for up to 3 years from the last dose of study drug]

   time from date of randomization to date of death due to any cause (rank preserving structural failure time method).

5. Best Overall Tumor Response During Double-blind Treatment Phase [Day 28 of each cycle : duration of double-blind treatment phase]

   Tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST).

6. Confirmed Objective Response (CR or PR) in Subjects [Day 28 of each cycle : duration of double-blind treatment phase]

   Overall confirmed objective response = confirmed Complete Response (CR) OR confirmed Partial Response (PR) according to RECIST. Confirmed responses were those that persisted on repeat imaging study ≥ 4 weeks after initial documentation of response.

7. Time to Tumor Response (TTR) [Day 28 of each cycle : duration of double-blind treatment phase]

   Time from date of randomization to first documentation of objective tumor response that was subsequently confirmed. TTR was only calculated for the subgroup of subjects with a confirmed objective tumor response.

8. Duration of Performance Status Maintenance [Day 28 of each cycle : duration of double-blind treatment phase]

   Time from randomization until the last time the performance status was no worse than at baseline or to death due to cancer in the absence of previous documentation of performance status worsening.

9. Time to Pain Progression Using McGill Pain Questionnaire-present Pain Intensity (MPQ-PPI) [Day 1 & 28 of each cycle : duration of double-blind treatment phase]

   25th Quartile: Time to Progression. Progression: a) No change (NC) in MPQ-PPI score (0=no pain to 5=excruciating pain) with increase total analgesic use >= 50% over baseline OR b) Increase score >= 1 point with either NC in total analgesic use or increase total analgesic use >= 50% over baseline. (50th Quartile not achieved.)

10. Subjects With Pain Relief Response Using McGill Pain Questionnaire-present Pain Intensity (MPQ-PPI) [Day 1 & 28 of each cycle : duration of double-blind treatment phase]

    MPQ-PPI: 0=no pain to 5= excruciating pain. Pain Relief Response= 1) Decrease by >= 1 points in MPQ-PPI score with either Decrease or No Change in total analgesic use >= 50% over baseline OR 2) No change in MPQ-PPI score with Decrease total analgesic use >= 50% over baseline.

11. Change From Baseline Score in EuroQoL Visual Analog Scale (EQ-VAS) [Day 1 & 28 of each cycle : duration of double-blind treatment phase]

    Change: median score at observation minus median score at baseline. EQ-VAS score on the self-rated "thermometer," indicating the patient's own assessment of their health status from 0 (worst) to 100 (best) imaginable health state.

12. Change From Baseline in EQ-5D Health State Profile Index [Day 1 & 28 of each cycle : duration of double-blind treatment phase]

    Change: median index score at observation minus median index score at baseline. EQ-5D is a generic instrument that describes health status in 5 dimensions (mobility, self-care, pain/discomfort, anxiety/depression, usual activities) with a weighted health Index based on general population values where where 0.0 = death and 1.0 = perfect health.

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

• Histologically-proven diagnosis of malignant GIST not amenable to surgery, radiation or combined modality treatment with curative intent

• Failed Gleevec treatment or intolerant to Gleevec therapy

Key Exclusion Criteria:

• Treatment with any chemotherapy, chemoembolization therapy, immunotherapy, or investigational agent since the last dose of Gleevec

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Duarte	California	United States	91010
2	Pfizer Investigational Site	Los Angeles	California	United States	90095-6984
3	Pfizer Investigational Site	Los Angeles	California	United States	90095
4	Pfizer Investigational Site	Pasadena	California	United States	91105
5	Pfizer Investigational Site	Santa Monica	California	United States	90404
6	Pfizer Investigational Site	Stanford	California	United States	94305
7	Pfizer Investigational Site	Washington	District of Columbia	United States	20010
8	Pfizer Investigational Site	Miami	Florida	United States	33136
9	Pfizer Investigational Site	Tampa	Florida	United States	33612
10	Pfizer Investigational Site	Park Ridge	Illinois	United States	60068
11	Pfizer Investigational Site	Boston	Massachusetts	United States	02115
12	Pfizer Investigational Site	Detroit	Michigan	United States	48201
13	Pfizer Investigational Site	Minneapolis	Minnesota	United States	55455
14	Pfizer Investigational Site	St. Louis	Missouri	United States	63110
15	Pfizer Investigational Site	New York	New York	United States	10021-6007
16	Pfizer Investigational Site	New York	New York	United States	10022
17	Pfizer Investigational Site	New York	New York	United States	10032
18	Pfizer Investigational Site	Durham	North Carolina	United States	27710
19	Pfizer Investigational Site	Cleveland	Ohio	United States	44195-0002
20	Pfizer Investigational Site	Columbus	Ohio	United States	43210
21	Pfizer Investigational Site	Columubs	Ohio	United States	43210
22	Pfizer Investigational Site	Portland	Oregon	United States	97201
23	Pfizer Investigational Site	Philadelphia	Pennsylvania	United States	19111
24	Pfizer Investigational Site	Nashville	Tennessee	United States	37232
25	Pfizer Investigational Site	Seattle	Washington	United States	98109
26	Pfizer Investigational Site	Seattle	Washington	United States	98195
27	Pfizer Investigational Site	Madison	Wisconsin	United States	53792-0001
28	Pfizer Investigational Site	Garran	Australian Capital Territory	Australia	2605
29	Pfizer Investigational Site	Camperdown	New South Wales	Australia	2050
30	Pfizer Investigational Site	Randwick	New South Wales	Australia	2031
31	Pfizer Investigational Site	Auchenflower	Queensland	Australia	4066
32	Pfizer Investigational Site	Ashford	South Australia	Australia	5035
33	Pfizer Investigational Site	Bedford Park	South Australia	Australia	5042
34	Pfizer Investigational Site	East Melbourne	Victoria	Australia	3002
35	Pfizer Investigational Site	Leuven		Belgium	3000
36	Pfizer Investigational Site	Toronto	Ontario	Canada	M5G 1X5
37	Pfizer Investigational Site	Montreal	Quebec	Canada	H2L 4M1
38	Pfizer Investigational Site	Lyon		France	69373
39	Pfizer Investigational Site	Marseille		France	13385
40	Pfizer Investigational Site	VILLEJUIF Cedex		France	94805
41	Pfizer Investigational Site	Aviano	PN	Italy	33081
42	Pfizer Investigational Site	Candiolo	Torino	Italy	10060
43	Pfizer Investigational Site	Bologna		Italy	40138
44	Pfizer Investigational Site	Genova		Italy	16132
45	Pfizer Investigational Site	Milano		Italy	20133
46	Pfizer Investigational Site	Milano		Italy	20141
47	Pfizer Investigational Site	Milano		Italy	20162
48	Pfizer Investigational Site	Torino		Italy	10153
49	Pfizer Investigational Site	Groningen	Gr	Netherlands	9713 GZ
50	Pfizer Investigational Site	Rotterdam	ZH	Netherlands	3075 EA
51	Pfizer Investigational Site	Singapore		Singapore	119074
52	Pfizer Investigational Site	Singapore		Singapore	169610
53	Pfizer Investigational Site	Singapore		Singapore	308433
54	Pfizer Investigational Site	L'Hospitalet del Llobregat	Barcelona	Spain	08907
55	Pfizer Investigational Site	Barcelona		Spain	08025
56	Pfizer Investigational Site	Madrid		Spain	28041
57	Pfizer Investigational Site	Lausanne		Switzerland	CH-1011
58	Pfizer Investigational Site	Sutton	Surrey	United Kingdom	SM2 5NG
59	Pfizer Investigational Site	Leeds		United Kingdom	LS9 7TF
60	Pfizer Investigational Site	London		United Kingdom	W1T 3AA
61	Pfizer Investigational Site	Newcastle-Upon-Tyne		United Kingdom	NE4 6BE

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.

• ClinicalTrials.gov Identifier: NCT00075218
• Other Study ID Numbers: A6181004; NCT00085618
• First Posted: Jan 8, 2004
• Last Update Posted: Sep 28, 2009
• Last Verified: Aug 1, 2009

• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors; Sunitinib

Study Results

Participant Flow

Recruitment Details	Enrollment began (medical clinic) in December 2003. Study was unblinded on 27 January 2005 (end of Double-blind treatment). Subjects experiencing disease progression could crossover to Open-label treatment. Open-label data collection ended May 2008.
Pre-assignment Detail	361 subjects randomized to double-blind treatment in 2:1 ratio (sunitinib vs. Placebo). 255 subjects continued on or crossed over to Open-label treatment.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment	Sunitinib Open-Label Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.	Subjects experiencing disease progression could have their treatment assignment unblinded, and subjects who had been receiving placebo could crossover to open-label treatment with sunitinib; subjects who had been receiving sunitinib during double-blind treatment of the study could continue to do so after unblinding if, in the opinion of the investigator, there was sufficient evidence of clinical benefit.
Period Title: Double-Blind Treatment
STARTED	243	118	0
Received Double-Blind Treatment	228	114	0
Crossed Over to Open-Label Treatment	152	103	0
COMPLETED	152	103	0
NOT COMPLETED	91	15	0
Period Title: Double-Blind Treatment
STARTED	0	0	255
COMPLETED	0	0	0
NOT COMPLETED	0	0	255

Baseline Characteristics

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment	Total
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.	Total of all reporting groups
Overall Participants	243	118	361
Age (Count of Participants)
<=18 years	0 0%	0 0%	0.0 0%
Between 18 and 65 years	170 70%	81 68.6%	251.0 69.5%
>=65 years	73 30%	37 31.4%	110.0 30.5%
Sex: Female, Male (Count of Participants)
Female	91 37.4%	71 60.2%	162.0 44.9%
Male	152 62.6%	47 39.8%	199.0 55.1%

Outcome Measures

1. Primary Outcome

Title	Time to Tumor Progression (TTP) as Assessed by Imaging Studies at End of Double-blind Treatment Phase
Description	Time from randomization to first documentation of objective tumor progression based on the assessment of an independent, third-party imaging laboratory using RECIST (Response Evaluation Criteria in Solid Tumors).
Time Frame	Day 28 of each 6-week cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

From the Intent to Treat (ITT) population, 82 subjects on sunitinib treatment were observed to have disease progression during blinded phase and were included in TTP analysis. 67 subjects on placebo were observed to have disease progression during blinded phase.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	207	105
Median (95% Confidence Interval) [weeks]	27.3	6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments	The study was designed to test the null hypothesis that the median TTP from placebo treatment is 4 months versus the alternative hypothesis that the median TTP from sunitinib treatment is at least 6 months with an overall 2-sided significance level of 0.05 and power of 90%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	The nominal levels of significance for the interim and final analyses were determined at the time of the analyses using the Lan-DeMets procedure with an O'Brien-Fleming stopping rule.
	Method	Log Rank
	Comments	two-sided unstratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.329
	Confidence Interval	() 95%; 0.233 to 0.466
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Time from randomization to first documentation of objective tumor progression or to death due to any cause (on treatment or within 28 days of last dose).
Time Frame	Day 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Median (95% Confidence Interval) [weeks]	22.9	6.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	No p-value adjustment for multiple comparisons.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.347
	Confidence Interval	() 95%; 0.253 to 0.475
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Overall Survival Status of Subjects
Description	Number of subjects alive at end of study.
Time Frame	clinic visit or telephone contact every 2 months for up to 3 years from the last dose of study drug

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Dead	176 72.4%	90 76.3%
Alive	67 27.6%	28 23.7%

4. Secondary Outcome

Title	Overall Survival
Description	Time from date of randomization to date of death due to any cause.
Time Frame	clinic visit or telephone contact every 2 months for up to 3 years from the last dose of study drug

Outcome Measure Data

Analysis Population Description

ITT population; Number subjects Dead = 176, 90 (sunitinib, placebo respectively). Subjects who were not known to be dead at the time the database was closed for analysis were censored on the date they were last known to be alive.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Median (95% Confidence Interval) [weeks]	72.7	64.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.306
	Comments	No p-value adjustment for multiple comparisons.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.876
	Confidence Interval	() 95%; 0.679 to 1.129
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Overall Survival Based on the Rank Preserving Structural Failure Time Method
Description	time from date of randomization to date of death due to any cause (rank preserving structural failure time method).
Time Frame	clinic visit or telephone contact every 2 months for up to 3 years from the last dose of study drug

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Median (95% Confidence Interval) [weeks]	72.7	39.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.306
	Comments	No p-value adjustment for multiple comparisons.
	Method	Rank Preserving Structural Failure Time
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.505
	Confidence Interval	() 95%; 0.262 to 1.134
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI for Hazard Ratio is from 2.5% and 97.5% Empirical Percentiles of 100,000 Bootstraps.

6. Secondary Outcome

Title	Best Overall Tumor Response During Double-blind Treatment Phase
Description	Tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST).
Time Frame	Day 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Complete Response (CR)	0 0%	0 0%
Partial Response (PR)	16 6.6%	0 0%
Stable Disease	128 52.7%	50 42.4%
Progressive Disease	45 18.5%	44 37.3%
Unable to Evaluate	1 0.4%	0 0%
Missing	53 21.8%	24 20.3%

7. Secondary Outcome

Title	Confirmed Objective Response (CR or PR) in Subjects
Description	Overall confirmed objective response = confirmed Complete Response (CR) OR confirmed Partial Response (PR) according to RECIST. Confirmed responses were those that persisted on repeat imaging study ≥ 4 weeks after initial documentation of response.
Time Frame	Day 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

ITT population.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Number [participants]	16 6.6%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	rate (percentage)
	Estimated Value	6.6
	Confidence Interval	() 95%; 3.8 to 10.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Used exact method based on binomial distribution.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	No p-value adjustment for multiple comparisons.
	Method	Pearson chi-square test
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference (%)
	Estimated Value	6.58
	Confidence Interval	() 95%; 3.47 to 9.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Time to Tumor Response (TTR)
Description	Time from date of randomization to first documentation of objective tumor response that was subsequently confirmed. TTR was only calculated for the subgroup of subjects with a confirmed objective tumor response.
Time Frame	Day 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

ITT population. Number of subjects analyzed = number of subjects with tumor response.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	16	0
Median (95% Confidence Interval) [weeks]	13.4

9. Secondary Outcome

Title	Duration of Performance Status Maintenance
Description	Time from randomization until the last time the performance status was no worse than at baseline or to death due to cancer in the absence of previous documentation of performance status worsening.
Time Frame	Day 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

ITT Population. Number of subjects at median observed to have status worsening or died before status worsening.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	106	0
Median (95% Confidence Interval) [weeks]	18.9

10. Primary Outcome

Title	Time to Tumor Progression (TTP) as Assessed in the Double-blind Treatment Phase at End of Study
Description	Time from randomization to first documentation of objective tumor progression based on the assessment of an independent, third-party imaging laboratory using RECIST (Response Evaluation Criteria in Solid Tumors).
Time Frame	Day 28 of each 6-week cycle : duration of double-blind treatment phase after Last Subject Last Visit (LSLV)

Outcome Measure Data

Analysis Population Description

From the Intent to Treat (ITT) population, 91 subjects on sunitinib treatment were observed to have disease progression during blinded phase and were included in TTP analysis. 73 subjects on placebo were observed to have disease progression during blinded phase.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Median (95% Confidence Interval) [weeks]	26.6	6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	two-sided unstratified log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.339
	Confidence Interval	() 95%; 0.244 to 0.472
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments	Stratified log-rank test
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log Rank
	Comments	log-rank test of treatment stratified by prior imatinib mesylate response and McGill Pain Questionnaire's Present Pain Intensity score
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.327
	Confidence Interval	() 95%; 0.232 to 0.460
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Time to Pain Progression Using McGill Pain Questionnaire-present Pain Intensity (MPQ-PPI)
Description	25th Quartile: Time to Progression. Progression: a) No change (NC) in MPQ-PPI score (0=no pain to 5=excruciating pain) with increase total analgesic use >= 50% over baseline OR b) Increase score >= 1 point with either NC in total analgesic use or increase total analgesic use >= 50% over baseline. (50th Quartile not achieved.)
Time Frame	Day 1 & 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

Pain-Relief-Response population. Subjects at 25th Quartile with pain progress during blinded phase.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	37	0
Median (95% Confidence Interval) [weeks (25th Quartile)]	12.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9322
	Comments
	Method	Log Rank
	Comments	2-sided, unstratified log-rank test
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.972
	Confidence Interval	() 95%; 0.508 to 1.860
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Subjects With Pain Relief Response Using McGill Pain Questionnaire-present Pain Intensity (MPQ-PPI)
Description	MPQ-PPI: 0=no pain to 5= excruciating pain. Pain Relief Response= 1) Decrease by >= 1 points in MPQ-PPI score with either Decrease or No Change in total analgesic use >= 50% over baseline OR 2) No change in MPQ-PPI score with Decrease total analgesic use >= 50% over baseline.
Time Frame	Day 1 & 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

Pain-Relief-Response population.

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	150	75
Number [participants]	46 18.9%	10 8.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sunitinib Double-Blind Treatment, Placebo Double-Blind Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0046
	Comments
	Method	Pearson chi-square
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference (percent)
	Estimated Value	17.3
	Confidence Interval	() 95%; 6.7 to 28.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	95% CI of Difference based on normal distribution. Percent = (number of subjects with response per total subjects per treatment in defined analysis population)*100.

13. Secondary Outcome

Title	Change From Baseline Score in EuroQoL Visual Analog Scale (EQ-VAS)
Description	Change: median score at observation minus median score at baseline. EQ-VAS score on the self-rated "thermometer," indicating the patient's own assessment of their health status from 0 (worst) to 100 (best) imaginable health state.
Time Frame	Day 1 & 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

ITT population. Number subjects with evaluable data: (n=sunitinib, placebo)

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Cycle 1 Day 28 (n=187, 89)	-3.0	0.0
Cycle 2 Day 1 (n=148, 53)	0.0	0.0
Cycle 2 Day 28 (n=132, 41)	-4.5	0.0
Cycle 3 Day 1 (n=102,16)	0.0	0.0
Cycle 3 Day 28 (n=91,13)	-5.0	-1.0
Cycle 4 Day 1 (n=73,10)	0.0	5.0

14. Secondary Outcome

Title	Change From Baseline in EQ-5D Health State Profile Index
Description	Change: median index score at observation minus median index score at baseline. EQ-5D is a generic instrument that describes health status in 5 dimensions (mobility, self-care, pain/discomfort, anxiety/depression, usual activities) with a weighted health Index based on general population values where where 0.0 = death and 1.0 = perfect health.
Time Frame	Day 1 & 28 of each cycle : duration of double-blind treatment phase

Outcome Measure Data

Analysis Population Description

ITT Population. Number subjects with evaluable data: (n=sunitinib, placebo)

Arm/Group Title	Sunitinib Double-Blind Treatment	Placebo Double-Blind Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.	Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.
Measure Participants	243	118
Cycle 1 Day 28 (n=185, 87)	0.000	0.000
Cycle 2 Day 1 (n=149, 53)	0.000	0.000
Cycle 2 Day 28 (n=129, 41)	-0.017	0.000
Cycle 3 Day 1 (n=104, 17)	0.000	0.000
Cycle 3 Day 28 (n=91, 13)	-0.036	0.000
Cycle 4 Day 1 (n=74, 10)	0.000	0.059

Adverse Events

Arm/Group Title	Sunitinib Double-Blind Treatment		Placebo Double-Blind Treatment		Sunitinib Open-Label Treatment
Arm/Group Description	Starting dose: 50 mg orally once daily as a single agent for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks. (Schedule 4/2). Subjects received best supportive care in addition to the study treatment.		Starting daily dose of 1 capsule, size- and color-matched to the sunitinib 50-mg capsule for 4 consecutive weeks followed by a 2-week off-treatment period to form a complete cycle of 6 weeks (Schedule 4/2). Subjects received best supportive care in addition to the study treatment. Subjects were provided the opportunity to receive open-label sunitinib at the time of confirmed disease progression or study unblinding.		Subjects experiencing disease progression could have their treatment assignment unblinded, and subjects who had been receiving placebo could crossover to open-label treatment with sunitinib; subjects who had been receiving sunitinib during double-blind treatment of the study could continue to do so after unblinding if, in the opinion of the investigator, there was sufficient evidence of clinical benefit.
All Cause Mortality
	Sunitinib Double-Blind Treatment		Placebo Double-Blind Treatment		Sunitinib Open-Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sunitinib Double-Blind Treatment		Placebo Double-Blind Treatment		Sunitinib Open-Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	83/ (NaN)		27/ (NaN)		122/ (NaN)
Blood and lymphatic system disorders
Anaemia	11/228 (4.8%)		1/114 (0.9%)		10/255 (3.9%)
Thrombocytopenia	5/228 (2.2%)		0/114 (0%)		4/255 (1.6%)
Neutropenia	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Febrile neutropenia	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Leukopenia	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Haemolytic anaemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Lymphopenia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Cardiac disorders
Cardiac arrest	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Cardiac disorder	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cardiac failure	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Cardiomyopathy	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Ejection fraction decreased	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Left ventricular failure	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Mitral valve imcompetence	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cardio-respiratory arrest	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Angina pectoris	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Bradycardia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Cardiac failure congestive	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Myocardial infarction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Pericardial effusion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Ventricular hypokinesia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Congenital, familial and genetic disorders
Pyloric stenosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Epidermolysis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Endocrine disorders
Hypothyroidism	1/228 (0.4%)		0/114 (0%)		4/255 (1.6%)
Gastrointestinal disorders
Abdominal pain	13/228 (5.7%)		6/114 (5.3%)		29/255 (11.4%)
Nausea	5/228 (2.2%)		3/114 (2.6%)		8/255 (3.1%)
Vomiting	5/228 (2.2%)		4/114 (3.5%)		12/255 (4.7%)
Ascites	4/228 (1.8%)		1/114 (0.9%)		3/255 (1.2%)
Diarrhoea	4/228 (1.8%)		0/114 (0%)		4/255 (1.6%)
Abdominal distension	2/228 (0.9%)		0/114 (0%)		3/255 (1.2%)
Constipation	2/228 (0.9%)		1/114 (0.9%)		5/255 (2%)
Gastrointestinal haemorrhage	2/228 (0.9%)		3/114 (2.6%)		4/255 (1.6%)
Intestinal obstruction	2/228 (0.9%)		1/114 (0.9%)		2/255 (0.8%)
Melaena	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Abdominal pain upper	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Anal fistula	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gastric haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gastric ulcer	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gastritis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gastritis haemorrhagic	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gastrointestinal obstruction	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Haematemesis	1/228 (0.4%)		1/114 (0.9%)		3/255 (1.2%)
Haemorrhoids	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Intestinal haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Oesophageal haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Rectal haemorrhage	1/228 (0.4%)		1/114 (0.9%)		5/255 (2%)
Small intestinal obstruction	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Ileus	0/228 (0%)		2/114 (1.8%)		2/255 (0.8%)
Subileus	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Abdominal discomfort	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Anal haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Duodenal fistula	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Duodenal ulcer	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Dyspepsia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Enterocutaneous fistula	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Gastrooesophageal reflux disease	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Inguinal hernia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Intra-abdominal haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Large intestinal haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Peritoneal haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tongue haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Upper gastrointestinal haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
General disorders
Disease progression	8/228 (3.5%)		4/114 (3.5%)		33/255 (12.9%)
Pyrexia	8/228 (3.5%)		1/114 (0.9%)		11/255 (4.3%)
Fatigue	2/228 (0.9%)		1/114 (0.9%)		3/255 (1.2%)
Oedema peripheral	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Asthenia	1/228 (0.4%)		1/114 (0.9%)		3/255 (1.2%)
Chills	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Drug interaction	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
General physical health deterioration	1/228 (0.4%)		3/114 (2.6%)		4/255 (1.6%)
Multi-organ failure	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Oedema	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Chest pain	0/228 (0%)		1/114 (0.9%)		3/255 (1.2%)
Performance status decreased	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Catheter related complication	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Impaired healing	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Infusion site extravasation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Mucosal inflammation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Pain	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Pneumatosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Ulcer haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hepatobiliary disorders
Acute hepatic failure	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Bile duct stone	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cholecystitis acute	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cholelithiasis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cholestasis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Hepatic failure	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Hepatic function abnormal	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Hepatic haemorrhage	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Cholecystitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hepatotoxicity	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Infections and infestations
Catheter sepsis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Central line infection	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Infection	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Mediastinitis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pneumonia	1/228 (0.4%)		1/114 (0.9%)		4/255 (1.6%)
Staphylococcal sepsis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Urinary tract infection	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Viral infection	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Bacteraemia	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Cystitis	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Lower respiratory tract infection	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Gastroenteritis	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Abdominal abscess	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Bacterial infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Campylobacter infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Cellulitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Empyema	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Gastrointestinal infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Liver abscess	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Perirectal abscess	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Respiratory tract infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Sepsis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Urosepsis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Injury, poisoning and procedural complications
Wound dehiscence	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Device malfunction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Feeding tube complication	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Medication error	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Neck injury	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Skin laceration	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Investigations
Aspartate aminotransferase increased	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Blood creatinine increased	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Haemoglobin decreased	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Ammonia increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood bilirubin increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood creatine phosphokinase increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood potassium decreased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood pressure increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Weight decreased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Metabolism and nutrition disorders
Dehydration	4/228 (1.8%)		0/114 (0%)		10/255 (3.9%)
Hypoglycaemia	4/228 (1.8%)		0/114 (0%)		0/255 (0%)
Food intolerance	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Hypercalcaemia	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Hypocalcaemia	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Hypokalaemia	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Anorexia	0/228 (0%)		1/114 (0.9%)		3/255 (1.2%)
Appetite disorder	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Cachexia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hypochloraemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hyponatraemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Musculoskeletal and connective tissue disorders
Back pain	1/228 (0.4%)		2/114 (1.8%)		1/255 (0.4%)
Fistula	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Flank pain	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Muscle spasms	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pain in extremity	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Bone pain	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Intervertebral disc protrusion	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Mobility decreased	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Musculoskeletal pain	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Myalgia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Neck pain	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Rotator cuff syndrome	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage	3/228 (1.3%)		0/114 (0%)		3/255 (1.2%)
Haemorrhagic tumour necrosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Multiple myeloma	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Tumour associated fever	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Tumour lysis syndrome	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cancer pain	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Hepatic neoplasm malignant	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Metastases to liver	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Neurilemmoma benign	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tumour perforation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Nervous system disorders
Cerebral ischaemia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Encephalopathy	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Myoclonus	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Somnolence	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Syncope	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Transient ischaemic attack	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Cerebrovascular accident	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Paralysis	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Hepatic encephalopathy	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Lethargy	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Cerebral haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Coma	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Convulsion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Dizziness	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Guillain-Barre syndrome	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Intracranial venous sinus thrombosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Lacunar infarction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Loss of consciousness	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Paraesthesia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Psychiatric disorders
Insomnia	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Nervousness	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Confusional state	0/228 (0%)		0/114 (0%)		4/255 (1.6%)
Agitation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Completed suicide	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Renal and urinary disorders
Haematuria	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Nephrotic syndrome	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Oliguria	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Renal colic	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Renal failure acute	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Urinary retention	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Hydronephrosis	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Renal failure	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Renal impairment	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Dysuria	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Reproductive system and breast disorders
Pelvic pain	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Uterine polyp	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Vaginal haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	4/228 (1.8%)		1/114 (0.9%)		2/255 (0.8%)
Pneumothorax	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pulmonary hypertension	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Epistaxis	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Dyspnoea	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Pleural effusion	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Lung consolidation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Skin and subcutaneous tissue disorders
Rash	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Diabetic ulcer	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Palmar-plantar erythrodysaesthesia syndrome	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Surgical and medical procedures
Hepatic embolisation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Stent placement	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Vascular disorders
Deep vein thrombosis	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Hypertensive crisis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Thrombosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Circulatory collapse	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Hypertension	0/228 (0%)		0/114 (0%)		4/255 (1.6%)
Hypotension	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Thrombophlebitis	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Embolism	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Jugular vein thrombosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Other (Not Including Serious) Adverse Events
	Sunitinib Double-Blind Treatment		Placebo Double-Blind Treatment		Sunitinib Open-Label Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	223/ (NaN)		110/ (NaN)		254/ (NaN)
Blood and lymphatic system disorders
Anaemia	46/228 (20.2%)		10/114 (8.8%)		80/255 (31.4%)
Neutropenia	33/228 (14.5%)		1/114 (0.9%)		64/255 (25.1%)
Thrombocytopenia	33/228 (14.5%)		1/114 (0.9%)		44/255 (17.3%)
Leukopenia	11/228 (4.8%)		1/114 (0.9%)		22/255 (8.6%)
Lymphopenia	2/228 (0.9%)		1/114 (0.9%)		9/255 (3.5%)
Febrile neutropenia	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Hand and foot syndrome secondary to sickle cell anaemia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Lymphadenopathy	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Pancytopenia	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Disseminated intravascular coagulation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Granulocytopenia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
haemolytic anaemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Leukocytosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Cardiac disorders
Ejection fraction decreased	19/228 (8.3%)		3/114 (2.6%)		5/255 (2%)
Left ventricular dysfunction	4/228 (1.8%)		1/114 (0.9%)		6/255 (2.4%)
Tachycardia	3/228 (1.3%)		0/114 (0%)		4/255 (1.6%)
Bradycardia	2/228 (0.9%)		0/114 (0%)		3/255 (1.2%)
Cardiac disorder	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Cardiomyopathy	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Palpitations	2/228 (0.9%)		2/114 (1.8%)		2/255 (0.8%)
Angina pectoris	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Arrhythmia supraventricular	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Atrial fibrillation	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Cardiac arrest	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Cardiac failure	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Cardiomegaly	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Electrocardiogram QT prolonged	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Left atrial dilatation	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Left ventricular failure	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Mitral valve incompetence	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pericardial effusion	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Sinus arrhythmia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Ventricular extrasystoles	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Bundle branch block left	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Sinus tachycardia	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Cardiac failure congestive	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Cardio-respiratory arrest	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Sinus bradycardia	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Ventricular hypokinesia	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Left ventricular hypertrophy	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Myocardial infarction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Myocardial ischaemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Splinter haemorhages	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Supraventricular tachycardia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Ventricular dysfunction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Congenital, familial and genetic disorders
Pyloric stenosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Dermoid cyst	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Epidermolysis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hydrocele	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Ear and labyrinth disorders
Ear discomfort	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Ear pain	1/228 (0.4%)		1/114 (0.9%)		3/255 (1.2%)
Hypoacusis	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Vertigo	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Tinnitus	0/228 (0%)		1/114 (0.9%)		3/255 (1.2%)
Dysacusis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hearing impaired	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Endocrine disorders
Hypothyroidism	9/228 (3.9%)		1/114 (0.9%)		45/255 (17.6%)
Adrenal insufficiency	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Cushingoid	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Hyperthyroidism	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Thyroid disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Eye disorders
Eye oedema	5/228 (2.2%)		0/114 (0%)		5/255 (2%)
Lacrimation increased	4/228 (1.8%)		1/114 (0.9%)		2/255 (0.8%)
Vision blurred	3/228 (1.3%)		1/114 (0.9%)		5/255 (2%)
Conjunctival haemorrhage	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Conjunctivitis	2/228 (0.9%)		2/114 (1.8%)		6/255 (2.4%)
Visual disturbance	2/228 (0.9%)		0/114 (0%)		4/255 (1.6%)
Diplopia	1/228 (0.4%)		2/114 (1.8%)		0/255 (0%)
Eyelid oedema	1/228 (0.4%)		0/114 (0%)		9/255 (3.5%)
Lacrimal disorder	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Photopsia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Vitreous floaters	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Eye pain	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Eye pruritus	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Dry eye	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Glaucoma	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Macular degeneration	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Orbital oedema	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Asthenopia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blepharitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Eye discharge	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Eye haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Eye irritation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Eye swelling	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Ocular hyperaemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Punctate keratitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Scleral haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Visual acuity reduced	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Gastrointestinal disorders
Diarrhoea	102/228 (44.7%)		21/114 (18.4%)		119/255 (46.7%)
Abdominal pain	82/228 (36%)		37/114 (32.5%)		106/255 (41.6%)
Nausea	80/228 (35.1%)		28/114 (24.6%)		114/255 (44.7%)
Vomiting	63/228 (27.6%)		23/114 (20.2%)		93/255 (36.5%)
Constipation	53/228 (23.2%)		22/114 (19.3%)		75/255 (29.4%)
Dyspepsia	45/228 (19.7%)		6/114 (5.3%)		56/255 (22%)
Stomatitis	37/228 (16.2%)		1/114 (0.9%)		44/255 (17.3%)
Abdominal pain upper	28/228 (12.3%)		10/114 (8.8%)		37/255 (14.5%)
Dry mouth	26/228 (11.4%)		4/114 (3.5%)		22/255 (8.6%)
Flatulence	24/228 (10.5%)		5/114 (4.4%)		26/255 (10.2%)
Abdominal distension	18/228 (7.9%)		9/114 (7.9%)		38/255 (14.9%)
Oral pain	16/228 (7%)		1/114 (0.9%)		30/255 (11.8%)
Glossodynia	13/228 (5.7%)		0/114 (0%)		20/255 (7.8%)
Gastrooesophageal reflux disease	10/228 (4.4%)		2/114 (1.8%)		23/255 (9%)
Ascites	9/228 (3.9%)		6/114 (5.3%)		9/255 (3.5%)
Abdominal discomfort	8/228 (3.5%)		0/114 (0%)		10/255 (3.9%)
Rectal haemorrhage	8/228 (3.5%)		2/114 (1.8%)		16/255 (6.3%)
Mouth ulceration	7/228 (3.1%)		0/114 (0%)		5/255 (2%)
Dysphagia	6/228 (2.6%)		1/114 (0.9%)		12/255 (4.7%)
Gastritis	4/228 (1.8%)		0/114 (0%)		3/255 (1.2%)
Gingival pain	4/228 (1.8%)		1/114 (0.9%)		3/255 (1.2%)
Haemorrhoids	4/228 (1.8%)		2/114 (1.8%)		12/255 (4.7%)
Oral discomfort	4/228 (1.8%)		1/114 (0.9%)		3/255 (1.2%)
Abdominal pain lower	3/228 (1.3%)		2/114 (1.8%)		8/255 (3.1%)
Eructation	3/228 (1.3%)		2/114 (1.8%)		5/255 (2%)
Lip dry	3/228 (1.3%)		0/114 (0%)		2/255 (0.8%)
Oesophagitis	3/228 (1.3%)		1/114 (0.9%)		6/255 (2.4%)
Oral mucosal discolouration	3/228 (1.3%)		0/114 (0%)		0/255 (0%)
Proctalgia	3/228 (1.3%)		0/114 (0%)		7/255 (2.7%)
Reflux oesophagitis	3/228 (1.3%)		0/114 (0%)		1/255 (0.4%)
Retching	3/228 (1.3%)		0/114 (0%)		2/255 (0.8%)
Salivary hypersecretion	3/228 (1.3%)		0/114 (0%)		0/255 (0%)
Toothache	3/228 (1.3%)		2/114 (1.8%)		5/255 (2%)
Duodenogastric reflux	2/228 (0.9%)		1/114 (0.9%)		2/255 (0.8%)
Gastrointestinal haemorrhage	2/228 (0.9%)		5/114 (4.4%)		5/255 (2%)
Gingival bleeding	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Glossitis	2/228 (0.9%)		0/114 (0%)		6/255 (2.4%)
Haematochezia	2/228 (0.9%)		2/114 (1.8%)		4/255 (1.6%)
Intestinal obstruction	2/228 (0.9%)		1/114 (0.9%)		2/255 (0.8%)
Lip pain	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Lip ulceration	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Melaena	2/228 (0.9%)		1/114 (0.9%)		4/255 (1.6%)
Painful defaecation	2/228 (0.9%)		0/114 (0%)		2/255 (0.8%)
Paraesthesia oral	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Small intestinal obstruction	2/228 (0.9%)		0/114 (0%)		3/255 (1.2%)
Stomach discomfort	2/228 (0.9%)		0/114 (0%)		4/255 (1.6%)
Tongue blistering	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Aerophagia	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Anal fissure	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Anal fistula	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Anal inflammation	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Anorectal discomfort	1/228 (0.4%)		0/114 (0%)		4/255 (1.6%)
Aphthous stomatitis	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Breath odour	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Chapped lips	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cheilosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Colitis ulcerative	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Epigastric discomfort	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Faecal incontinence	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Gastric haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gastric ulcer	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gastritis haemorrhagic	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gastrointestinal obstruction	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Gastrointestinal pain	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Gingival swelling	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Haematemesis	1/228 (0.4%)		2/114 (1.8%)		6/255 (2.4%)
Haemorrhoidal haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Inguinal hernia	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Intestinal haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Lip swelling	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Loose tooth	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Mouth haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Odynophagia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Oesophageal haemorrhage	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Oesophageal pain	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Oesophageal ulcer	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Periodontal disease	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Periodontitis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Proctitis	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Rectal lesion	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Steatorrhoea	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Tooth discolouration	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Enterovesical fistula	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Faeces discoloured	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Ileus	0/228 (0%)		2/114 (1.8%)		2/255 (0.8%)
Pancreatitis acute	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Subileus	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Varices oesophageal	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Abdominal tenderness	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Hiatus hernia	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Anal haemorrhage	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Gingivitis	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Peritoneal haemorrhage	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Rectal tenesmus	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Upper gastrointestinal haemorrhage	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Abdominal hernia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Abdominal mass	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Abdominal rigidity	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Defaecation urgency	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Dental caries	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Diverticulum	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Duodenal fistula	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Duodenal ulcer	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Enamel anomaly	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Enterocutaneous fistula	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Gastrointestinal disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Gastrointestinal motility disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Gastrointestinal sounds abnormal	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hyperchlorhydria	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hypoaesthesia oral	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Intra-abdominal haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Large intestinal haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Salivary gland enlargement	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Sensitivity of teeth	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Swollen tongue	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tongue disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tongue haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tongue spasm	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tongue ulceration	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tooth erosion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Umbilical hernia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Cheilitis	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Colitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
General disorders
Fatigue	104/228 (45.6%)		40/114 (35.1%)		156/255 (61.2%)
Asthenia	51/228 (22.4%)		11/114 (9.6%)		62/255 (24.3%)
Mucosal inflammation	39/228 (17.1%)		0/114 (0%)		49/255 (19.2%)
Pyrexia	39/228 (17.1%)		11/114 (9.6%)		52/255 (20.4%)
Oedema peripheral	30/228 (13.2%)		15/114 (13.2%)		73/255 (28.6%)
Oedema	17/228 (7.5%)		0/114 (0%)		14/255 (5.5%)
Chest pain	10/228 (4.4%)		5/114 (4.4%)		17/255 (6.7%)
Chills	8/228 (3.5%)		2/114 (1.8%)		9/255 (3.5%)
Disease progression	8/228 (3.5%)		4/114 (3.5%)		33/255 (12.9%)
Pain	8/228 (3.5%)		2/114 (1.8%)		13/255 (5.1%)
Face oedema	3/228 (1.3%)		0/114 (0%)		9/255 (3.5%)
Localised oedema	3/228 (1.3%)		0/114 (0%)		4/255 (1.6%)
Early satiety	2/228 (0.9%)		3/114 (2.6%)		9/255 (3.5%)
Influenza like illness	2/228 (0.9%)		2/114 (1.8%)		5/255 (2%)
Malaise	2/228 (0.9%)		0/114 (0%)		6/255 (2.4%)
Chest discomfort	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Discomfort	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Drug interaction	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Facial pain	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Gait disturbance	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
General physical health deterioration	1/228 (0.4%)		3/114 (2.6%)		5/255 (2%)
Infusion site reaction	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Multi-organ failure	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Performance status decreased	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Feeling hot	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Ill-defined disorder	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Impaired healing	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Catheter related complication	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Catheter site discharge	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Catheter site excoriation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Catheter site pain	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Cyst	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Effusion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Feeling cold	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hernia pain	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Infusion site extravasation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Irritability	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Mucosal dryness	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Necrosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Peripheral coldness	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Pneumatosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Thirst	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Ulcer haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Xerosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hepatobiliary disorders
Hepatic pain	3/228 (1.3%)		1/114 (0.9%)		6/255 (2.4%)
Hyperbilirubinaemia	3/228 (1.3%)		0/114 (0%)		4/255 (1.6%)
Jaundice	3/228 (1.3%)		0/114 (0%)		3/255 (1.2%)
Hepatomegaly	2/228 (0.9%)		2/114 (1.8%)		2/255 (0.8%)
Acute hepatic failure	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Bile duct stone	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cholangitis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cholecystitis acute	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cholelithiasis	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Cholestasis	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Hepatic failure	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Hepatic function abnormal	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Hepatic haemorrhage	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Portal hypertension	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Hepatotoxicity	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Portal vein thrombosis	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Cholecystitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Foetor hepaticus	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Immune system disorders
Hypersensitivity	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Seasonal allergy	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Infections and infestations
Urinary tract infection	10/228 (4.4%)		3/114 (2.6%)		22/255 (8.6%)
Influenza	8/228 (3.5%)		2/114 (1.8%)		13/255 (5.1%)
Upper respiratory tract infection	6/228 (2.6%)		1/114 (0.9%)		18/255 (7.1%)
Cystitis	5/228 (2.2%)		2/114 (1.8%)		3/255 (1.2%)
Infection	4/228 (1.8%)		0/114 (0%)		6/255 (2.4%)
Nasopharyngitis	4/228 (1.8%)		3/114 (2.6%)		11/255 (4.3%)
Oral herpes	4/228 (1.8%)		1/114 (0.9%)		4/255 (1.6%)
Sinusitis	4/228 (1.8%)		1/114 (0.9%)		8/255 (3.1%)
Bronchitis	3/228 (1.3%)		1/114 (0.9%)		2/255 (0.8%)
Tooth abscess	3/228 (1.3%)		0/114 (0%)		1/255 (0.4%)
Tooth infection	3/228 (1.3%)		1/114 (0.9%)		4/255 (1.6%)
Central line infection	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Folliculitis	2/228 (0.9%)		0/114 (0%)		5/255 (2%)
Gastroenteritis	2/228 (0.9%)		1/114 (0.9%)		11/255 (4.3%)
Nail infection	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Abscess limb	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Bacteraemia	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Catheter sepsis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Furuncle	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Gastroenteritis viral	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Gingival abscess	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Gingival infection	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Herpes zoster	1/228 (0.4%)		0/114 (0%)		5/255 (2%)
Lobar pneumonia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Localised infection	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Lower respiratory tract infection	1/228 (0.4%)		1/114 (0.9%)		6/255 (2.4%)
Mediastinitis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Nipple infection	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Oral candidiasis	1/228 (0.4%)		3/114 (2.6%)		3/255 (1.2%)
Oral fungal infection	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Oral infection	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pilonidal cyst	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pneumonia	1/228 (0.4%)		1/114 (0.9%)		5/255 (2%)
Sinusitis bacterial	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Skin infection	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Staphylococcal infection	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Staphylococcal sepsis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Subcutaneous abscess	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Tinea infection	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Tinea pedis	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Tonsillitis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Viral infection	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Viral oesophagitis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Wound infection	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Arthritis infective	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Laryngitis	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Postoperative wound infection	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Respiratory tract infection	0/228 (0%)		0/114 (0%)		5/255 (2%)
Rhinitis	0/228 (0%)		0/114 (0%)		6/255 (2.4%)
Cellulitis	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Ear infection	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Pharyngitis	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Sepsis	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Abdominal abscess	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Anal infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Bacterial infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Campylobacter infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Diverticulitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Empyema	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Fungal infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Gastrointestinal infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Genital herpes	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Herpes simplex	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Infected skin ulcer	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Liver abscess	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Lung infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Necrotising ulcerative gingivostomatitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Oesophageal candidiasis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Orchitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Osteomyelitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Otitis media	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Perirectal abscess	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Proctitis monilial	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Pyelonephritis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Urinary tract infection fungal	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Urosepsis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Viral upper respiratory tract infection	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Injury, poisoning and procedural complications
Contusion	9/228 (3.9%)		1/114 (0.9%)		9/255 (3.5%)
Procedural pain	3/228 (1.3%)		1/114 (0.9%)		2/255 (0.8%)
Back injury	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Excoriation	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Medical device pain	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Periorbital haematoma	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Procedural site reaction	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Radiation oesophagitis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Spinal compression fracture	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Spinal fracture	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Sunburn	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Wound dehiscence	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Fall	0/228 (0%)		1/114 (0.9%)		3/255 (1.2%)
Hepatic haematoma	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Injury	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Overdose	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Skin laceration	0/228 (0%)		0/114 (0%)		4/255 (1.6%)
Thermal burn	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Wound	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Anal injury	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Device malfunction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Feeding tube complication	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Joint sprain	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Ligament rupture	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Limb injury	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Medical device complication	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Medical device site reaction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Medication error	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Muscle strain	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Neck injury	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Post gastric surgery syndrome	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Post procedural diarrhoea	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Postoperative constipation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Postoperative fever	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Skeletal injury	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Investigations
Weight decreased	14/228 (6.1%)		6/114 (5.3%)		45/255 (17.6%)
Platelet count decreased	9/228 (3.9%)		0/114 (0%)		13/255 (5.1%)
Blood creatinine increased	7/228 (3.1%)		1/114 (0.9%)		20/255 (7.8%)
Haemoglobin decreased	7/228 (3.1%)		1/114 (0.9%)		11/255 (4.3%)
Lipase increased	6/228 (2.6%)		3/114 (2.6%)		8/255 (3.1%)
Blood amylase increased	5/228 (2.2%)		2/114 (1.8%)		6/255 (2.4%)
Blood bilirubin increased	5/228 (2.2%)		2/114 (1.8%)		3/255 (1.2%)
White blood cell count decreased	5/228 (2.2%)		0/114 (0%)		12/255 (4.7%)
Blood alkaline phosphatase increased	4/228 (1.8%)		2/114 (1.8%)		10/255 (3.9%)
Blood creatine phosphokinase increased	4/228 (1.8%)		1/114 (0.9%)		2/255 (0.8%)
Alanine aminotransferase increased	3/228 (1.3%)		3/114 (2.6%)		8/255 (3.1%)
Aspartate aminotransferase increased	3/228 (1.3%)		1/114 (0.9%)		9/255 (3.5%)
Neutrophil count decreased	3/228 (1.3%)		0/114 (0%)		11/255 (4.3%)
Urine output decreased	3/228 (1.3%)		1/114 (0.9%)		1/255 (0.4%)
Activated partial thromboplastin time prolonged	2/228 (0.9%)		0/114 (0%)		2/255 (0.8%)
International normalised ratio increased	2/228 (0.9%)		0/114 (0%)		2/255 (0.8%)
Prothrombin time prolonged	2/228 (0.9%)		0/114 (0%)		2/255 (0.8%)
Alanine aminotransferase abnormal	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Ammonia increased	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Aspartate aminotransferase abnormal	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Blood alkaline phosphatase abnormal	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Blood bicarbonate decreased	1/228 (0.4%)		2/114 (1.8%)		2/255 (0.8%)
Blood bilirubin	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Blood creatine phosphokinase	1/228 (0.4%)		1/114 (0.9%)		3/255 (1.2%)
Blood creatinine	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Blood magnesium decreased	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Blood potassium increased	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Blood pressure increased	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Blood thyroid stimulating hormone increased	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Blood urea increased	1/228 (0.4%)		1/114 (0.9%)		3/255 (1.2%)
Blood urine present	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Haemoglobin	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Heart rate increased	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Neutrophil count	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Neutrophil count normal	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Oxygen saturation decreased	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Transaminases increased	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Blood glucose increased	0/228 (0%)		1/114 (0.9%)		3/255 (1.2%)
Blood sodium increased	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Breath sounds abnormal	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Cardiac murmur	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Electrocardiogram abnormal	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Heart rate irregular	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Occult blood positive	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Pancreatic enzymes increased	0/228 (0%)		2/114 (1.8%)		1/255 (0.4%)
Platelet count increased	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Weight increased	0/228 (0%)		0/114 (0%)		6/255 (2.4%)
Blood lactate dehydrogenase increased	0/228 (0%)		0/114 (0%)		5/255 (2%)
Blood potassium decreased	0/228 (0%)		0/114 (0%)		4/255 (1.6%)
Blood uric acid increased	0/228 (0%)		0/114 (0%)		4/255 (1.6%)
Blood albumin decreased	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Liver function test abnormal	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Platelet count	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Bacterial culture positive	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood alkaline phosphatase	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood calcium decreased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood glucose decreased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood phosphorus decreased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
C-reactive protein increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
ECG signs of myocardial ischaemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Electrocardiogram ST segment depression	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Gamma-glutamyltransferase increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hepatic enzyme increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Lymph node palpable	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Lymphocyte count decreased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Mean cell volume increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Multiple gated acquisition scan abnormal	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Venous pressure jugular increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Vitamin B12 decreased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
White blood cell count	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
White blood cell count increased	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood sodium decreased	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Metabolism and nutrition disorders
Anorexia	76/228 (33.3%)		19/114 (16.7%)		92/255 (36.1%)
Decreased appetite	10/228 (4.4%)		5/114 (4.4%)		25/255 (9.8%)
Hypokalaemia	10/228 (4.4%)		1/114 (0.9%)		13/255 (5.1%)
Dehydration	9/228 (3.9%)		0/114 (0%)		19/255 (7.5%)
Hypoalbuminaemia	6/228 (2.6%)		1/114 (0.9%)		11/255 (4.3%)
Hyperglycaemia	4/228 (1.8%)		0/114 (0%)		10/255 (3.9%)
Hypocalcaemia	4/228 (1.8%)		1/114 (0.9%)		4/255 (1.6%)
Hypoglycaemia	4/228 (1.8%)		1/114 (0.9%)		6/255 (2.4%)
Hyponatraemia	3/228 (1.3%)		2/114 (1.8%)		4/255 (1.6%)
Hypercholesterolaemia	2/228 (0.9%)		0/114 (0%)		4/255 (1.6%)
Hyperuricaemia	2/228 (0.9%)		1/114 (0.9%)		3/255 (1.2%)
Food intolerance	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Hypercalcaemia	1/228 (0.4%)		2/114 (1.8%)		2/255 (0.8%)
Hyperkalaemia	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Hyperphosphataemia	1/228 (0.4%)		1/114 (0.9%)		1/255 (0.4%)
Hypertriglyceridaemia	1/228 (0.4%)		0/114 (0%)		4/255 (1.6%)
Hypophosphataemia	1/228 (0.4%)		0/114 (0%)		4/255 (1.6%)
Hypoproteinaemia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Metabolic acidosis	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Acidosis	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Appetite disorder	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Gout	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Increased appetite	0/228 (0%)		2/114 (1.8%)		1/255 (0.4%)
Malnutrition	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Hypomagnesaemia	0/228 (0%)		0/114 (0%)		5/255 (2%)
Cachexia	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Cow's milk intolerance	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Fluid retention	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hypochloraemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Iron deficiency	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Lactose intolerance	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Polydipsia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Musculoskeletal and connective tissue disorders
Back pain	31/228 (13.6%)		14/114 (12.3%)		51/255 (20%)
Pain in extremity	28/228 (12.3%)		4/114 (3.5%)		46/255 (18%)
Arthralgia	23/228 (10.1%)		8/114 (7%)		51/255 (20%)
Muscle spasms	15/228 (6.6%)		5/114 (4.4%)		27/255 (10.6%)
Myalgia	15/228 (6.6%)		4/114 (3.5%)		25/255 (9.8%)
Flank pain	9/228 (3.9%)		0/114 (0%)		10/255 (3.9%)
Musculoskeletal pain	9/228 (3.9%)		5/114 (4.4%)		28/255 (11%)
Muscular weakness	7/228 (3.1%)		1/114 (0.9%)		11/255 (4.3%)
Neck pain	6/228 (2.6%)		2/114 (1.8%)		12/255 (4.7%)
Bone pain	5/228 (2.2%)		2/114 (1.8%)		9/255 (3.5%)
Musculoskeletal stiffness	4/228 (1.8%)		0/114 (0%)		3/255 (1.2%)
Joint stiffness	2/228 (0.9%)		0/114 (0%)		4/255 (1.6%)
Limb discomfort	2/228 (0.9%)		0/114 (0%)		4/255 (1.6%)
Musculoskeletal chest pain	2/228 (0.9%)		3/114 (2.6%)		5/255 (2%)
Pain in jaw	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Exostosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Fistula	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Groin pain	1/228 (0.4%)		3/114 (2.6%)		5/255 (2%)
Intervertebral disc disorder	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Joint effusion	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Joint range of motion decreased	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Muscle tightness	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Muscle twitching	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Osteoporosis	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Tendonitis	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Costochondritis	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Intervertebral disc protrusion	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Mobility decreased	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Rheumatoid arthritis	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Arthritis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Joint swelling	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Muscle contracture	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Musculoskeletal discomfort	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Myopathy	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Rotator cuff syndrome	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Sensation of heaviness	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Spinal osteoarthritis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tendon disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour haemorrhage	3/228 (1.3%)		0/114 (0%)		3/255 (1.2%)
Basal cell carcinoma	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Haemangioma	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Haemorrhagic tumour necrosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Multiple myeloma	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Neoplasm	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Tumour associated fever	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Tumour lysis syndrome	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Tumour pain	1/228 (0.4%)		0/114 (0%)		6/255 (2.4%)
Vascular neoplasm	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cancer pain	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Neoplasm progression	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Metastases to liver	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Anal neoplasm	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hepatic neoplasm malignant	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Metastases to bone	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Neurilemmoma benign	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Tumour perforation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Nervous system disorders
Dysgeusia	54/228 (23.7%)		3/114 (2.6%)		57/255 (22.4%)
Headache	48/228 (21.1%)		18/114 (15.8%)		67/255 (26.3%)
Dizziness	22/228 (9.6%)		7/114 (6.1%)		31/255 (12.2%)
Paraesthesia	11/228 (4.8%)		1/114 (0.9%)		16/255 (6.3%)
Hypoaesthesia	8/228 (3.5%)		4/114 (3.5%)		12/255 (4.7%)
Neuropathy peripheral	7/228 (3.1%)		2/114 (1.8%)		8/255 (3.1%)
Ageusia	6/228 (2.6%)		0/114 (0%)		5/255 (2%)
Peripheral sensory neuropathy	5/228 (2.2%)		2/114 (1.8%)		5/255 (2%)
Sciatica	4/228 (1.8%)		0/114 (0%)		3/255 (1.2%)
Somnolence	4/228 (1.8%)		2/114 (1.8%)		9/255 (3.5%)
Balance disorder	3/228 (1.3%)		1/114 (0.9%)		0/255 (0%)
Hyperaesthesia	3/228 (1.3%)		1/114 (0.9%)		3/255 (1.2%)
Lethargy	3/228 (1.3%)		1/114 (0.9%)		9/255 (3.5%)
Syncope	3/228 (1.3%)		1/114 (0.9%)		3/255 (1.2%)
Tremor	3/228 (1.3%)		1/114 (0.9%)		5/255 (2%)
Dizziness postural	2/228 (0.9%)		0/114 (0%)		2/255 (0.8%)
Memory impairment	2/228 (0.9%)		1/114 (0.9%)		4/255 (1.6%)
Migraine	2/228 (0.9%)		0/114 (0%)		3/255 (1.2%)
Parosmia	2/228 (0.9%)		1/114 (0.9%)		0/255 (0%)
Sinus headache	2/228 (0.9%)		1/114 (0.9%)		5/255 (2%)
Amnesia	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Ataxia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Cerebral ischaemia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Depressed level of consciousness	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Diabetic neuropathy	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Disturbance in attention	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Encephalopathy	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Facial palsy	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Head discomfort	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Myoclonus	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Peripheral motor neuropathy	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Restless legs syndrome	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Sensory disturbance	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Syncope vasovagal	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Transient ischaemic attack	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Burning sensation	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Cerebrovascular accident	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Coma	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Hemicephalalgia	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Neuralgia	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Paralysis	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Hepatic encephalopathy	0/228 (0%)		0/114 (0%)		5/255 (2%)
Dysarthria	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Loss of consciousness	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Aphonia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Asterixis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Carotid artery disease	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Cerebral haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Cervical root pain	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Convulsion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Dysaesthesia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Guillain-barre syndrome	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hemiparesis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hypogeusia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Intention tremor	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Intracranial venous sinus thrombosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Lacunar infarction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Migraine with aura	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Movement disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Petit mal epilepsy	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Psychiatric disorders
Insomnia	25/228 (11%)		11/114 (9.6%)		34/255 (13.3%)
Anxiety	7/228 (3.1%)		2/114 (1.8%)		11/255 (4.3%)
Depression	7/228 (3.1%)		2/114 (1.8%)		23/255 (9%)
Agitation	2/228 (0.9%)		1/114 (0.9%)		7/255 (2.7%)
Confusional state	2/228 (0.9%)		2/114 (1.8%)		14/255 (5.5%)
Nervousness	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Sleep disorder	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Depressed mood	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Mood altered	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Abnormal dreams	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Apathy	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Completed suicide	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Dysphemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Emotional disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hallucination	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Psychomotor retardation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Psychotic disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Renal and urinary disorders
Chromaturia	12/228 (5.3%)		2/114 (1.8%)		6/255 (2.4%)
Dysuria	10/228 (4.4%)		1/114 (0.9%)		12/255 (4.7%)
Haematuria	6/228 (2.6%)		2/114 (1.8%)		8/255 (3.1%)
Urinary retention	4/228 (1.8%)		0/114 (0%)		3/255 (1.2%)
Hydronephrosis	3/228 (1.3%)		3/114 (2.6%)		6/255 (2.4%)
Pollakiuria	3/228 (1.3%)		4/114 (3.5%)		11/255 (4.3%)
Polyuria	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Proteinuria	2/228 (0.9%)		1/114 (0.9%)		3/255 (1.2%)
Bladder pain	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Choluria	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Nephrotic syndrome	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Nocturia	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Oliguria	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Renal colic	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Renal failure	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Renal failure acute	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Urine odour abnormal	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Bladder spasm	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Hydroureter	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Micturition urgency	0/228 (0%)		1/114 (0.9%)		3/255 (1.2%)
Ureteric obstruction	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Urethral stenosis	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Urinary incontinence	0/228 (0%)		1/114 (0.9%)		3/255 (1.2%)
Renal impairment	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Focal segmental glomerulosclerosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Obstructive uropathy	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Renal cyst	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Residual urine	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Reproductive system and breast disorders
Gynaecomastia	4/228 (1.8%)		0/114 (0%)		2/255 (0.8%)
Pelvic pain	4/228 (1.8%)		3/114 (2.6%)		11/255 (4.3%)
Oedema genital	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Atrophic vulvovaginitis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Genital discomfort	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Genital pain	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Genital rash	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Menstruation delayed	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Metrorrhagia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Nipple pain	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Pelvic discomfort	1/228 (0.4%)		1/114 (0.9%)		2/255 (0.8%)
Vaginal erythema	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Vaginal haemorrhage	1/228 (0.4%)		0/114 (0%)		4/255 (1.6%)
Vaginal pain	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Vulval ulceration	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Vulvovaginal burning sensation	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Benign prostatic hyperplasia	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Breast mass	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Breast pain	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Perineal pain	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Prostatitis	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Scrotal oedema	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Erectile dysfunction	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Genital haemorrhage	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Genital lesion	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Genital rash	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Balanoposthitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Breast swelling	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Dyspareunia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Genital erythema	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Menstruation irregular	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Penile haemorrhage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Penile oedema	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Perineal fistula	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Pruritus genital	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Uterine polyp	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	25/228 (11%)		16/114 (14%)		56/255 (22%)
Epistaxis	22/228 (9.6%)		0/114 (0%)		27/255 (10.6%)
Cough	19/228 (8.3%)		14/114 (12.3%)		43/255 (16.9%)
Pharyngolaryngeal pain	9/228 (3.9%)		3/114 (2.6%)		17/255 (6.7%)
Hiccups	4/228 (1.8%)		1/114 (0.9%)		6/255 (2.4%)
Pleural effusion	4/228 (1.8%)		1/114 (0.9%)		7/255 (2.7%)
Pulmonary embolism	4/228 (1.8%)		3/114 (2.6%)		5/255 (2%)
Rhinorrhoea	4/228 (1.8%)		0/114 (0%)		7/255 (2.7%)
Dysphonia	3/228 (1.3%)		1/114 (0.9%)		3/255 (1.2%)
Dry throat	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Dyspnoea exertional	2/228 (0.9%)		2/114 (1.8%)		9/255 (3.5%)
Nasal discomfort	2/228 (0.9%)		0/114 (0%)		5/255 (2%)
Productive cough	2/228 (0.9%)		1/114 (0.9%)		4/255 (1.6%)
Atelectasis	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Dyspnoea paroxysmal nocturnal	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Hypoxia	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Nasal congestion	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Nasal disorder	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Nasal dryness	1/228 (0.4%)		0/114 (0%)		6/255 (2.4%)
Nasal mucosal disorder	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Nasal ulcer	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Painful respiration	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pharyngeal inflammation	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pharyngeal oedema	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pharyngolaryngeal discomfort	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Pneumothorax	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pulmonary hypertension	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pulmonary thrombosis	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Rales	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Rhinitis allergic	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Throat irritation	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pneumonia aspiration	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Pulmonary congestion	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Respiratory tract congestion	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Sinus congestion	0/228 (0%)		1/114 (0.9%)		4/255 (1.6%)
Sinus disorder	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Wheezing	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Lung disorder	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Orthopnoea	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Pleuritic pain	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Allergic sinusitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Apnoea	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Haemoptysis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hyperventilation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Increased upper airway secretion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Increased viscosity of bronchial secretion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Lung consolidation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Paranasal sinus hypersecretion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Pleurisy	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Postnasal drip	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Respiratory disorder	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Rhonchi	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Sneezing	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Skin and subcutaneous tissue disorders
Skin discolouration	64/228 (28.1%)		7/114 (6.1%)		77/255 (30.2%)
Rash	40/228 (17.5%)		7/114 (6.1%)		48/255 (18.8%)
Palmar-plantar erythrodysaesthesia syndrome	25/228 (11%)		1/114 (0.9%)		56/255 (22%)
Hair colour changes	19/228 (8.3%)		2/114 (1.8%)		50/255 (19.6%)
Dry skin	17/228 (7.5%)		3/114 (2.6%)		33/255 (12.9%)
Alopecia	14/228 (6.1%)		1/114 (0.9%)		22/255 (8.6%)
Skin reaction	13/228 (5.7%)		0/114 (0%)		22/255 (8.6%)
Pruritus	11/228 (4.8%)		4/114 (3.5%)		21/255 (8.2%)
Erythema	10/228 (4.4%)		3/114 (2.6%)		18/255 (7.1%)
Eczema	8/228 (3.5%)		2/114 (1.8%)		14/255 (5.5%)
Night sweats	8/228 (3.5%)		3/114 (2.6%)		10/255 (3.9%)
Periorbital oedema	8/228 (3.5%)		0/114 (0%)		13/255 (5.1%)
Skin hyperpigmentation	8/228 (3.5%)		0/114 (0%)		8/255 (3.1%)
Dermatitis	6/228 (2.6%)		0/114 (0%)		6/255 (2.4%)
Hyperhidrosis	5/228 (2.2%)		3/114 (2.6%)		8/255 (3.1%)
Skin exfoliation	5/228 (2.2%)		0/114 (0%)		8/255 (3.1%)
Blister	4/228 (1.8%)		0/114 (0%)		9/255 (3.5%)
Ecchymosis	4/228 (1.8%)		0/114 (0%)		6/255 (2.4%)
Hyperkeratosis	4/228 (1.8%)		0/114 (0%)		10/255 (3.9%)
Petechiae	4/228 (1.8%)		0/114 (0%)		5/255 (2%)
Skin fissures	4/228 (1.8%)		0/114 (0%)		8/255 (3.1%)
Acne	3/228 (1.3%)		0/114 (0%)		4/255 (1.6%)
Nail disorder	3/228 (1.3%)		0/114 (0%)		2/255 (0.8%)
Skin lesion	3/228 (1.3%)		1/114 (0.9%)		9/255 (3.5%)
Dermatitis acneiform	2/228 (0.9%)		1/114 (0.9%)		0/255 (0%)
Dermatitis exfoliative	2/228 (0.9%)		0/114 (0%)		2/255 (0.8%)
Increased tendency to bruise	2/228 (0.9%)		0/114 (0%)		2/255 (0.8%)
Nail discolouration	2/228 (0.9%)		0/114 (0%)		1/255 (0.4%)
Pigmentation disorder	2/228 (0.9%)		0/114 (0%)		4/255 (1.6%)
Rash erythematous	2/228 (0.9%)		0/114 (0%)		2/255 (0.8%)
Rash macular	2/228 (0.9%)		1/114 (0.9%)		2/255 (0.8%)
Urticaria	2/228 (0.9%)		1/114 (0.9%)		0/255 (0%)
Acrodermatitis	1/228 (0.4%)		0/114 (0%)		5/255 (2%)
Cold sweat	1/228 (0.4%)		1/114 (0.9%)		0/255 (0%)
Dermal cyst	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Diabetic ulcer	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Erythema nodosum	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Madarosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pain of skin	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Palmar erythema	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Plantar erythema	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Rash generalised	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Skin atrophy	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Skin depigmentation	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Skin hypopigmentation	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Skin toxicity	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Skin ulcer	1/228 (0.4%)		0/114 (0%)		3/255 (1.2%)
Swelling face	1/228 (0.4%)		0/114 (0%)		2/255 (0.8%)
Dermatitis allergic	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Onychoclasis	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Pruritus generalised	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Skin irritation	0/228 (0%)		1/114 (0.9%)		3/255 (1.2%)
Subcutaneous nodule	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Telangiectasia	0/228 (0%)		1/114 (0.9%)		2/255 (0.8%)
Purpura	0/228 (0%)		0/114 (0%)		5/255 (2%)
Decubitus ulcer	0/228 (0%)		0/114 (0%)		4/255 (1.6%)
Skin disorder	0/228 (0%)		0/114 (0%)		4/255 (1.6%)
Exfoliative rash	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Yellow skin	0/228 (0%)		0/114 (0%)		3/255 (1.2%)
Hair texture abnormal	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Actinic keratosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Blood blister	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Dermatosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hair growth abnormal	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Photosensitivity reaction	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Prurigo	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Psoriasis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Seborrhoeic dermatitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Skin chapped	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Skin induration	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Toxic epidermal necrolysis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Surgical and medical procedures
Skin lesion excision	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Pneumatic compression therapy	0/228 (0%)		1/114 (0.9%)		1/255 (0.4%)
Cyst drainage	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Debridement	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Hepatic embolisation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Mediastinal operation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Packed red blood cell transfusion	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Sinus operation	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Stent placement	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Vascular disorders
Hypertension	40/228 (17.5%)		9/114 (7.9%)		71/255 (27.8%)
Hot flush	9/228 (3.9%)		3/114 (2.6%)		7/255 (2.7%)
Deep vein thrombosis	4/228 (1.8%)		0/114 (0%)		5/255 (2%)
Hypotension	3/228 (1.3%)		1/114 (0.9%)		6/255 (2.4%)
Pallor	3/228 (1.3%)		0/114 (0%)		1/255 (0.4%)
Haemorrhage	2/228 (0.9%)		1/114 (0.9%)		2/255 (0.8%)
Hypertensive crisis	2/228 (0.9%)		0/114 (0%)		3/255 (1.2%)
Vasculitis	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Venous thrombosis limb	2/228 (0.9%)		0/114 (0%)		0/255 (0%)
Lymphoedema	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Orthostatic hypotension	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Systolic hypertension	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Thrombosis	1/228 (0.4%)		0/114 (0%)		0/255 (0%)
Vasodilatation	1/228 (0.4%)		0/114 (0%)		1/255 (0.4%)
Circulatory collapse	0/228 (0%)		1/114 (0.9%)		0/255 (0%)
Flushing	0/228 (0%)		0/114 (0%)		4/255 (1.6%)
Thrombophlebitis	0/228 (0%)		0/114 (0%)		2/255 (0.8%)
Embolism	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Essential hypertension	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Jugular vein thrombosis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Peripheral ischaemia	0/228 (0%)		0/114 (0%)		1/255 (0.4%)
Phlebitis	0/228 (0%)		0/114 (0%)		1/255 (0.4%)

Limitations/Caveats

Duration of Tumor Response could not be reliably estimated at the time of analysis.

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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 < 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), < 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.