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Clinical Trial Results:
A randomized, double-blind, placebo-controlled, Phase III study to evaluate the efficacy and safety of pazopanib as adjuvant therapy for subjects with localized or locally advanced renal cell carcinoma (RCC) following nephrectomy. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

Summary
EudraCT number	2010-020965-26
Trial protocol	SK DE DK IE CZ ES BE GR GB AT PL HU IT
Global end of trial date	15 Apr 2019

Results information
Results version number	v2(current)
This version publication date	28 Jan 2022
First version publication date	01 May 2020
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

113387

ISRCTN number

US NCT number

NCT01235962

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma, AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

15 Apr 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

15 Apr 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this ongoing study is to evaluate disease free survival (DFS) with pazopanib 600 mg daily initial dose as compared with placebo as adjuvant therapy for subjects with localized/locally advanced RCC following nephrectomy.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Nov 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 26

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Brazil: 39

Country: Number of subjects enrolled

Canada: 94

Country: Number of subjects enrolled

Chile: 13

Country: Number of subjects enrolled

China: 37

Country: Number of subjects enrolled

Czechia: 88

Country: Number of subjects enrolled

Denmark: 55

Country: Number of subjects enrolled

France: 83

Country: Number of subjects enrolled

Germany: 123

Country: Number of subjects enrolled

United Kingdom: 76

Country: Number of subjects enrolled

Greece: 14

Country: Number of subjects enrolled

Hungary: 27

Country: Number of subjects enrolled

Ireland: 34

Country: Number of subjects enrolled

Israel: 14

Country: Number of subjects enrolled

Italy: 70

Country: Number of subjects enrolled

Japan: 61

Country: Number of subjects enrolled

Korea, Republic of: 74

Country: Number of subjects enrolled

Luxembourg: 2

Country: Number of subjects enrolled

Poland: 63

Country: Number of subjects enrolled

Russian Federation: 115

Country: Number of subjects enrolled

Slovakia: 42

Country: Number of subjects enrolled

Spain: 53

Country: Number of subjects enrolled

Turkey: 9

Country: Number of subjects enrolled

United States: 315

Worldwide total number of subjects

1538

EEA total number of subjects

665

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

1130

From 65 to 84 years

408

85 years and over

Subject disposition

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Recruitment details

A total of 1538 subjects were enrolled and analyzed.

Screening details

The study was planned to include 1500 subjects.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

ITT pazopanib 800 mg

Arm description

Pazopanib 800 mg daily based on safety evaluation. Complete treatment is 12 months.

Arm type

Experimental

Investigational medicinal product name

pazopanib

Investigational medicinal product code

PZP034

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

For subjects randomized prior to the approval of Amendment 2, the scheduled starting dose was 800 mg daily (4 × 200 mg tablets).

ITT placebo 800 mg

Arm description

Placebo matching pazopanib 800 mg daily. Complete treatment is 12 months.

Arm type

Placebo

Investigational medicinal product name

pazopanib placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

For subjects randomized prior to the approval of Amendment 2, the scheduled starting dose was 800 mg daily (4 × 200 mg placebo tablets).

ITT pazopanib 600 mg

Arm description

Pazopanib 600 mg daily initial dose for 8-12 weeks. Dose can be escalated to 800 mg daily based on safety evaluation. Complete treatment is 12 months.

Arm type

Experimental

Investigational medicinal product name

pazopanib

Investigational medicinal product code

PZP034

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subsequent to Amendment 2, each subject started the study treatment at 600 mg daily (3 × 200 mg tablets) for 8 to 12 weeks. Based on evaluation of each subject’s safety and tolerability profile, the Investigator determined whether the subject should be dose escalated to 800 mg daily (4 × 200 mg tablets) or maintained at 600 mg daily.

ITT placebo 600 mg

Arm description

Placebo matching pazopanib 600 mg daily. Complete treatment is 12 months.

Arm type

Placebo

Investigational medicinal product name

pazopanib placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Subsequent to Amendment 2, each subject started the study treatment at 600 mg daily (3 × 200 mg placebo tablets) for 8 to 12 weeks. Based on evaluation of each subject’s safety and tolerability profile, the Investigator determined whether the subject should be dose escalated to 800 mg daily (4 × 200 mg placebo tablets) or maintained at 600 mg daily.

Number of subjects in period 1	ITT pazopanib 800 mg	ITT placebo 800 mg	ITT pazopanib 600 mg	ITT placebo 600 mg
Started	198	205	571	564
Prem. withdrawn = did not complete study	46 ^[1]	35 ^[2]	118 ^[3]	86 ^[4]
Completed	152	170	453	478
Not completed	46	35	118	86
Consent withdrawn by subject	20	19	62	49
Physician decision	5	-	9	5
Lost to follow-up	21	16	47	32

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the number of subjects is correct
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the number of subjects is correct
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the number of subjects is correct
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: the number of subjects is correct

Baseline characteristics

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Reporting group title

ITT pazopanib 800 mg

Reporting group description

Pazopanib 800 mg daily based on safety evaluation. Complete treatment is 12 months.

Reporting group title

ITT placebo 800 mg

Reporting group description

Placebo matching pazopanib 800 mg daily. Complete treatment is 12 months.

Reporting group title

ITT pazopanib 600 mg

Reporting group description

Pazopanib 600 mg daily initial dose for 8-12 weeks. Dose can be escalated to 800 mg daily based on safety evaluation. Complete treatment is 12 months.

Reporting group title

ITT placebo 600 mg

Reporting group description

Placebo matching pazopanib 600 mg daily. Complete treatment is 12 months.

Reporting group values	ITT pazopanib 800 mg	ITT placebo 800 mg	ITT pazopanib 600 mg	ITT placebo 600 mg	Total
Number of subjects	198	205	571	564	1538
Age Categorical
Units: Participants
=>18 to <65	154	140	430	406	1130
=>65 to <75	36	55	122	131	344
=>75 to <85	8	10	19	27	64
Sex: Female, Male
Units: Participants
Female	59	51	173	164	447
Male	139	154	398	400	1091
Race/Ethnicity, Customized
Units: Subjects
White	168	178	471	481	1298
Asian	28	26	71	70	195
African American/African Heritage	1	0	7	1	9
Other	0	1	4	2	7
Missing	1	0	18	10	29

Subject analysis set title

ITT All - pazopanib

Subject analysis set type

Intention-to-treat

Subject analysis set description

All randomized subjects with a scheduled initial dose of 600 mg or 800 mg daily pazopanib

Subject analysis set title

ITT All - placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

All randomized subjects with a scheduled initial dose of 600 or 800 mg daily placebo

Subject analysis sets values	ITT All - pazopanib	ITT All - placebo
Number of subjects	769	769
Age Categorical
Units: Participants
=>18 to <65	584	546
=>65 to <75	158	186
=>75 to <85	27	37
Age continuous
Units:
	±	±
Sex: Female, Male
Units: Participants
Female	232	215
Male	537	554
Race/Ethnicity, Customized
Units: Subjects
White	639	659
Asian	99	96
African American/African Heritage	8	1
Other	4	3
Missing	19	10

End points

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Reporting group title

ITT pazopanib 800 mg

Reporting group description

Pazopanib 800 mg daily based on safety evaluation. Complete treatment is 12 months.

Reporting group title

ITT placebo 800 mg

Reporting group description

Placebo matching pazopanib 800 mg daily. Complete treatment is 12 months.

Reporting group title

ITT pazopanib 600 mg

Reporting group description

Pazopanib 600 mg daily initial dose for 8-12 weeks. Dose can be escalated to 800 mg daily based on safety evaluation. Complete treatment is 12 months.

Reporting group title

ITT placebo 600 mg

Reporting group description

Placebo matching pazopanib 600 mg daily. Complete treatment is 12 months.

Subject analysis set title

ITT All - pazopanib

Subject analysis set type

Intention-to-treat

Subject analysis set description

All randomized subjects with a scheduled initial dose of 600 mg or 800 mg daily pazopanib

Subject analysis set title

ITT All - placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

All randomized subjects with a scheduled initial dose of 600 or 800 mg daily placebo

Primary: Disease-free survival (DFS) with pazopanib 600 mg daily initial dose vs. placebo

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End point title

Disease-free survival (DFS) with pazopanib 600 mg daily initial dose vs. placebo ^[1]

End point description

DFS is defined as the interval between the date of randomization and the earliest date of disease recurrence/metastasis or death due to any cause.

End point type

Primary

End point timeframe

approximately 5 years

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: months
median (confidence interval 95%)	999 (999 to 999)	999 (999 to 999)

DFS ITT paz 600mg vs. pbo 600mg

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1649

Method

Stratified Log-Rank

Parameter type

Adjusted Hazard Ratio

Point estimate

0.862

Confidence interval

level

95%

sides

2-sided

lower limit

0.699

upper limit

1.063

Secondary: Overall survival (OS) with pazopanib 600 mg daily initial dose vs. placebo

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End point title

Overall survival (OS) with pazopanib 600 mg daily initial dose vs. placebo ^[2]

End point description

Overall survival is defined as the time from randomization until death due to any cause. For subjects who do not die, time to death will be censored at the last date of known contact.

End point type

Secondary

End point timeframe

approximately 8.5 years

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: months
median (confidence interval 95%)	89.5 (9 to 999)	999 (999 to 999)

OS ITT paz 600mg vs. pbo 600mg

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.988

Method

Stratified Log-Rank

Parameter type

Adjusted Hazard Ratio

Point estimate

0.998

Confidence interval

level

95%

sides

2-sided

lower limit

0.759

upper limit

1.311

Secondary: DFS rates at yearly time points with pazopanib 600 mg daily initial dose vs. placebo

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End point title

DFS rates at yearly time points with pazopanib 600 mg daily initial dose vs. placebo ^[3]

End point description

End point type

Secondary

End point timeframe

yearly for 4 years

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: Proportion of subjects
median (confidence interval 95%)
DFS at 1 year (n = 423, 394)	0.85 (0.81 to 0.88)	0.76 (0.72 to 0.79)
DFS at 2 years (n = 308, 300)	0.72 (0.67 to 0.75)	0.68 (0.64 to 0.72)
DFS at 3 years (n = 118, 118)	0.65 (0.61 to 0.70)	0.64 (0.59 to 0.68)
DFS at 4 years (n = 0, 0)	0 (0 to 0)	0 (0 to 0)

No statistical analyses for this end point

Secondary: DFS with pazopanib vs. placebo

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End point title

DFS with pazopanib vs. placebo

End point description

DFS is defined as the interval between the date of randomization and the earliest date of disease recurrence/metastasis or death due to any cause.

End point type

Secondary

End point timeframe

approximately 5 years

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: months
median (confidence interval 95%)	999 (999 to 999)	99 (48.1 to 999)

DFS ITT All-paz vs. ITT All-pbo

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0126

Method

Stratified Log-Rank

Parameter type

Adjusted Hazard Ratio

Point estimate

0.802

Confidence interval

level

95%

sides

2-sided

lower limit

0.675

upper limit

0.954

Secondary: OS with pazopanib vs. placebo

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End point title

OS with pazopanib vs. placebo

End point description

Overall survival is defined as the time from randomization until death due to any cause. For subjects who do not die, time to death will be censored at the last date of known contact.

End point type

Secondary

End point timeframe

approximately 8.5 years

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: months
median (confidence interval 95%)	999 (999 to 999)	999 (999 to 999)

OS ITT All-paz vs. ITT All-pbo

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9959

Method

Stratified Log-Rank

Parameter type

Adjusted Hazard Ratio

Point estimate

1.001

Confidence interval

level

95%

sides

2-sided

lower limit

0.796

upper limit

1.257

Secondary: DFS rates at yearly time points with pazopanib vs. placebo

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End point title

DFS rates at yearly time points with pazopanib vs. placebo

End point description

End point type

Secondary

End point timeframe

yearly for 4 years

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: Proportion of subjects
median (confidence interval 95%)
DFS at 1 year (n = 579, 538)	0.85 (0.82 to 0.87)	0.75 (0.72 to 0.78)
DFS at 2 years (n = 436, 419)	0.72 (0.68 to 0.75)	0.66 (0.63 to 0.70)
DFS at 3 years (n = 231, 215)	0.65 (0.62 to 0.69)	0.61 (0.58 to 0.65)
DFS at 4 years (n = 48, 46)	0.62 (0.58 to 0.66)	0.56 (0.51 to 0.61)

No statistical analyses for this end point

Secondary: DFS pazopanib 800 mg daily initial dose vs. placebo

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End point title

DFS pazopanib 800 mg daily initial dose vs. placebo ^[4]

End point description

DFS is defined as the interval between the date of randomization and the earliest date of disease recurrence/metastasis or death due to any cause.

End point type

Secondary

End point timeframe

approximately 5 years

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 800 mg	ITT placebo 800 mg
Number of subjects analysed	198	205
Units: months
median (confidence interval 95%)	999 (999 to 999)	48.1 (30.1 to 999)

DFS ITT paz 800mg vs. pbo 800mg

Comparison groups

ITT pazopanib 800 mg v ITT placebo 800 mg

Number of subjects included in analysis

403

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0201

Method

Stratified Log-Rank

Parameter type

Adjusted Hazard Ratio

Point estimate

0.693

Confidence interval

level

95%

sides

2-sided

lower limit

0.51

upper limit

0.943

Secondary: OS with pazopanib 800 mg daily initial dose vs. placebo

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End point title

OS with pazopanib 800 mg daily initial dose vs. placebo ^[5]

End point description

Overall survival is defined as the time from randomization until death due to any cause. For subjects who do not die, time to death will be censored at the last date of known contact.

End point type

Secondary

End point timeframe

approximately 8.5 years

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 800 mg	ITT placebo 800 mg
Number of subjects analysed	198	205
Units: months
median (confidence interval 95%)	999 (999 to 999)	999 (999 to 999)

OS ITT paz 800mg vs. pbo 800mg

Comparison groups

ITT pazopanib 800 mg v ITT placebo 800 mg

Number of subjects included in analysis

403

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9865

Method

Stratified Log-Rank

Parameter type

Adjusted Hazard Ratio

Point estimate

1.004

Confidence interval

level

95%

sides

2-sided

lower limit

0.662

upper limit

1.521

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/Functional Assessment of Cancer Therapy-Kidney Symptom Index -19 (FACT FKSI-19) total score

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End point title

Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/Functional Assessment of Cancer Therapy-Kidney Symptom Index -19 (FACT FKSI-19) total score ^[6]

End point description

Health outcome and quality of life as measured by NCCN/FACT FKSI-19 questionnaire. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains (FKSI-DRS-P, FKSI-DRS-E, FKSI-TSE, FKSI-FWB) experienced in the past 7 days. Participants are asked to respond to a total of 19 questions regarding symptoms, side effects, and well being by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total score of 0 to 76). A negative mean indicates a worsening of condition. DFS: disease-free survival; FU: follow up

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 423, 401)	-3.83 ± 0.452	-0.43 ± 0.459
24M DFS FU (n = 335, 340)	0.19 ± 0.419	0.23 ± 0.418
36M DFS FU (n = 294, 290)	-0.14 ± 0.454	-0.26 ± 0.456
48M DFS FU (n = 144, 140)	-0.13 ± 0.526	0.22 ± 0.529
54M DFS FU (n = 60, 66)	0.09 ± 0.653	0.26 ± 0.635

FACT FKSI-19 (600 mg) total score - W52

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

analysis of covariance

Parameter type

Mean Difference (Week 52)

Point estimate

-3.397

Confidence interval

level

95%

sides

2-sided

lower limit

-4.486

upper limit

-2.307

FACT FKSI-19 (600 mg) total score - 24M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.93

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU)

Point estimate

-0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-1.003

upper limit

0.917

FACT FKSI-19 (600 mg) total score - 36M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.828

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU)

Point estimate

0.119

Confidence interval

level

95%

sides

2-sided

lower limit

-0.958

upper limit

1.196

FACT FKSI-19 (600 mg) total score - 48M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.603

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU)

Point estimate

-0.347

Confidence interval

level

95%

sides

2-sided

lower limit

-1.658

upper limit

0.964

FACT FKSI-19 (600 mg) total score - 54M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.841

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-1.843

upper limit

1.503

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain score

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End point title

Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain score ^[7]

End point description

Health outcome and quality of life as measured by NCCN/FACT FKSI-19 questionnaire. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains. The DRS-P domain assesses symptoms experienced in the past 7 days. Participants are asked to respond to 12 questions ("I have a lack of energy," "I feel pain," for example) by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total domain score of 0 to 48). Higher scores represent better health.

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 427, 406)	-2.06 ± 0.278	-0.44 ± 0.282
24M DFS FU (n = 340, 341)	-0.32 ± 0.273	-0.20 ± 0.273
36M DFS FU (n = 300, 293)	-0.61 ± 0.291	-0.53 ± 0.294
48M DFS FU (n = 147, 141)	-0.67 ± 0.332	-0.46 ± 0.336
54M DFS FU (n = 61, 66)	-0.21 ± 0.449	-0.55 ± 0.439

FACT FKSI-19 (600 mg) DRS-P score - W52

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

analysis of covariance

Parameter type

Mean Difference (Week 52)

Point estimate

-1.619

Confidence interval

level

95%

sides

2-sided

lower limit

-2.283

upper limit

-0.955

FACT FKSI-19 (600 mg) DRS-P score - 24M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.726

Method

analysis of covariance

Parameter type

Mean Difference (24 M DFS FU)

Point estimate

-0.114

Confidence interval

level

95%

sides

2-sided

lower limit

-0.75

upper limit

0.522

FACT FKSI-19 (600 mg) DRS-P score - 36M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.801

Method

analysis of covariance

Parameter type

Mean Difference (36 M DFS FU)

Point estimate

-0.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.789

upper limit

0.609

FACT FKSI-19 (600 mg) DRS-P score - 48M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.617

Method

analysis of covariance

Parameter type

Meat Difference (48 M DFS FU)

Point estimate

-0.212

Confidence interval

level

95%

sides

2-sided

lower limit

-1.044

upper limit

0.32

FACT FKSI-19 (600 mg) DRS-P score - 54M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.565

Method

adjusted for baseline score using mixedm

Parameter type

Mean Difference (54 M DFS FU)

Point estimate

0.341

Confidence interval

level

95%

sides

2-sided

lower limit

-0.828

upper limit

1.51

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Disease Related Symptoms-emotional (DRS-E) Domain Score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Disease Related Symptoms-emotional (DRS-E) Domain Score ^[8]

End point description

Health outcome and quality of life as measured by NCCN/FACT FKSI-19 questionnaire. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains. The DRS-E domain assesses symptoms experienced in the past 7 days. Participants are asked to respond to the question of "I worry that my condition will get worse" by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total domain score of 0 to 4). A negative change from Baseline (BL) represents a worsening of condition.

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU,48M DFS FU, 54M DFS FU

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 425, 402)	0.01 ± 0.054	0.09 ± 0.055
24M DFS FU (n = 338, 340)	0.11 ± 0.056	0.16 ± 0.056
36M DFS FU (n = 296, 291)	0.13 ± 0.059	0.12 ± 0.059
48M DFS FU (n = 146, 141)	0.08 ± 0.075	0.20 ± 0.076
54M DFS FU (n = 60, 66)	0.04 ± 0.090	0.24 ± 0.087

FACT FKSI-19 (600 mg) DRS-E score - 24M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.442

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU)

Point estimate

-0.052

Confidence interval

level

95%

sides

2-sided

lower limit

-0.185

upper limit

0.081

FACT FKSI-19 (600 mg) DRS-E score - W52

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.238

Method

analysis of covariance

Parameter type

Mean Difference (Week 52)

Point estimate

-0.077

Confidence interval

level

95%

sides

2-sided

lower limit

-0.205

upper limit

0.051

FACT FKSI-19 (600 mg) DRS-E score - 48M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.223

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU)

Point estimate

-0.119

Confidence interval

level

95%

sides

2-sided

lower limit

-0.311

upper limit

0.073

FACT FKSI-19 (600 mg) DRS-E score - 54M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.085

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

-0.203

Confidence interval

level

95%

sides

2-sided

lower limit

-0.435

upper limit

0.028

FACT FKSI-19 (600 mg) DRS-E score - 36M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.819

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU)

Point estimate

0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.125

upper limit

0.158

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score ^[9]

End point description

Health outcome and quality of life as measured by NCCN/FACT FKSI-19 questionnaire. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains. The TSE domain assesses side effects experienced in the past 7 days. Participants are asked to respond to 3 questions ("I have nausea," "I have diarrhea," and "I am bothered by side effects of treatment") by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total domain score of 0 to 12). Higher scores represent better health.

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU,48M DFS FU, 54M DFS FU

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 426, 404)	-1.73 ± 0.101	-0.34 ± 0.103
24M DFS FU (n = 338, 341)	0.12 ± 0.061	0.01 ± 0.060
36M DFS FU (n = 299, 292)	0.05 ± 0.067	-0.03 ± 0.067
48M DFS FU (n = 146, 140)	-0.04 ± 0.087	-0.01 ± 0.088
54M DFS FU (n = 61, 66)	0.07 ± 0.089	0.09 ± 0.086

FACT FKSI-19 (600 mg) TSE score - W52

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

analysis of covariance

Parameter type

Mean Difference (Week 52)

Point estimate

-1.394

Confidence interval

level

95%

sides

2-sided

lower limit

-1.66

upper limit

-1.129

FACT FKSI-19 (600 mg) TSE score - 24M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.083

Method

analysis of covariance

Parameter type

Mean difference (24M DFS FU)

Point estimate

0.117

Confidence interval

level

95%

sides

2-sided

lower limit

-0.015

upper limit

0.249

FACT FKSI-19 (600 mg) TSE score - 36M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.307

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU)

Point estimate

0.081

Confidence interval

level

95%

sides

2-sided

lower limit

-0.074

upper limit

0.236

FACT FKSI-19 (600 mg) TSE score - 48M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.796

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU)

Point estimate

-0.029

Confidence interval

level

95%

sides

2-sided

lower limit

-0.249

upper limit

0.191

FACT FKSI-19 (600 mg) TSE score - 54M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.885

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

-0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.237

upper limit

0.205

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score ^[10]

End point description

Health outcome and quality of life as measured by NCCN/FACT FKSI-19 questionnaire. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains. The FWB domain assesses well being in the past 7 days. Participants are asked to respond to 3 questions ("I am able to work," "I am able to enjoy life," and "I am content with the quality of my life now") by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total domain score of 0 to 12). Higher scores represent better health.

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU,48M DFS FU, 54M DFS FU

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 426, 406)	0.06 ± 0.153	0.33 ± 0.155
24M DFS FU (n = 339, 341)	0.39 ± 0.168	0.32 ± 0.168
36M DFS FU (n = 299, 293)	0.43 ± 0.177	0.24 ± 0.178
48M DFS FU (n = 146, 141)	0.51 ± 0.219	0.42 ± 0.222
54M DFS FU (n = 61, 66)	0.31 ± 0.308	0.59 ± 0.299

FACT FKSI-19 (600 mg) FWB score - W52

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.143

Method

analysis of covariance

Parameter type

Mean Differencec (Week 52)

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.633

upper limit

0.092

FACT FKSI-19 (600 mg) FWB score - 24M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.736

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU)

Point estimate

0.069

Confidence interval

level

95%

sides

2-sided

lower limit

-0.336

upper limit

0.475

FACT FKSI-19 (600 mg) FWB score - 36M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.397

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU)

Point estimate

0.188

Confidence interval

level

95%

sides

2-sided

lower limit

-0.247

upper limit

0.623

FACT FKSI-19 (600 mg) FWB score - 48M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.781

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU)

Point estimate

0.081

Confidence interval

level

95%

sides

2-sided

lower limit

-0.488

upper limit

0.649

FACT FKSI-19 (600 mg) FWB score - 54M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.503

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

-0.278

Confidence interval

level

95%

sides

2-sided

lower limit

-1.094

upper limit

0.539

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using EuroQoL-5D (EQ-5D) score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using EuroQoL-5D (EQ-5D) score ^[11]

End point description

Health outcome and quality of life measured by EQ-5D thermometer (thermo) score and EQ-5D utility index (UI) score. The EQ-5D is a participant-answered questionnaire measuring 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D has two separate components: utility score and thermometer score. The EQ-5D total utility score ranges from 0 (worst health state) to 1 (perfect health state); 1 reflects the best outcome. The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: no statistical analysis was planned for this endpoint

End point values	ITT pazopanib 600 mg	ITT placebo 600 mg
Number of subjects analysed	571	564
Units: scores on a scale
least squares mean (standard error)
Week 52 thermo. score (n=417,399)	0.713 ± 0.858	1.430 ± 0.868
24M DFS FU thermo. score (n = 328, 334)	3.356 ± 0.882	3.641 ± 0.877
36M DFS FU thermo. score (n = 288, 287)	3.640 ± 0.882	2.459 ± 0.883
48M DFS FU thermo. score (n = 144, 141)	3.909 ± 1.014	3.184 ± 1.015
54M DFS FU thermo. score (n = 60, 65)	3.076 ± 1.607	1.053 ± 1.560
Week 52 UI score (n = 419, 401)	-0.019 ± 0.009	-0.001 ± 0.009
24M DFS FU UI score (n = 334, 337)	-0.004 ± 0.010	0.016 ± 0.010
36M DFS FU UI score (n =294, 288)	0.002 ± 0.011	-0.008 ± 0.011
48M DFS FU UI score (n = 144, 141)	-0.002 ± 0.013	0.008 ± 0.013
54M DFS FU UI score (n = 61, 65)	0.004 ± 0.017	-0.013 ± 0.017

EQ-5D (600 mg) thermo. score - W52

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.49

Method

analysis of covariance

Parameter type

Mean Difference (Week 52 thermo)

Point estimate

-0.717

Confidence interval

level

95%

sides

2-sided

lower limit

-2.751

upper limit

1.318

EQ-5D (600 mg) thermo. score - 24M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.788

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU- thermo)

Point estimate

-0.285

Confidence interval

level

95%

sides

2-sided

lower limit

-2.358

upper limit

1.788

EQ-5D (600 mg) thermo. score - 36M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.266

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU- thermo)

Point estimate

1.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.901

upper limit

3.262

EQ-5D (600 mg) thermo. score - 48M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.57

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU - thermo)

Point estimate

0.725

Confidence interval

level

95%

sides

2-sided

lower limit

-1.779

upper limit

3.229

EQ-5D (600 mg) thermo. score - 54M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.346

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU - thermo)

Point estimate

2.023

Confidence interval

level

95%

sides

2-sided

lower limit

-2.205

upper limit

6.251

EQ-5D (600 mg) UI score - W52

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.111

Method

analysis of covariance

Parameter type

Mean Difference (Week 52 - UI)

Point estimate

-0.018

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.004

EQ-5D (600 mg) UI score - 24M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.094

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU - UI)

Point estimate

-0.02

Confidence interval

level

95%

sides

2-sided

lower limit

-0.044

upper limit

0.003

EQ-5D (600 mg) UI score - 36M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.49

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU - UI)

Point estimate

0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.037

EQ-5D (600 mg) UI score - 48M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.58

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU - UI)

Point estimate

-0.009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.043

upper limit

0.024

EQ-5D(600 mg) UI score - 54M DFS FU

Comparison groups

ITT pazopanib 600 mg v ITT placebo 600 mg

Number of subjects included in analysis

1135

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.473

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU - UI)

Point estimate

0.017

Confidence interval

level

95%

sides

2-sided

lower limit

-0.029

upper limit

0.063

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 total score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 total score

End point description

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 575, 554)	-4.01 ± 0.385	-0.47 ± 0.388
24M DFS FU (n = 462, 458)	0.23 ± 0.361	0.33 ± 0.362
36M DFS FU (n = 405, 392)	0.16 ± 0.385	-0.07 ± 0.389
48M DFS FU (n = 244, 232)	0.47 ± 0.421	0.39 ± 0.427
54M DFS FU (n = 156, 153)	0.27 ± 0.505	-0.14 ± 0.509

FACT FKSI-19 (ITT All) total score - W52

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

analysis of covariance

Parameter type

Mean Difference (Week 52)

Point estimate

-3.536

Confidence interval

level

95%

sides

2-sided

lower limit

-4.466

upper limit

-2.606

FACT FKSI-19 (ITT All) total score - 24M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.812

Method

analysis of covariance

Parameter type

Mean difference (24M DFS FU)

Point estimate

-0.102

Confidence interval

level

95%

sides

2-sided

lower limit

-0.942

upper limit

0.738

FACT FKSI-19 (ITT All) total score - 36M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.621

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU)

Point estimate

0.233

Confidence interval

level

95%

sides

2-sided

lower limit

-0.69

upper limit

1.155

FACT FKSI-19 (ITT All) total score - 48M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.878

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU)

Point estimate

0.082

Confidence interval

level

95%

sides

2-sided

lower limit

-0.959

upper limit

1.122

FACT FKSI-19 (ITT All) total score - 54M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.533

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

0.412

Confidence interval

level

95%

sides

2-sided

lower limit

-0.887

upper limit

1.712

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain score

End point description

Health outcome and quality of life measured by NCCN/FACT FKSI-19 questionnaire for ITT ALL. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains. The DRS-P domain assesses symptoms experienced in the past 7 days. Participants are asked to respond to 12 questions ("I have a lack of energy," "I feel pain," for example) by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total domain score of 0 to 48). Higher scores represent better health.

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 579, 559)	-2.03 ± 0.235	-0.51 ± 0.237
24M DFS FU (n = 467, 460)	-0.24 ± 0.232	-0.25 ± 0.233
36M DFS FU (n = 412, 395)	-0.41 ± 0.247	-0.45 ± 0.250
48M DFS FU (n = 248, 233)	-0.25 ± 0.270	-0.19 ± 0.275
54M DFS FU (n =157, 153)	-0.23 ± 0.329	-0.68 ± 0.333

FACT FKSI-19 (ITT All) DRS-P score - W52

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

analysis of covariance

Parameter type

Mean Difference (Week 52)

Point estimate

-1.515

Confidence interval

level

95%

sides

2-sided

lower limit

-2.078

upper limit

-0.952

FACT FKSI-19 (ITT All) DRS-P score - 24M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.961

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU)

Point estimate

0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.534

upper limit

0.561

FACT FKSI-19 (ITT All) DRS-P score - 36M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.888

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU)

Point estimate

0.043

Confidence interval

level

95%

sides

2-sided

lower limit

-0.555

upper limit

0.641

FACT FKSI-19 (ITT All) DRS-P score - 48M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.858

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU)

Point estimate

-0.061

Confidence interval

level

95%

sides

2-sided

lower limit

-0.736

upper limit

0.614

FACT FKSI-19 (ITT All) DRS-P score - 54M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

0.452

Confidence interval

level

95%

sides

2-sided

lower limit

-0.404

upper limit

1.309

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-emotional (DRS-E) Domain Score

Top of page

End point title

End point description

Health outcome and quality of life measured by NCCN/FACT FKSI-19 questionnaire for ITT ALL. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains. The DRS-E domain assesses symptoms experienced in the past 7 days. Participants are asked to respond to the question of "I worry that my condition will get worse" by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total domain score of 0 to 4). A negative change from Baseline (BL) represents a worsening of condition.

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 578, 555)	0.04 ± 0.045	0.14 ± 0.046
24M DFS FU (n = 465, 458)	0.15 ± 0.048	0.19 ± 0.048
36M DFS FU (n = 407, 393)	0.19 ± 0.050	0.15 ± 0.051
48M DFS FU (n = 246, 243)	0.16 ± 0.059	0.20 ± 0.060
54M DFS FU (n = 156, 153)	0.16 ± 0.065	0.17 ± 0.066

FACT FKSI-19 (ITT All) DRS-E score - W52

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.059

Method

analysis of covariance

Parameter type

Mean Difference (Week 52)

Point estimate

-0.103

Confidence interval

level

95%

sides

2-sided

lower limit

-0.211

upper limit

0.004

FACT FKSI-19 (ITT All) DRS-E score - 24M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.487

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU)

Point estimate

-0.041

Confidence interval

level

95%

sides

2-sided

lower limit

-0.155

upper limit

0.074

FACT FKSI-19 (ITT All) DRS-E score - 36M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.885

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU)

Point estimate

0.037

Confidence interval

level

95%

sides

2-sided

lower limit

-0.085

upper limit

0.16

FACT FKSI-19 (ITT All) DRS-E score - 48M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.676

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU)

Point estimate

-0.032

Confidence interval

level

95%

sides

2-sided

lower limit

-0.183

upper limit

0.119

FACT FKSI-19 (ITT All) DRS-E score - 54M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.859

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

-0.015

Confidence interval

level

95%

sides

2-sided

lower limit

-0.183

upper limit

0.153

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score

End point description

Health outcome and quality of life measured by NCCN/FACT FKSI-19 questionnaire for ITT ALL. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains. The TSE domain assesses side effects experienced in the past 7 days. Participants are asked to respond to 3 questions ("I have nausea," "I have diarrhea," and "I am bothered by side effects of treatment") by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total domain score of 0 to 12). Higher scores represent better health.

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 578, 557)	-1.86 ± 0.089	-0.33 ± 0.090
24M DFS FU (n = 465, 460)	0.12 ± 0.052	0.04 ± 0.052
36M DFS FU (n = 411, 394)	0.11 ± 0.057	-0.02 ± 0.058
48M DFS FU (n = 247, 232)	0.05 ± 0.065	-0.00 ± 0.066
54M DFS FU (n = 157, 153)	0.09 ± 0.074	0.03 ± 0.074

FACT FKSI-19 (ITT All) TSE score - W52

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

analysis of covariance

Parameter type

Mean Diffeence (Week 52)

Point estimate

-1.535

Confidence interval

level

95%

sides

2-sided

lower limit

-1.769

upper limit

-1.3

FACT FKSI-19 (ITT All) TSE score - 24M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.127

Method

analysis of covariance

Parameter type

Mean Diffeence (24M DFS FU)

Point estimate

0.089

Confidence interval

level

95%

sides

2-sided

lower limit

-0.025

upper limit

0.202

FACT FKSI-19 (ITT All) TSE score - 36M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.069

Method

analysis of covariance

Parameter type

Mean Diffeence (36M DFS FU)

Point estimate

0.123

Confidence interval

level

95%

sides

2-sided

lower limit

-0.009

upper limit

0.255

FACT FKSI-19 (ITT All) TSE score - 48M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.544

Method

analysis of covariance

Parameter type

Mean Diffeence (48M DFS FU)

Point estimate

0.049

Confidence interval

level

95%

sides

2-sided

lower limit

-0.11

upper limit

0.208

FACT FKSI-19 (ITT All) TSE score - 54M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.518

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

0.061

Confidence interval

level

95%

sides

2-sided

lower limit

-0.124

upper limit

0.246

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score

End point description

Health outcome and quality of life measured by NCCN/FACT FKSI-19 questionnaire for ITT ALL. The FKSI-19 is a disease-specific instrument that measures disease and treatment-related symptoms specifically in renal cancer patients in 4 domains. The FWB domain assesses well being in the past 7 days. Participants are asked to respond to 3 questions ("I am able to work," "I am able to enjoy life," and "I am content with the quality of my life now") by using a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much; possible total domain score of 0 to 12). Higher scores represent better health.

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: scores on a scale
least squares mean (standard error)
Week 52 (n = 579, 559)	-0.08 ± 0.134	0.30 ± 0.136
24M DFS FU (n = 467, 460)	0.30 ± 0.147	0.41 ± 0.147
36M DFS FU (n = 411, 395)	0.3 ± 0.151	0.29 ± 0.153
48M DFS FU (n =247, 243)	0.50 ± 0.179	0.38 ± 0.183
54M DFS FU (n = 157, 153)	0.39 ± 0.206	0.44 ± 0.208

FACT FKSI-19 (ITT All) FWB score - W52

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.022

Method

analysis of covariance

Parameter type

Mean Diffeence (Week 52)

Point estimate

-0.374

Confidence interval

level

95%

sides

2-sided

lower limit

-0.695

upper limit

-0.053

FACT FKSI-19 (ITT All) FWB score - 24M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.567

Method

analysis of covariance

Parameter type

Mean Diffeence (24M DFS FU)

Point estimate

-0.104

Confidence interval

level

95%

sides

2-sided

lower limit

-0.462

upper limit

0.253

FACT FKSI-19 (ITT All) FWB score - 36M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.706

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU)

Point estimate

0.072

Confidence interval

level

95%

sides

2-sided

lower limit

-0.302

upper limit

0.446

FACT FKSI-19 (ITT All) FWB score - 48M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.612

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU)

Point estimate

0.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.343

upper limit

0.583

FACT FKSI-19 (ITT All) FWB score - 54M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.87

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU)

Point estimate

-0.045

Confidence interval

level

95%

sides

2-sided

lower limit

-0.587

upper limit

0.496

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using EuroQoL-5D (EQ-5D) score

Top of page

End point title

Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using EuroQoL-5D (EQ-5D) score

End point description

Health outcome and quality of life measured by using EQ-5D thermometer score and EQ-5D utility index (UI) score. The EQ-5D is a participant-answered questionnaire measuring 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D has two separate components: utility score and thermometer score. The EQ-5D total utility score ranges from 0 (worst health state) to 1 (perfect health state); 1 reflects the best outcome. The thermometer score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).

End point type

Secondary

End point timeframe

Week 52, 24M DFS FU, 36M DFS FU, 48M DFS FU, 54M DFS FU

End point values	ITT All - pazopanib	ITT All - placebo
Number of subjects analysed	769	769
Units: scores on a scale
least squares mean (standard error)
Week 52 thermo. (n = 568, 546)	0.744 ± 0.733	2.859 ± 0.742
24M DFS FU thermo. (n = 452, 450)	4.043 ± 0.741	4.296 ± 0.743
36M DFS FU thermo. (n = 398, 387)	3.997 ± 0.774	3.150 ± 0.781
48M DFS FU thermo. (n = 245, 232)	4.683 ± 0.863	4.552 ± 0.877
54M DFS FU thermos. (n = 155, 149)	3.650 ± 1.028	3.249 ± 1.043
Week 52 UI score (n = 571, 548)	-0.023 ± 0.008	0.003 ± 0.008
24M DFS FU UI score (n = 460, 453)	0.001 ± 0.008	0.017 ± 0.008
36M DFS FU UI score (n = 404, 387)	0.004 ± 0.009	-0.004 ± 0.009
48M DFS FU UI score (n = 244, 231)	-0.004 ± 0.010	0.010 ± 0.010
54M DFS FU UI score (n = 156, 147)	-0.004 ± 0.012	0.003 ± 0.012

EQ-5D (ITT All) thermo. score - W52

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.018

Method

analysis of covariance

Parameter type

Mean Difference (Week 52 - thermo.)

Point estimate

-2.116

Confidence interval

level

95%

sides

2-sided

lower limit

-3.872

upper limit

-0.359

EQ-5D (ITT All) thermo. score - 24M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.778

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU - thermo)

Point estimate

-0.253

Confidence interval

level

95%

sides

2-sided

lower limit

-2.014

upper limit

1.508

EQ-5D (ITT All) thermo. score - 36M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.376

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU - thermo)

Point estimate

0.847

Confidence interval

level

95%

sides

2-sided

lower limit

-1.03

upper limit

2.724

EQ-5D (ITT All) thermo. score - 48M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.905

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU - thermo)

Point estimate

0.131

Confidence interval

level

95%

sides

2-sided

lower limit

-2.032

upper limit

2.294

EQ-5D (ITT All) thermo. score - 54M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.768

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU - thermo)

Point estimate

0.401

Confidence interval

level

95%

sides

2-sided

lower limit

-2.269

upper limit

3.071

EQ-5D (ITT All) UI score - W52

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.007

Method

analysis of covariance

Parameter type

Mean Difference (Week 52 - UI)

Point estimate

-0.026

Confidence interval

level

95%

sides

2-sided

lower limit

-0.044

upper limit

-0.007

EQ-5D (ITT All) UI score - 24M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.13

Method

analysis of covariance

Parameter type

Mean Difference (24M DFS FU - UI)

Point estimate

-0.016

Confidence interval

level

95%

sides

2-sided

lower limit

-0.036

upper limit

0.005

EQ-5D (ITT All) UI score - 36M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.52

Method

analysis of covariance

Parameter type

Mean Difference (36M DFS FU - UI)

Point estimate

0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.015

upper limit

0.03

EQ-5D (ITT All) UI score - 48M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.276

Method

analysis of covariance

Parameter type

Mean Difference (48M DFS FU - UI)

Point estimate

-0.014

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.011

EQ-5D (ITT All) UI score - 54M DFS FU

Comparison groups

ITT All - pazopanib v ITT All - placebo

Number of subjects included in analysis

1538

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.665

Method

analysis of covariance

Parameter type

Mean Difference (54M DFS FU - UI)

Point estimate

-0.007

Confidence interval

level

95%

sides

2-sided

lower limit

-0.037

upper limit

0.024

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

ITT pazopanib 800 mg

Reporting group description

Pazopanib 800 mg daily dose based on safety evaluation. Complete treatment is 12 months.

Reporting group title

ITT placebo 800 mg

Reporting group description

Placebo matching pazopanib 800 mg daily. Complete treatment is 12 months.

Reporting group title

ITT pazopanib 600 mg

Reporting group description

ITT pazopanib 600 mg Pazopanib 600 mg daily initial dose for 8-12 weeks. Dose can be escalated to 800 mg daily based on safety evaluation. Complete treatment is 12 months.

Reporting group title

ITT placebo 600 mg

Reporting group description

Placebo matching pazopanib 600 mg daily. Complete treatment is 12 months.

Reporting group title

ITT All - Pazopanib

Reporting group description

All randomized subjects with a scheduled initial dose of 600 or 800 mg daily pazopanib.

Reporting group title

ITT All - Placebo

Reporting group description

All randomized subjects with a scheduled initial dose of 600 or 800 mg daily placebo.

Serious adverse events	ITT pazopanib 800 mg	ITT placebo 800 mg	ITT pazopanib 600 mg	ITT placebo 600 mg	ITT All - Pazopanib	ITT All - Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	44 / 198 (22.22%)	14 / 204 (6.86%)	123 / 568 (21.65%)	54 / 558 (9.68%)	167 / 766 (21.80%)	68 / 762 (8.92%)
number of deaths (all causes)	1	0	3	0	4	0
number of deaths resulting from adverse events	1	0	0	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Biliary neoplasm
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gallbladder cancer
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	1 / 558 (0.18%)	1 / 766 (0.13%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian epithelial cancer
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Papillary thyroid cancer
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	2 / 558 (0.36%)	0 / 766 (0.00%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid cancer
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour thrombosis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	3 / 198 (1.52%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	4 / 766 (0.52%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	1 / 1	0 / 0	3 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	2 / 198 (1.01%)	0 / 204 (0.00%)	1 / 568 (0.18%)	1 / 558 (0.18%)	3 / 766 (0.39%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	1 / 1	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 198 (0.51%)	2 / 204 (0.98%)	1 / 568 (0.18%)	0 / 558 (0.00%)	2 / 766 (0.26%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung transplant rejection
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	0 / 558 (0.00%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial hyperplasia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Menorrhagia
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Alveolitis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	2 / 568 (0.35%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	3 / 558 (0.54%)	0 / 766 (0.00%)	4 / 762 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Panic disorder
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	15 / 198 (7.58%)	0 / 204 (0.00%)	51 / 568 (8.98%)	2 / 558 (0.36%)	66 / 766 (8.62%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	11 / 11	0 / 0	38 / 40	1 / 1	49 / 51	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	12 / 568 (2.11%)	0 / 558 (0.00%)	13 / 766 (1.70%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	9 / 9	0 / 0	10 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bilirubin conjugated increased
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	3 / 568 (0.53%)	0 / 558 (0.00%)	3 / 766 (0.39%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood glucose increased
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	4 / 568 (0.70%)	0 / 558 (0.00%)	4 / 766 (0.52%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic enzymes increased
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	3 / 568 (0.53%)	0 / 558 (0.00%)	3 / 766 (0.39%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	0 / 558 (0.00%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle rupture
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Patella fracture
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	0 / 558 (0.00%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thermal burn
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	0 / 558 (0.00%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 198 (0.00%)	2 / 204 (0.98%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	3 / 762 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	2 / 558 (0.36%)	0 / 766 (0.00%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiomyopathy
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Coronary artery stenosis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain hypoxia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	2 / 568 (0.35%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	2 / 568 (0.35%)	2 / 558 (0.36%)	2 / 766 (0.26%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	2 / 558 (0.36%)	0 / 766 (0.00%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	2 / 558 (0.36%)	1 / 766 (0.13%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 2	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polycythaemia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	2 / 568 (0.35%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Macular hole
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	2 / 568 (0.35%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal tear
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Visual impairment
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 198 (1.01%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	3 / 766 (0.39%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	0 / 558 (0.00%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	3 / 568 (0.53%)	0 / 558 (0.00%)	4 / 766 (0.52%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer perforation
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematochezia
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	0 / 558 (0.00%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	0 / 558 (0.00%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	2 / 568 (0.35%)	0 / 558 (0.00%)	3 / 766 (0.39%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 2	0 / 0	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	2 / 568 (0.35%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	0 / 568 (0.00%)	0 / 558 (0.00%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Biliary colic
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	1 / 568 (0.18%)	3 / 558 (0.54%)	1 / 766 (0.13%)	4 / 762 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	2 / 558 (0.36%)	0 / 766 (0.00%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	5 / 198 (2.53%)	0 / 204 (0.00%)	3 / 568 (0.53%)	1 / 558 (0.18%)	8 / 766 (1.04%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	2 / 2	0 / 0	3 / 3	1 / 1	5 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatocellular injury
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver disorder
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver injury
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	2 / 568 (0.35%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	2 / 558 (0.36%)	1 / 766 (0.13%)	2 / 762 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrotic syndrome
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	2 / 568 (0.35%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Renal tubular necrosis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Basedow's disease
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	2 / 766 (0.26%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal wall abscess
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendiceal abscess
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis viral
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic gangrene
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	3 / 558 (0.54%)	0 / 766 (0.00%)	3 / 762 (0.39%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis salmonella
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	1 / 558 (0.18%)	1 / 766 (0.13%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 198 (0.00%)	1 / 204 (0.49%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Superinfection bacterial
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	1 / 558 (0.18%)	1 / 766 (0.13%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	3 / 568 (0.53%)	0 / 558 (0.00%)	4 / 766 (0.52%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertriglyceridaemia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	0 / 568 (0.00%)	1 / 558 (0.18%)	0 / 766 (0.00%)	1 / 762 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperuricaemia
subjects affected / exposed	0 / 198 (0.00%)	0 / 204 (0.00%)	1 / 568 (0.18%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 198 (0.51%)	0 / 204 (0.00%)	0 / 568 (0.00%)	0 / 558 (0.00%)	1 / 766 (0.13%)	0 / 762 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	ITT pazopanib 800 mg	ITT placebo 800 mg	ITT pazopanib 600 mg	ITT placebo 600 mg	ITT All - Pazopanib	ITT All - Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	194 / 198 (97.98%)	147 / 204 (72.06%)	541 / 568 (95.25%)	448 / 558 (80.29%)	735 / 766 (95.95%)	595 / 762 (78.08%)
Vascular disorders
Hypertension
subjects affected / exposed	108 / 198 (54.55%)	30 / 204 (14.71%)	294 / 568 (51.76%)	107 / 558 (19.18%)	402 / 766 (52.48%)	137 / 762 (17.98%)
occurrences all number	137	37	367	137	504	174
General disorders and administration site conditions
Asthenia
subjects affected / exposed	24 / 198 (12.12%)	12 / 204 (5.88%)	79 / 568 (13.91%)	53 / 558 (9.50%)	103 / 766 (13.45%)	65 / 762 (8.53%)
occurrences all number	28	19	96	69	124	88
Fatigue
subjects affected / exposed	74 / 198 (37.37%)	53 / 204 (25.98%)	222 / 568 (39.08%)	144 / 558 (25.81%)	296 / 766 (38.64%)	197 / 762 (25.85%)
occurrences all number	90	62	255	167	345	229
Mucosal inflammation
subjects affected / exposed	21 / 198 (10.61%)	5 / 204 (2.45%)	46 / 568 (8.10%)	17 / 558 (3.05%)	67 / 766 (8.75%)	22 / 762 (2.89%)
occurrences all number	22	5	58	19	80	24
Oedema peripheral
subjects affected / exposed	12 / 198 (6.06%)	10 / 204 (4.90%)	17 / 568 (2.99%)	29 / 558 (5.20%)	29 / 766 (3.79%)	39 / 762 (5.12%)
occurrences all number	10	10	17	34	27	44
Pyrexia
subjects affected / exposed	13 / 198 (6.57%)	7 / 204 (3.43%)	21 / 568 (3.70%)	22 / 558 (3.94%)	34 / 766 (4.44%)	29 / 762 (3.81%)
occurrences all number	18	6	17	28	35	34
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	15 / 198 (7.58%)	12 / 204 (5.88%)	51 / 568 (8.98%)	52 / 558 (9.32%)	66 / 766 (8.62%)	64 / 762 (8.40%)
occurrences all number	14	12	56	57	70	69
Dysphonia
subjects affected / exposed	14 / 198 (7.07%)	2 / 204 (0.98%)	55 / 568 (9.68%)	10 / 558 (1.79%)	69 / 766 (9.01%)	12 / 762 (1.57%)
occurrences all number	17	2	65	10	82	12
Dyspnoea
subjects affected / exposed	17 / 198 (8.59%)	10 / 204 (4.90%)	35 / 568 (6.16%)	26 / 558 (4.66%)	52 / 766 (6.79%)	36 / 762 (4.72%)
occurrences all number	16	21	37	27	53	48
Epistaxis
subjects affected / exposed	16 / 198 (8.08%)	5 / 204 (2.45%)	47 / 568 (8.27%)	11 / 558 (1.97%)	63 / 766 (8.22%)	16 / 762 (2.10%)
occurrences all number	24	5	52	22	76	27
Psychiatric disorders
Insomnia
subjects affected / exposed	10 / 198 (5.05%)	8 / 204 (3.92%)	29 / 568 (5.11%)	28 / 558 (5.02%)	39 / 766 (5.09%)	36 / 762 (4.72%)
occurrences all number	22	9	28	30	50	39
Investigations
Alanine aminotransferase increased
subjects affected / exposed	51 / 198 (25.76%)	11 / 204 (5.39%)	146 / 568 (25.70%)	26 / 558 (4.66%)	197 / 766 (25.72%)	37 / 762 (4.86%)
occurrences all number	61	14	165	36	226	50
Aspartate aminotransferase increased
subjects affected / exposed	48 / 198 (24.24%)	5 / 204 (2.45%)	129 / 568 (22.71%)	22 / 558 (3.94%)	177 / 766 (23.11%)	27 / 762 (3.54%)
occurrences all number	55	5	134	25	189	30
Blood bilirubin increased
subjects affected / exposed	8 / 198 (4.04%)	5 / 204 (2.45%)	32 / 568 (5.63%)	6 / 558 (1.08%)	40 / 766 (5.22%)	11 / 762 (1.44%)
occurrences all number	13	7	35	7	48	14
Blood creatinine increased
subjects affected / exposed	14 / 198 (7.07%)	14 / 204 (6.86%)	29 / 568 (5.11%)	32 / 558 (5.73%)	43 / 766 (5.61%)	46 / 762 (6.04%)
occurrences all number	19	16	36	34	55	50
Platelet count decreased
subjects affected / exposed	10 / 198 (5.05%)	1 / 204 (0.49%)	32 / 568 (5.63%)	7 / 558 (1.25%)	42 / 766 (5.48%)	8 / 762 (1.05%)
occurrences all number	14	1	36	11	50	12
Weight decreased
subjects affected / exposed	10 / 198 (5.05%)	2 / 204 (0.98%)	33 / 568 (5.81%)	7 / 558 (1.25%)	43 / 766 (5.61%)	9 / 762 (1.18%)
occurrences all number	9	2	32	7	41	9
Nervous system disorders
Dizziness
subjects affected / exposed	26 / 198 (13.13%)	17 / 204 (8.33%)	50 / 568 (8.80%)	52 / 558 (9.32%)	76 / 766 (9.92%)	69 / 762 (9.06%)
occurrences all number	25	20	52	71	77	91
Dysgeusia
subjects affected / exposed	43 / 198 (21.72%)	5 / 204 (2.45%)	171 / 568 (30.11%)	15 / 558 (2.69%)	214 / 766 (27.94%)	20 / 762 (2.62%)
occurrences all number	46	7	191	16	237	23
Headache
subjects affected / exposed	58 / 198 (29.29%)	35 / 204 (17.16%)	139 / 568 (24.47%)	78 / 558 (13.98%)	197 / 766 (25.72%)	113 / 762 (14.83%)
occurrences all number	75	46	167	97	242	143
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	12 / 198 (6.06%)	0 / 204 (0.00%)	25 / 568 (4.40%)	2 / 558 (0.36%)	37 / 766 (4.83%)	2 / 762 (0.26%)
occurrences all number	16	0	34	3	50	3
Thrombocytopenia
subjects affected / exposed	12 / 198 (6.06%)	1 / 204 (0.49%)	22 / 568 (3.87%)	6 / 558 (1.08%)	34 / 766 (4.44%)	7 / 762 (0.92%)
occurrences all number	13	1	24	8	37	9
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	27 / 198 (13.64%)	24 / 204 (11.76%)	85 / 568 (14.96%)	46 / 558 (8.24%)	112 / 766 (14.62%)	70 / 762 (9.19%)
occurrences all number	37	28	100	59	137	87
Abdominal pain upper
subjects affected / exposed	18 / 198 (9.09%)	5 / 204 (2.45%)	58 / 568 (10.21%)	18 / 558 (3.23%)	76 / 766 (9.92%)	23 / 762 (3.02%)
occurrences all number	18	5	67	19	85	24
Diarrhoea
subjects affected / exposed	129 / 198 (65.15%)	48 / 204 (23.53%)	361 / 568 (63.56%)	139 / 558 (24.91%)	490 / 766 (63.97%)	187 / 762 (24.54%)
occurrences all number	209	69	550	198	759	267
Constipation
subjects affected / exposed	17 / 198 (8.59%)	17 / 204 (8.33%)	28 / 568 (4.93%)	38 / 558 (6.81%)	45 / 766 (5.87%)	55 / 762 (7.22%)
occurrences all number	17	22	27	45	44	67
Dyspepsia
subjects affected / exposed	17 / 198 (8.59%)	13 / 204 (6.37%)	43 / 568 (7.57%)	17 / 558 (3.05%)	60 / 766 (7.83%)	30 / 762 (3.94%)
occurrences all number	19	15	49	44	68	59
Flatulence
subjects affected / exposed	8 / 198 (4.04%)	6 / 204 (2.94%)	32 / 568 (5.63%)	18 / 558 (3.23%)	40 / 766 (5.22%)	24 / 762 (3.15%)
occurrences all number	8	7	35	18	43	25
Nausea
subjects affected / exposed	89 / 198 (44.95%)	28 / 204 (13.73%)	226 / 568 (39.79%)	89 / 558 (15.95%)	315 / 766 (41.12%)	117 / 762 (15.35%)
occurrences all number	133	34	301	112	434	146
Stomatitis
subjects affected / exposed	23 / 198 (11.62%)	10 / 204 (4.90%)	55 / 568 (9.68%)	23 / 558 (4.12%)	78 / 766 (10.18%)	33 / 762 (4.33%)
occurrences all number	25	13	63	25	88	38
Vomiting
subjects affected / exposed	37 / 198 (18.69%)	8 / 204 (3.92%)	95 / 568 (16.73%)	21 / 558 (3.76%)	132 / 766 (17.23%)	29 / 762 (3.81%)
occurrences all number	51	10	132	24	183	34
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	26 / 198 (13.13%)	6 / 204 (2.94%)	64 / 568 (11.27%)	19 / 558 (3.41%)	90 / 766 (11.75%)	25 / 762 (3.28%)
occurrences all number	24	6	65	19	89	25
Dry skin
subjects affected / exposed	14 / 198 (7.07%)	9 / 204 (4.41%)	38 / 568 (6.69%)	32 / 558 (5.73%)	52 / 766 (6.79%)	41 / 762 (5.38%)
occurrences all number	13	10	40	33	53	43
Hair colour changes
subjects affected / exposed	90 / 198 (45.45%)	9 / 204 (4.41%)	232 / 568 (40.85%)	28 / 558 (5.02%)	322 / 766 (42.04%)	37 / 762 (4.86%)
occurrences all number	87	9	233	29	320	38
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	42 / 198 (21.21%)	8 / 204 (3.92%)	103 / 568 (18.13%)	24 / 558 (4.30%)	145 / 766 (18.93%)	32 / 762 (4.20%)
occurrences all number	51	9	117	28	168	37
Pruritus
subjects affected / exposed	12 / 198 (6.06%)	17 / 204 (8.33%)	25 / 568 (4.40%)	41 / 558 (7.35%)	37 / 766 (4.83%)	58 / 762 (7.61%)
occurrences all number	14	17	23	44	37	61
Rash
subjects affected / exposed	24 / 198 (12.12%)	14 / 204 (6.86%)	63 / 568 (11.09%)	36 / 558 (6.45%)	87 / 766 (11.36%)	50 / 762 (6.56%)
occurrences all number	36	19	70	37	106	56
Renal and urinary disorders
Proteinuria
subjects affected / exposed	14 / 198 (7.07%)	5 / 204 (2.45%)	24 / 568 (4.23%)	2 / 558 (0.36%)	38 / 766 (4.96%)	7 / 762 (0.92%)
occurrences all number	16	6	24	2	40	8
Endocrine disorders
Hypothyroidism
subjects affected / exposed	24 / 198 (12.12%)	2 / 204 (0.98%)	55 / 568 (9.68%)	4 / 558 (0.72%)	79 / 766 (10.31%)	6 / 762 (0.79%)
occurrences all number	29	2	53	4	82	6
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	18 / 198 (9.09%)	13 / 204 (6.37%)	47 / 568 (8.27%)	68 / 558 (12.19%)	65 / 766 (8.49%)	81 / 762 (10.63%)
occurrences all number	22	15	53	80	75	95
Back pain
subjects affected / exposed	29 / 198 (14.65%)	15 / 204 (7.35%)	53 / 568 (9.33%)	78 / 558 (13.98%)	82 / 766 (10.70%)	93 / 762 (12.20%)
occurrences all number	37	15	55	114	92	129
Muscle spasms
subjects affected / exposed	13 / 198 (6.57%)	10 / 204 (4.90%)	26 / 568 (4.58%)	11 / 558 (1.97%)	39 / 766 (5.09%)	21 / 762 (2.76%)
occurrences all number	13	13	30	11	43	24
Myalgia
subjects affected / exposed	16 / 198 (8.08%)	8 / 204 (3.92%)	39 / 568 (6.87%)	32 / 558 (5.73%)	55 / 766 (7.18%)	40 / 762 (5.25%)
occurrences all number	17	10	48	35	65	45
Pain in extremity
subjects affected / exposed	22 / 198 (11.11%)	12 / 204 (5.88%)	42 / 568 (7.39%)	30 / 558 (5.38%)	64 / 766 (8.36%)	42 / 762 (5.51%)
occurrences all number	24	13	53	34	77	47
Infections and infestations
Nasopharyngitis
subjects affected / exposed	13 / 198 (6.57%)	12 / 204 (5.88%)	27 / 568 (4.75%)	40 / 558 (7.17%)	40 / 766 (5.22%)	52 / 762 (6.82%)
occurrences all number	13	15	35	46	48	61
Upper respiratory tract infection
subjects affected / exposed	11 / 198 (5.56%)	7 / 204 (3.43%)	12 / 568 (2.11%)	21 / 558 (3.76%)	23 / 766 (3.00%)	28 / 762 (3.67%)
occurrences all number	11	8	13	27	24	35
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	42 / 198 (21.21%)	11 / 204 (5.39%)	112 / 568 (19.72%)	22 / 558 (3.94%)	154 / 766 (20.10%)	33 / 762 (4.33%)
occurrences all number	48	11	123	23	171	34

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Were there any global substantial amendments to the protocol? Yes

01 Feb 2011

Protocol Amendment 1 was a country specific amendment for France to include specific requirements 1) regarding potassium assessments and eligibility, 2) Added alert for medications known to be associated with QT prolongation or Torsades de pointes (TdP).

12 Aug 2011

Protocol Amendment 2 introduced the following changes: 1) Treatment to start at 600 mg for all subjects for 8-12 weeks. Dose escalation to 800 mg based on evaluation of subject’s safety and tolerability profile; 2) Revisions in the dose modification guidelines; 3) Addition of pharmacokinetic research; 4) Clarifications on several inclusion/exclusion criteria and screening baseline windows; 5) Clarifications on imaging assessment methods for different anatomic regions; 6) addition of Week 24 visit; and 7) Addition of routine pregnancy tests for female subjects with child-bearing potential.

09 Jan 2013

Protocol Amendment 3 introduced the following changes: 1) Revisions on study objectives in Section 2 of the Protocol – primary objective is to evaluate pazopanib 600 mg daily initial dose vs. placebo for DFS; secondary objectives are to evaluate i) pazopanib 600 mg daily initial dose vs. placebo, ii) pazopanib vs. placebo in all subjects regardless of initial dose, iii) pazopanib 800 mg daily initial dose vs. placebo; 2) Revisions in Section 9 of the Protocol on statistical hypothesis and sample size reestimations using subjects randomized into 600 mg daily initial dose as the primary analysis population on DFS and OS; 3) Revisions on secondary analyses; 4) Revisions on Section 3 of the Protocol in accordance with revisions in Section 2 and Section 9; 5) In Section 5.2 of the Protocol, clarified scheduled initial dose; 6) In Section 5.9 of the protocol and other relevant sections – clarified criteria for liver toxicity category E and cut-off for total bilirubin fractionation; 7) In Section 6 of the Protocol, clarified concomitant medication collection timing and added caution on concomitant use of simvastatin; 8) Addition of visit Week 6.5 for serum liver test monitoring.

06 Aug 2015

The primary purpose of Protocol Amendment 4 was to modify the timing of the primary analysis: in an adjuvant setting, where the cure rate model is likely to apply, the power of the study may be reduced if the analysis is not performed until 15-Oct-2016. Therefore, the cut-off date for the analysis was moved earlier, while still requiring the target number of 319 DFS events to be achieved. Major changes included: 1) Change of timing of Primary Analysis to be performed 1 year earlier than planned, following data cut-off on 15-Oct-2015, with an exploratory follow-up analysis of DFS to be performed with a data cut-off of 15-Oct-2016; 2) Change of study physician contact information; 3) Specify the alpha spending function used for type I error control in OS group sequential analysis (first interim analysis at the time of the primary analysis following data cut-off on 15-Oct-2015, and 2nd interim analysis at the time of the follow-up, exploratory DFS analysis following data cut-off on 15-OCT-2016); 4) Addition of PK data analysis section.

Were there any global interruptions to the trial? No

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

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Disease-free survival (DFS) with pazopanib 600 mg daily initial dose vs. placebo

Primary: Disease-free survival (DFS) with pazopanib 600 mg daily initial dose vs. placebo

Secondary: Overall survival (OS) with pazopanib 600 mg daily initial dose vs. placebo

Secondary: Overall survival (OS) with pazopanib 600 mg daily initial dose vs. placebo

Secondary: DFS rates at yearly time points with pazopanib 600 mg daily initial dose vs. placebo

Secondary: DFS rates at yearly time points with pazopanib 600 mg daily initial dose vs. placebo

Secondary: DFS with pazopanib vs. placebo

Secondary: DFS with pazopanib vs. placebo

Secondary: OS with pazopanib vs. placebo

Secondary: OS with pazopanib vs. placebo

Secondary: DFS rates at yearly time points with pazopanib vs. placebo

Secondary: DFS rates at yearly time points with pazopanib vs. placebo

Secondary: DFS pazopanib 800 mg daily initial dose vs. placebo

Secondary: DFS pazopanib 800 mg daily initial dose vs. placebo

Secondary: OS with pazopanib 800 mg daily initial dose vs. placebo

Secondary: OS with pazopanib 800 mg daily initial dose vs. placebo

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/Functional Assessment of Cancer Therapy-Kidney Symptom Index -19 (FACT FKSI-19) total score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/Functional Assessment of Cancer Therapy-Kidney Symptom Index -19 (FACT FKSI-19) total score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Disease Related Symptoms-emotional (DRS-E) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Disease Related Symptoms-emotional (DRS-E) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using NCCN/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using EuroQoL-5D (EQ-5D) score

Secondary: Health-related quality of life (HRQoL) with pazopanib 600 mg daily initial dose vs. placebo assessed using EuroQoL-5D (EQ-5D) score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 total score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 total score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-physical (DRS-P) Domain score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-emotional (DRS-E) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Disease-related Symptoms-emotional (DRS-E) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Treatment Side Effects (TSE) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using National Comprehensive Cancer Network (NCCN)/FACT FKSI-19 Scale Functional Well Being (FWB) Domain Score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using EuroQoL-5D (EQ-5D) score

Secondary: Health-related quality of life (HRQoL) with pazopanib vs. placebo for ITT ALL assessed using EuroQoL-5D (EQ-5D) score

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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