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Clinical Trial Results:
A 2-part Phase III Randomized, Open Label, Multicenter Study of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

Summary
EudraCT number	2013-001176-38
Trial protocol	NL SE IT ES GB CZ SK HU NO FR GR PL PT
Global end of trial date

Results information
Results version number	v1(current)
This version publication date	14 Jul 2024
First version publication date	14 Jul 2024
Other versions

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

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Trial information

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Sponsor protocol code

C4221004

ISRCTN number

US NCT number

NCT01909453

WHO universal trial number (UTN)

Other trial identifiers

CMEK162B2301: Other Study ID

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

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

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

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

Analysis stage

Interim

Date of interim/final analysis

17 Oct 2023

Is this the analysis of the primary completion data?

Yes

Primary completion date

16 Nov 2016

Global end of trial reached?

Main objective of the trial

To determine whether treatment with Combo 450 prolongs PFS compared with vemurafenib, in subjects with BRAF V600 mutant locally advanced unresectable or metastatic melanoma

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Dec 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 5

Country: Number of subjects enrolled

Australia: 16

Country: Number of subjects enrolled

Brazil: 26

Country: Number of subjects enrolled

Canada: 34

Country: Number of subjects enrolled

Colombia: 2

Country: Number of subjects enrolled

France: 59

Country: Number of subjects enrolled

Germany: 194

Country: Number of subjects enrolled

Greece: 29

Country: Number of subjects enrolled

Hungary: 30

Country: Number of subjects enrolled

Israel: 15

Country: Number of subjects enrolled

Italy: 113

Country: Number of subjects enrolled

Japan: 21

Country: Number of subjects enrolled

Korea, Republic of: 17

Country: Number of subjects enrolled

Mexico: 2

Country: Number of subjects enrolled

Netherlands: 46

Country: Number of subjects enrolled

Norway: 7

Country: Number of subjects enrolled

Poland: 10

Country: Number of subjects enrolled

Portugal: 18

Country: Number of subjects enrolled

Russian Federation: 22

Country: Number of subjects enrolled

Singapore: 2

Country: Number of subjects enrolled

Slovakia: 6

Country: Number of subjects enrolled

South Africa: 7

Country: Number of subjects enrolled

Spain: 104

Country: Number of subjects enrolled

Sweden: 17

Country: Number of subjects enrolled

Switzerland: 11

Country: Number of subjects enrolled

Türkiye: 2

Country: Number of subjects enrolled

United Kingdom: 27

Country: Number of subjects enrolled

United States: 41

Country: Number of subjects enrolled

Czechia: 38

Worldwide total number of subjects

921

EEA total number of subjects

671

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)

661

From 65 to 84 years

254

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 921 subjects (577 in part 1 and 344 in part 2) were randomized in this study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)

Arm description

Subjects received 450 milligram (mg) of LGX818 orally once daily (QD) along with 45 mg of MEK162 twice daily (BID) for in each 28 day treatment cycle until progressive disease (PD) as confirmed by Blinded Independent Review Committee (BIRC), withdrawal of consent, intolerable toxicity, study discontinuation, lost to follow-up or death.

Arm type

Experimental

Investigational medicinal product name

MEK162

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

MEK162 45 mg twice a day in each 28-day treatment cycle, administered as 15 mg tablets.

Investigational medicinal product name

LGX818

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LGX818 450 mg once a day in each 28-day treatment cycle, administered as 100 mg and 50 mg capsules.

Part 1: LGX818 300 mg

Arm description

Subjects received 300 mg of LGX818 orally once daily in each 28 day treatment cycle until PD as confirmed by BIRC, withdrawal of consent, intolerable toxicity, study discontinuation, lost to follow-up or death.

Arm type

Experimental

Investigational medicinal product name

LGX818

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LGX818 300 mg once a day in each 28-day treatment cycle, administered as 100 mg and 50 mg capsules.

Part 1: Vemurafenib 960 mg BID

Arm description

Subjects received 960 mg of vemurafenib according to the locally approved prescribing information twice daily in each 28 day treatment cycle until PD as confirmed by BIRC, withdrawal of consent, intolerable toxicity, study discontinuation, lost to follow-up or death.

Arm type

Active comparator

Investigational medicinal product name

Vemurafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Vemurafenib 960 mg twice a day in each 28-day treatment cycle, administered as 240 mg tablets.

Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)

Arm description

Subjects received 300 mg of LGX818 orally once daily along with 45 mg of MEK162 twice daily in each 28 day treatment cycle until PD as confirmed by BIRC, withdrawal of consent, intolerable toxicity, study discontinuation, lost to follow-up or death.

Arm type

Experimental

Investigational medicinal product name

MEK162

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

MEK162 45 mg twice a day in each 28-day treatment cycle, administered as 15 mg tablets.

Investigational medicinal product name

LGX818

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LGX818 300 mg once a day in each 28-day treatment cycle, administered as 100 mg and 50 mg capsules.

Part 2: LGX818 300 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

LGX818

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LGX818 300 mg once a day in each 28-day treatment cycle, administered as 100 mg and 50 mg capsules.

Number of subjects in period 1	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg
Started	192	194	191	258	86
Completed	1	2	0	2	0
Not completed	191	192	191	256	86
Adverse event, serious fatal	10	2	4	7	3
Physician decision	13	29	18	38	13
Study Terminated By Sponsor	2	1	-	3	-
Adverse event, non-fatal	25	26	26	35	8
Randomized but not treated	-	2	5	1	2
Progressive Disease	106	105	115	138	47
Treatment ongoing	13	3	2	17	2
Subject/Guardian Decision	20	23	20	17	10
Lost to follow-up	1	-	-	-	1
New Therapy For Study Indication	-	-	1	-	-
Protocol deviation	1	1	-	-	-

Baseline characteristics

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Reporting group title

Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)

Reporting group description

Reporting group title

Part 1: LGX818 300 mg

Reporting group description

Reporting group title

Part 1: Vemurafenib 960 mg BID

Reporting group description

Reporting group title

Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)

Reporting group description

Reporting group title

Part 2: LGX818 300 mg

Reporting group description

Reporting group values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Total
Number of subjects	192	194	191	258	86	921
Age Categorical
Units: subjects
<=18 years	0	0	0	0	0	0
Between 18 and 65 years	132	154	140	175	60	661
>=65 years	60	40	51	83	26	260
Sex: Female, Male
Units: subjects
Female	77	86	80	107	42	392
Male	115	108	111	151	44	529
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic/latino	20	33	14	41	12	120
Chinese	1	0	0	0	0	1
Japanese	3	3	5	7	3	21
Korean	1	2	2	8	4	17
Russian	10	8	5	12	7	42
Turkish	0	2	0	1	0	3
Mixed ethnicity	1	3	1	2	0	7
Other	131	116	129	158	44	578
Other South Asian	0	1	0	0	0	1
Other Southeast Asian	1	0	1	0	0	2
Unknown	18	23	25	22	9	97
Missing	6	3	9	7	7	32
Race (NIH/OMB)
Units: Subjects
Caucasian	180	175	168	236	79	838
Asian	5	6	8	15	7	41
Native American	0	2	2	0	0	4
Other	3	2	2	2	0	9
Uknown	3	9	11	4	0	27
Missing	1	0	0	0	0	1
Black	0	0	0	1	0	1

End points

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Reporting group title

Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)

Reporting group description

Reporting group title

Part 1: LGX818 300 mg

Reporting group description

Reporting group title

Part 1: Vemurafenib 960 mg BID

Reporting group description

Reporting group title

Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)

Reporting group description

Reporting group title

Part 2: LGX818 300 mg

Reporting group description

Subject analysis set title

Part 1 + Part 2: LGX818 300 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects of Part 1 and 2 received 300 mg of LGX818 orally once daily for each 28 day treatment cycle until PD as confirmed by BIRC, withdrawal of consent, intolerable toxicity, and study discontinuation, lost to follow-up or death.

Primary: Part 1: Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) in Combo 450 Group as Compared to Vemurafenib Group

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End point title

Part 1: Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) in Combo 450 Group as Compared to Vemurafenib Group ^[1] ^[2]

End point description

PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occured first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC/central review and survival information. If a subject did not have an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 square millimeter (mm^2). Full analysis set (FAS) included all randomized subjects.

End point type

Primary

End point timeframe

From randomization until documented disease progression (PD), initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 29 months)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint was summarized for specified reporting arms only.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	191
Units: months
median (confidence interval 95%)	14.9 (11.0 to 20.2)	7.3 (5.6 to 7.9)

No statistical analyses for this end point

Primary: Part 1: PFS by BIRC in Combo 450 Group as Compared to LGX818 Group

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End point title

Part 1: PFS by BIRC in Combo 450 Group as Compared to LGX818 Group ^[3] ^[4]

End point description

PFS was defined as the time from the date of randomization to the date of the first documented PD or death due to any cause, whichever occured first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC and survival information. If a subject did not have an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm^2. FAS included all randomized subjects.

End point type

Primary

End point timeframe

From randomization until documented PD, initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to 29 months), excluding Part 1: LGX818 300 mg group; up to 35 months for Part 1: LGX 300 mg group

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: This endpoint was summarized for specified reporting arms only.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg
Number of subjects analysed	192	194
Units: months
median (confidence interval 95%)	14.9 (11.0 to 20.2)	9.6 (7.4 to 14.8)

No statistical analyses for this end point

Secondary: Part 2: PFS by BIRC in Combo 300 Group as Compared to LGX818 Group

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End point title

Part 2: PFS by BIRC in Combo 300 Group as Compared to LGX818 Group ^[5]

End point description

PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD) or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC and survival information. If a subject did not had an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm^2. FAS included all randomized subjects. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

From randomization until documented PD, initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

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: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	258	86	280
Units: months
median (confidence interval 95%)	12.9 (10.9 to 14.9)	7.4 (5.6 to 9.2)	9.2 (7.4 to 11.1)

No statistical analyses for this end point

Secondary: Part 1: Percentage of Subject With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

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End point title

Part 1: Percentage of Subject With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03 ^[6]

End point description

AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that resulted in death; was life-threatening; required inpatient hospitalization/prolongation of existing hospitalization; results in persistent/significant disability/incapacity; resulted in congenital anomaly/birth defect or important medical event. Per NCI-CTCAE v4.03, severity was graded as Grade(G)1: asymptomatic/mild symptoms; G2: moderate; G3: severe/medically significant; G4: life-threatening consequence; G5: death. AEs of all grades were reported. Safety analysis set=all subjects who received at least one dose of study medication and had at least one valid post-baseline safety evaluation. Number of subjects analyzed=number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline up to 30 days from last dose of study drug (up to maximum of 471.7, 471.4 and 465.4 weeks of treatment for Combo450, LGX818 300 and vemurafenib arms, respectively)

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: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	192	186
Units: percentage of subjects
number (not applicable)
Subjects with AEs	98.4	99.5	100
Subjects with SAEs	44.3	37.0	41.9

No statistical analyses for this end point

Secondary: Part 1: Overall Survival (OS)

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End point title

Part 1: Overall Survival (OS) ^[7]

End point description

Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a death had not been observed by the date of analysis cutoff, OS was censored at the date of last contact. FAS included all randomized subjects.

End point type

Secondary

End point timeframe

From randomization until date of death or censoring date whichever occurred first (up to maximum of 471.7, 471.4 and 465.4 weeks of treatment for Combo450, LGX818 300 and vemurafenib arms, respectively)

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: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	194	191
Units: months
median (confidence interval 95%)	33.6 (24.4 to 39.2)	23.5 (19.6 to 33.6)	16.9 (14.0 to 24.5)

No statistical analyses for this end point

Secondary: Part 1: Number of Subjects With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.03

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End point title

Part 1: Number of Subjects With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.03 ^[8]

End point description

Number of subjects with clinically notable shift from baseline in laboratory parameter values based on NCI-CTCAE grade, Version 4.03 where Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or non-invasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift from baseline in laboratory parameter = worsening by at least 2 grades or to >=grade 3. Safety analysis set included all subjects who received at least one dose of study medication and have at least one valid post-baseline safety evaluation. Number of subjects analyzed signifies the number of subjects evaluable for this endpoint. n= subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline up to 30 days from last dose of study drug (up to maximum of 471.7, 471.4 and 465.4 weeks of treatment for Combo450, LGX818 300 and vemurafenib arms, respectively)

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: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	192	186
Units: subjects
Hemoglobin (hypo) (n=192,186,192)	28	12	17
Hemoglobin (hyper) (n=192,186,192)	0	1	0
Leukocytes (hypo) (n=192,186,192)	8	4	4
Lymphocytes (hypo) (n=191,186,192)	30	21	42
Lymphocytes (hyper) (n=191,186,192)	15	11	6
Neutrophils (hypo) (n=192,186,192)	20	7	3
Platelets (hypo) (n=192,186,192)	3	4	1
Prothrombin INR (hyper) (n=188,181,180)	0	1	2
Alanine Aminotransferase (hyper) (n=192,186,192)	16	8	8
Albumin (hypo) (n=192,186,192)	5	5	2
Alkaline Phosphatase (hyper) (n=192,186,192)	8	3	4
Aspartate Aminotransferase (hyper) (n=192,186,192)	12	4	5
Bilirubin (hyper) (n=192,186,192)	1	0	15
Corrected Calcium (hypo) (n=191,186,192)	3	3	3
Corrected Calcium (hyper) (n=191,186,192)	1	1	2
Creatinine kinase (hyper) (n=190,186,191)	41	2	2
Creatinine (hyper) (n=192,186,192)	48	17	52
Fasting glucose (hypo) (n=149,125,155)	2	4	3
Fasting glucose (hyper) (n=149,125,155)	26	14	11
Gamma glutamyl transferase (hyper) (n=191,186,192)	45	30	15
Magnesium (hyper) (n=190,186,192)	2	3	1
Phosphate (hypo) (n=190,186,192)	30	25	35
Potassium (hypo) (n=192,186,192)	2	1	3
Potassium (hyper) (n=192,186,192)	12	6	6
Sodium (hypo) (n=192,186,192)	10	1	1
Sodium (hyper) (n=192,186,192)	1	1	0
Urate (hyper) (n=191,186,191)	2	3	9

No statistical analyses for this end point

Secondary: Part 1: Number of Subjects With Newly Occurring Notable Abnormal Vital Signs

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End point title

Part 1: Number of Subjects With Newly Occurring Notable Abnormal Vital Signs ^[9]

End point description

Notable abnormal vital signs were: Low/high systolic blood pressure (SBP) (millimeter of mercury [mmHg]): less than or equal to (<=) 90 mmHg with decrease from baseline of greater than or equal to (>=) 20 mmHg/>= 160 mmHg with increase from baseline of >=20 mmHg. Low/high diastolic blood pressure (DBP) [mmHg]: <= 50 mmHg with decrease from baseline of >=15 mmHg/>=100 mmHg with increase from baseline of >=15 mmHg. Low/high Pulse rate: <=50 beats per minute (bpm) with decrease from baseline of >=15 bpm/>= 120 bpm with increase from baseline of >=15 bpm. Low/high Weight [kilogram]: >=20 percent (%) decrease from baseline/>= 10% increase from baseline. Low/high Body temperature degree Celsius (C): <= 36 degree C/>= 37.5 degree C. Safety analysis set was used. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint and n= subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline up to 30 days from last dose of study drug (up to maximum of 471.7, 471.4 and 465.4 weeks of treatment for Combo450, LGX818 300 and vemurafenib arms, respectively)

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: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	192	186
Units: subjects
Sitting Pulse Rate (bpm): High (n=184,182,186)	3	7	9
Sitting Pulse Rate (bpm): Low (n=181,182,185)	6	10	4
Sitting SBP (mmHg): High (n=177,173,177)	37	17	33
Sitting SBP (mmHg): Low (n=184,182,188)	10	4	1
Sitting DBP(mmHg): High (n=183,181,182)	34	8	14
Sitting DBP (mmHg): Low (n=185,184,188)	11	11	6
Weight (kg): High (n=184,184,187)	55	11	8
Weight (kg): Low (n=184,184,187)	4	10	13
Body temperature (degree C): High (n=176,181,185)	23	14	18
Body temperature (degree C): Low (n=134,141,132)	81	75	59

No statistical analyses for this end point

Secondary: Part 1: Number of Subjects With Newly Occurring Notable Electrocardiogram (ECG) Values

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End point title

Part 1: Number of Subjects With Newly Occurring Notable Electrocardiogram (ECG) Values ^[10]

End point description

Newly occurring notable ECG values were reported for QT (ms[millisecond]), QTcF, QT interval corrected for heart rate using Fridericia’s formula (ms), QTcB, QT interval corrected for heart rate using Bazett's formula (ms) and heart rate (bpm). Newly occurring was defined as subjects not meeting criterion at baseline and meeting criterion post-baseline. Ranges for newly occurring notable ECG values (QT, QTcF, QTcB) are New >450, New >480, New >500, increase (inc.) from baseline >30, Increase from baseline >60. Heart rate: New < 60, New >100 was considered as newly occurring notable value. Safety analysis set included all subjects who received at least one dose of study medication and had at least one valid post-baseline safety evaluation. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint and n= subjects with available data for each specified category. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

Baseline up to 30 days from last dose of study drug (up to maximum of 471.7, 471.4 and 465.4 weeks of treatment for Combo450, LGX818 300 and vemurafenib arms, respectively)

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: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	192	186
Units: subjects
QT: Increase >30 ms (181,179,187)	113	74	84
QT: Increase >60 ms (181,179,187)	32	24	28
QT: New >450 ms (170,173,180)	28	21	22
QT: New >480 ms (n=177,178,187)	5	7	3
QT: New >500 ms (n=179,179,187)	2	4	2
QTcF: Increase >30 ms (n=180,179,186)	60	62	76
QTcF: Increase >60 ms (n=180,179,186)	11	11	13
QTcF: New >450 ms (n=172,174,178)	33	42	42
QTcF: New >480 ms (n=178,179,186)	7	10	6
QTcF: New >500 ms (n=179,179,186)	1	7	3
QTcB: Increase >30 ms (n=180,177,184)	60	79	79
QTcB: Increase >60 ms (n=180,177,184)	14	19	16
QTcB: New >450 ms (n=159,155,155)	54	78	66
QTcB: New >480 ms (n=175,176183)	17	28	20
QTcB: New >500 ms (n=180,177,183)	4	13	10
Heart rate: New <60 bpm(n=159,153,163)	62	38	21
Heart rate: New <100 bpm(n=175,170,182)	19	24	20

No statistical analyses for this end point

Secondary: Part 1: Number of Subjects With Worst Post-baseline Left Ventricular Dysfunction Events (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade

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End point title

Part 1: Number of Subjects With Worst Post-baseline Left Ventricular Dysfunction Events (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade ^[11]

End point description

Subjects with worst post-baseline LVEF Values were graded as Grade 0: Non missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute reduction from baseline >=10% and < 20%; Grade 3: LVEF between 20% and 39% or absolute reduction from baseline >=20%; Grade 4: LVEF lower than 20%. Baseline was defined as the last non-missing value prior to the first dose of study treatment. Missing data were due to subjects who died or withdrew consent prior to the first scheduled evaluation or missed evaluations as protocol deviations. Safety analysis set included all subjects who received at least one dose of study medication and had at least one valid post-baseline safety evaluation. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline up to 30 days from last dose of study drug (up to maximum of 471.7, 471.4 and 465.4 weeks of treatment for Combo450, LGX818 300 and vemurafenib arms, respectively)

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: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	192	186
Units: subjects
Grade 0	120	159	160
Grade 2	62	18	17
Grade 3	4	5	2
Grade 4	0	0	0
Missing	6	10	7

No statistical analyses for this end point

Secondary: Part 1: Number of Subjects With Dermatologic-Related Adverse Events of Special Interest (AESI) Graded According to the NCI-CTCAE Version 4.03

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End point title

Part 1: Number of Subjects With Dermatologic-Related Adverse Events of Special Interest (AESI) Graded According to the NCI-CTCAE Version 4.03 ^[12]

End point description

AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Dermatologic-related AESI included severe cutaneous adverse reactions. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported in this endpoint. Safety analysis set. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline up to 30 days from last dose of study drug (up to maximum of 471.7, 471.4 and 465.4 weeks of treatment for Combo450, LGX818 300 and vemurafenib arms, respectively)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	192	186
Units: subjects
Severe cutaneous adverse reactions	2	2	10

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects With AEs and SAEs as Graded by NCI-CTCAE Version 4.03

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End point title

Part 2: Percentage of Subjects With AEs and SAEs as Graded by NCI-CTCAE Version 4.03 ^[13]

End point description

AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was any untoward medical occurrence at any dose that results in death; is life-threatening; requires inpatient hospitalization/prolongation of existing hospitalization; results in persistent/significant disability/incapacity; results in congenital anomaly/birth defect or that is considered to be important medical event. Per NCI-CTCAE v4.03, severity was graded as G1: asymptomatic/mild symptoms; G2: moderate; G3: severe/medically significant; G4: life-threatening consequence; G5: death. AEs of all grades were reported. Safety analysis set was used. ‘Number of subjects analyzed’ =number of subjects evaluable for this endpoint. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	257	84	276
Units: percentage of subjects
number (not applicable)
AEs	98.4	97.6	98.9
SAEs	38.1	36.9	37.0

No statistical analyses for this end point

Secondary: Part 1: Number of Subjects With Ocular-Related AESI Graded According to the NCI-CTCAE Version 4.03

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End point title

Part 1: Number of Subjects With Ocular-Related AESI Graded According to the NCI-CTCAE Version 4.03 ^[14]

End point description

AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Ocular-related AESI included uveitis-type events. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. AEs of grade 3 or 4 are reported in this endpoint. Safety analysis set. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline up to 30 days from last dose of study drug (up to maximum of 471.7, 471.4 and 465.4 weeks of treatment for Combo450, LGX818 300 and vemurafenib arms, respectively)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	192	186
Units: subjects
Uveitis-type events	11	2	8

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.0

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End point title

Part 2: Number of Subjects With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.0 ^[15]

End point description

Number of subjects with clinically notable shift from baseline in laboratory parameter values based on NCI-CTCAE grade, Version 4.03 where, Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2: Moderate; minimal, local or noninvasive intervention indicated. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death. Clinically notable shift from baseline in laboratory parameter = worsening by at least 2 grades or to >=grade 3. Safety analysis set was used. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint and n= subjects with available data for each specified category. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	257	84	276
Units: subjects
Hemoglobin (hypo) (n=257,84,276)	23	6	18
Prothrombin INR (hyper) (n=246,80,268)	5	0	1
Lymphocytes (hypo) (n=257,84,275)	44	13	34
Lymphocytes (hyper) (n=257,84,275)	13	3	14
Neutrophils (hypo) (n=257,84,276)	35	6	13
Platelets (hypo) (n=256,84,276)	3	1	5
Leukocytes (hypo) (n=257,84,276)	16	3	7
Albumin (hypo) (n=257,84,276)	9	4	9
Alkaline phosphatase (hyper) (n=257,84,276)	12	2	5
Alanine aminotransferase (hyper) (n=257,84,276)	20	1	9
Aspartate aminotransferase (hyper) (n=257,84,276)	17	1	5
Bilirubin (hyper) (n=257,84,276)	4	0	0
Creatine kinase (hyper) (n=257,84,274)	57	1	3
Corrected Calcium (hypo) (n=257,84,275)	5	2	5
Creatinine (hyper) (n=257,84,276)	65	14	31
Gamma-glutamyl transferase(hyper) (n=257,84,257)	45	7	37
Fasting Glucose (hypo) (n=207,67,216)	5	0	4
Fasting Glucose (hyper) (n=207,67,216)	29	4	18
Corrected Calcium (hyper) (n=257,84,275)	4	0	1
Magnesium (hyper) (n=257,84,274)	3	0	3
Phosphate (hypo) (n=257,84,274)	34	10	35
Potassium (hypo) (n=257,84)	2	1	2
Potassium (hyper) (n=257,84,276)	13	3	9
Sodium (hypo) (n=257,84,276)	6	2	3
Sodium (hyper) (n=257,84,276)	3	0	1
Urate (hyper) (n=257,84,275)	3	1	4
Hemoglobin (hyper) (n=257,84,276)	2	0	1
Activated partial TP time (hyper) (n=246,80,268)	1	0	0

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects With Newly Occurring Notable Abnormal Vital Signs

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End point title

Part 2: Number of Subjects With Newly Occurring Notable Abnormal Vital Signs ^[16]

End point description

Notable abnormal vital signs were: Low/high SBP in mmHg: <= 90 mmHg with decrease from baseline of >= 20 mmHg/>= 160 mmHg with increase from baseline of >=20 mmHg, Low/high DBP [mmHg]: <=50 mmHg with decrease from baseline of >=15 mmHg/>=100 mmHg with increase from baseline of >=15 mmHg, Low/high pulse rate [bpm]: <=50 bpm with decrease from baseline of >=15 bpm/>=120 bpm with increase from baseline of >=15 bpm, Low/high weight (kg): >=20 % decrease from baseline/>= 10% increase from baseline Low/high Body temperature degree C: <= 36 degree C/>= 37.5 degree C. Safety analysis set was used. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint and n= subjects with available data for each specified category. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	257	84	276
Units: subjects
Sitting Pulse Rate (bpm): High (n=252,78,262)	10	3	10
Sitting Pulse Rate (bpm): Low(n=254,77,258)	16	1	11
Sitting SBP (mmHg): High (n=243,76,253)	51	5	22
Sitting SBP (mmHg): Low (n=255,78,262)	15	5	9
Sitting DBP (mmHg): High (n=253,78,261)	49	6	14
Sitting DBP (mmHg): Low(n=255,77,262)	12	2	13
Weight (kg): High(n=256,80,264)	58	3	14
Weight (kg): Low (n=256,80,264)	0	1	11
Body temperature (°C): High(n=252,77,253)	24	5	19
Body temperature (°C): Low(n=201,55,189)	128	23	98

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects With Newly Occurring Notable ECG Values

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End point title

Part 2: Number of Subjects With Newly Occurring Notable ECG Values ^[17]

End point description

Newly occurring notable ECG values were reported for QT (ms), QTcF (ms), QTcB (ms) and heart rate (bpm). Newly occurring was defined as subjects not meeting criterion at baseline and meeting criterion post-baseline. Ranges for newly occurring notable ECG values (QT, QTcF, QTcB) are New >450, New >480, New >500, increase (inc.) from baseline >30, Increase from baseline >60. Heart rate: New < 60, New >100 was considered as newly occurring notable value. Safety analysis set included all subjects who received at least one dose of study medication and had at least one valid post-baseline safety evaluation. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint and n= subjects with available data for each specified category. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	257	84	276
Units: subjects
QT (ms): Inc. from baseline > 30 (n=251,79,260)	146	35	109
QT (ms): Inc. from baseline > 60 (n=251,79,260)	45	7	31
QT (ms): New > 450 (n=239,76,246)	44	8	29
QT (ms): New > 480 (n=249,79,256)	12	2	9
QT (ms): New > 500 (n=251,79,258)	5	0	4
QTcF (ms): Inc. from baseline > 30 (n=250,78,258)	81	24	86
QTcF (ms): Inc. from baseline > 60 (n=250,78,258)	17	8	19
QTcF (ms): New > 450 (n=240,70,242)	46	15	57
QTcF (ms): New > 480 (n=249,78,256)	16	7	17
QTcF (ms): New > 500 (n=250,78,257)	2	1	8
QTcB (ms): New > 450 (n=216,67,226)	87	31	109
QTcB (ms): New > 480 (n=247,77,252)	28	6	34
QTcB (ms): New > 500(n=250,79,259)	13	2	15
QTcB (ms): Inc. from baseline > 30(n=250,79,259)	87	26	105
QTcB (ms): Inc. from baseline > 60(n=250,79,259)	26	9	28
Heart rate (bpm): New < 60(n=213,67,226)	88	7	45
Heart rate (bpm): New > 100(n=241,74,249)	12	11	35

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects With Worst Post-baseline LVEF Values by MUGA Scans or Transthoracic ECHO, by CTCAE Grade

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End point title

Part 2: Number of Subjects With Worst Post-baseline LVEF Values by MUGA Scans or Transthoracic ECHO, by CTCAE Grade ^[18]

End point description

Subjects with worst post-baseline LVEF Values were graded as Grade 0: Non missing value below Grade 2; Grade 2: LVEF between 40% and 50% or absolute reduction from baseline >=10% and < 20%;Grade 3: LVEF between 20% and 39% or absolute reduction from baseline >=20%; Grade 4: LVEF lower than 20%. Baseline was defined as the last non-missing value prior to the first dose of study treatment. Missing data were due to subjects who died or withdrew consent prior to the first scheduled evaluation or missed evaluations as protocol deviations. Safety analysis set included all subjects who received at least one dose of study medication and had at least one valid post-baseline safety evaluation. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint and n= subjects with available data for each specified category. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	257	84	276
Units: subjects
Grade 0	172	70	229
Grade 2	77	9	27
Grade 3	6	0	5
Grade 4	0	0	0
Missing	2	5	15

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects With Dermatologic-Related AESI Graded According to the NCI-CTCAE Version 4.03

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End point title

Part 2: Number of Subjects With Dermatologic-Related AESI Graded According to the NCI-CTCAE Version 4.03 ^[19]

End point description

AESI consisted of events for which there was a specific clinical interest with regard to LGX818 and/or MEK162 treatment. Dermatologic-related AESI included severe cutaneous adverse reactions. As per NCI-CTCAE version 4.03, severity was graded as Grade(G) 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; G2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental ADL; G3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; G4: life-threatening consequence, urgent intervention indicated; G5: death related to AE. AEs of G3/4 are reported are reported in this endpoint. Safety analysis set. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 300 mg	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	192	257	84	276
Units: subjects
Cutaneous adverse reactions	2	4	0	2

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects With Ocular-Related AESI Graded According to the NCI-CTCAE Version 4.03

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End point title

Part 2: Number of Subjects With Ocular-Related AESI Graded According to the NCI-CTCAE Version 4.03 ^[20]

End point description

End point type

Secondary

End point timeframe

Baseline up to 30 days after last dose of study drug (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 300 mg	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	192	257	84	276
Units: subjects
Uveitis-type events	2	15	1	3

No statistical analyses for this end point

Secondary: Part 2: Overall Survival (OS)

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End point title

Part 2: Overall Survival (OS) ^[21]

End point description

End point type

Secondary

End point timeframe

From randomization until date of death or censoring date, whichever occurred first (up to maximum of 417.7 and 471.4 weeks of treatment for Combo 300 and LGX818 300 respectively)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg
Number of subjects analysed	258	86
Units: Months
median (confidence interval 95%)	27.1 (21.6 to 33.3)	19.4 (14.5 to 28.1)

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Objective Response Rate (ORR)

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End point title

Part 1 and Part 2: Objective Response Rate (ORR)

End point description

ORR, calculated as the percentage of subjects with a best overall response of complete response (CR) or partial response (PR). CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Results are reported for confirmed BIRC response. FAS included all randomized subjects. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

From randomization until disease progression, censoring date or death, whichever occurred first(up to maximum of 417.7, 465.4, 471.4, 471.4 and 415.4 weeks of treatment for LGX818 300, vemurafenib, combo 300, combo 450 and Part 1 and 2 arms, respectively

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	191	194	191	258	86	280
Units: percentage of subjects
number (confidence interval 95%)	64.1 (56.8 to 70.8)	51.5 (44.3 to 58.8)	40.8 (33.8 to 48.2)	67.8 (61.8 to 73.5)	51.2 (40.1 to 62.1)	51.4 (45.4 to 57.4)

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Disease Control Rate (DCR)

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End point title

Part 1 and Part 2: Disease Control Rate (DCR)

End point description

DCR was calculated as the percentage of subjects with a best overall response (BOR) of CR, PR, or stable disease (SD). CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Two sets of DCR were considered, one for confirmed and one for unconfirmed responses. Results are reported for confirmed and unconfirmed responses combined. SD: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. DCR was based on central review. FAS included all randomized subjects. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

From randomization until disease progression or death, whichever occurred first (up to 111 months)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	192	194	191	258	86	280
Units: percentage of subjects
number (confidence interval 95%)	92.2 (87.4 to 95.6)	84.0 (78.1 to 88.9)	81.2 (74.9 to 86.4)	90.7 (86.5 to 93.9)	79.1 (69.0 to 87.1)	82.5 (77.5 to 86.8)

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Time to Objective Response (TTR)

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End point title

Part 1 and Part 2: Time to Objective Response (TTR)

End point description

TTR was the time between date of randomization until first documented response of CR or PR. Subjects who did not achieve a PR or CR were censored at the last adequate tumor assessment date when they did not have a PFS event or at maximum follow-up (i.e. first patient first visit [FPFV] to last patient last visit [LPLV] used for the analysis) when they had a PFS event. CR was defined as disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. TTR was estimated in the treatment arms using a Kaplan-Meier method. TTR was based on central review. FAS included all randomized subjects. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	192	194	191	258	86	280
Units: months
median (confidence interval 95%)	1.9 (1.9 to 1.9)	2.0 (1.9 to 3.6)	2.2 (1.9 to 3.8)	1.9 (1.9 to 1.9)	1.9 (1.9 to 2.3)	1.9 (1.9 to 3.5)

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Duration of Response (DOR)

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End point title

Part 1 and Part 2: Duration of Response (DOR)

End point description

DOR was calculated, as time from date of first documented response(CR/PR) to the first documented progression/death due to underlying cancer. DOR was estimated for responders(i.e. subjects achieving at least once CR/PR) only using a Kaplan-Meier method. CR=disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to <10 mm. PR=at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. If a subject with CR/PR had no progression or death due to underlying disease, the subject was censored at the date of last adequate tumor assessment. Results are based on confirmed BIRC response. Analysis population included all the subjects who achieved at least once confirmed CR/PR. Number of subjects analyzed = number of subjects evaluable for this endpoint. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	123	100	78	175	44	144
Units: months
median (confidence interval 95%)	18.6 (12.7 to 27.6)	15.5 (11.1 to 29.5)	12.3 (6.9 to 14.5)	15.4 (11.8 to 20.6)	11.0 (7.3 to 17.1)	14.8 (11.0 to 21.2)

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Time to Definitive 10% Deterioration in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale

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End point title

Part 1 and Part 2: Time to Definitive 10% Deterioration in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale

End point description

FACT-M:melanoma specific questionnaire to assess subject health-related quality of life(QOL). Melanoma specific subscale consists of 16 items related to signs,symptoms,physical/social activities most relevant to subjects with advanced-stage melanoma. Other items include physical,functional&social/family well-being(7items each),emotional(6items). Each item range- 0(not at all) to 4(very much), combined to produce subscale scores.Total score range for FACT-M:0to172,higher scores:better QOL.Melanoma subscale score range from 0(worst response)to64(best response),higher score:better QOL. Time to definitive 10% deterioration:time from date of randomization to date of event with at least 10% relative to baseline worsening of corresponding scale score with no later improvement/death due to any cause. FAS included all randomized subjects. 99999-data could not be estimated due to low number of subjects with events. Planned to report combined result data of Part 1 Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

Date of randomization to date of event or death due to any cause, which ever occurred first (up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	192	194	191	258	86	280
Units: months
median (confidence interval 95%)	99999 (22.1 to 99999)	30.5 (18.4 to 30.5)	22.1 (15.2 to 99999)	99999 (99999 to 99999)	99999 (9.4 to 99999)	20.5 (16.6 to 30.5)

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Change From Baseline in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

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End point title

Part 1 and Part 2: Change From Baseline in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

End point description

FACT-M: melanoma specific questionnaire to assess subject health-related QOL. Melanoma specific subscale consists of 16items related to signs, symptoms, physical/social activities most relevant to subjects with advanced-stage melanoma. Other items include physical, functional and social/family well-being (7items each), emotional well-being (6 items). Each item range from 0(not at all) to 4(very much), combined to produce subscale scores. Total score range for FACT-M-0 to 172, higher scores represented better quality of life. Melanoma subscale score range from 0(worst response) to 64(best response), higher score indicated better quality of life. FAS included all randomized subjects. Number of subjects analyzed = number of subjects evaluable for this endpoint. n= subjects with available data for each specified category. 99999=data could not be estimated due to low number of subjects with events. Planned to report combined result data of Part 1 and Part 2 for LGX818 300mg arm.

End point type

Secondary

End point timeframe

Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	165	177	159	234	83	260
Units: units on a scale
arithmetic mean (standard deviation)
Baseline(n=177,159,234,83,165,260)	52.39 ( 9.053 )	52.76 ( 8.206 )	52.01 ( 8.650 )	52.08 ( 8.493 )	51.13 ( 9.567 )	52.24 ( 8.679 )
Change at C3 D1 (n=148,128,212,67,141,215)	0.92 ( 9.539 )	-3.58 ( 8.133 )	-1.55 ( 9.023 )	2.79 ( 7.296 )	-2.16 ( 9.700 )	-3.14 ( 8.654 )
Change at C5 D1 (n=132,106,200,60,128,192)	-0.01 ( 9.157 )	-3.77 ( 7.576 )	-1.90 ( 7.572 )	2.58 ( 7.244 )	-0.60 ( 7.948 )	-2.78 ( 7.814 )
Change at C7 D1 (n=109,84,177,52,120,161)	1.35 ( 9.595 )	-3.05 ( 6.633 )	-2.19 ( 8.651 )	2.64 ( 7.766 )	-3.14 ( 9.559 )	-3.08 ( 7.670 )
Change at C9 D1 (n=79,63,161,41,103,120)	0.52 ( 9.096 )	-2.69 ( 6.513 )	-1.90 ( 7.491 )	3.23 ( 7.720 )	-1.83 ( 7.323 )	-2.39 ( 6.782 )
Change at C11 D1(n=72,46,143,31,87,103)	0.18 ( 7.768 )	-3.67 ( 6.418 )	-0.51 ( 7.436 )	2.54 ( 7.796 )	-2.41 ( 7.653 )	-3.29 ( 6.800 )
Change at C13 D1(n=65,39,126,26,77,91)	-0.33 ( 8.855 )	-2.71 ( 7.187 )	-0.97 ( 8.818 )	1.97 ( 8.127 )	-3.31 ( 7.902 )	-2.88 ( 7.359 )
Change at C15 D1(n=56,29,95,18,68,74)	0.40 ( 7.943 )	-2.48 ( 6.829 )	-1.72 ( 9.906 )	2.08 ( 9.196 )	-4.14 ( 5.662 )	-2.88 ( 6.566 )
Change at C17 D1(n=50,23,64,14,58,64)	0.27 ( 7.775 )	-1.66 ( 6.681 )	0.70 ( 6.071 )	2.45 ( 9.012 )	-2.64 ( 9.724 )	-1.88 ( 7.375 )
Change at C19 D1(n=51,20,26,9,47,60)	-0.59 ( 7.257 )	-2.80 ( 6.172 )	0.23 ( 9.094 )	1.23 ( 10.618 )	0.00 ( 11.467 )	-2.38 ( 7.150 )
Change at C21 D1(n=39,15,12,1,33,40)	-0.69 ( 6.947 )	-2.59 ( 6.528 )	-3.33 ( 6.399 )	2.58 ( 8.218 )	-2.00 ( 99999 )	-2.58 ( 6.445 )
Change at C23 D1(n=34,12,0,0,22,34)	-1.67 ( 7.003 )	-1.38 ( 6.818 )	-0.17 ( 4.687 )	99999 ( 99999 )	99999 ( 99999 )	-1.38 ( 6.818 )
Change at C25 D1(n=25,7,0,0,18,25)	-1.83 ( 6.205 )	-1.00 ( 6.880 )	-0.14 ( 5.305 )	99999 ( 99999 )	99999 ( 99999 )	-1.00 ( 6.880 )
Change at EOT visit(n=8,7,6,5,2,13)	18.50 ( 23.335 )	-5.18 ( 11.458 )	-2.31 ( 4.715 )	6.58 ( 7.197 )	-1.61 ( 9.115 )	-3.81 ( 10.370 )

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Time to Definitive 10% Deterioration in the Global Health Status Score of the European Organization for Research and Treatment of Cancer’s Core quality of Life Questionnaire (EORTC QLQ-C30)

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End point title

Part 1 and Part 2: Time to Definitive 10% Deterioration in the Global Health Status Score of the European Organization for Research and Treatment of Cancer’s Core quality of Life Questionnaire (EORTC QLQ-C30)

End point description

EORTC QLQ-C30 is 30 item questionnaire composed of 5multi-item functional subscales(physical,role, cognitive,emotional,social functioning), 3symptom scales(fatigue,nausea/vomiting&pain),global health/QOL subscale&6single items assessing other cancer related symptoms(dyspnea,sleep disturbance,appetite,diarrhea, constipation&financial impact of cancer). It employed 28-four point Likert scales with responses from"not at all"to"very much"&two 7point Likert scales for global health&overall QOL. Global health status scale score ranged from 0-100. Higher score: better level of functioning. Time to definitive 10% deterioration: time from date of randomization to date of event with at least 10% relative to baseline worsening of corresponding scale score with no later improvement/death due to any cause. FAS included all randomized subjects. 99999: data could not be estimated due to low number of subjects with events. Planned to report combined result data of Part 1&Part 2 for LGX818 300mg arm.

End point type

Secondary

End point timeframe

Date of randomization to date of event or death due to any cause, which ever occurred first (maximum up to 29 months for Part 1, excluding Part 1: LGX818 300 mg group; up to 35 months for Part 2 and Part 1 LGX 300 mg group)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	192	194	191	258	86	280
Units: months
median (confidence interval 95%)	23.9 (20.4 to 99999)	14.7 (8.1 to 24.0)	16.6 (11.9 to 99999)	18.4 (16.8 to 19.1)	9.5 (5.6 to 99999)	11.1 (7.7 to 20.2)

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Change From Baseline in EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Index Score at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

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End point title

Part 1 and Part 2: Change From Baseline in EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Index Score at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

End point description

EQ-5D-5L is standardized subject completed questionnaire that measures health status in terms of single index value/utility score. It consisted of 2components: health state profile(descriptive system)&visual analogue scale(VAS) in which subjectS rate their overall health status from 0(worst imaginable)-100(best imaginable), higher scores=better health status. EQ-5D health state profile comprises of 5dimensions: mobility,self-care,usual activities,pain/discomfort&anxiety/depression. Each dimension has 5response levels:1=no,2=slight, 3=moderate,4=severe&5=extreme problems. EQ-5D-5L health status index score range between 0-1. Higher score=better health status. FAS included all randomized subjects. Number of subjects analyzed=number of subjects evaluable for this endpoint. n=subjects with available data for each specified category. 99999=data could not be estimated due to low number of subjects with events. Planned to report combined result data of Part 1&Part 2 for LGX818 300mg arm.

End point type

Secondary

End point timeframe

Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	167	181	161	235	83	264
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=181,161,235,83,167,264)	0.74 ( 0.210 )	0.76 ( 0.181 )	0.73 ( 0.222 )	0.75 ( 0.219 )	0.73 ( 0.244 )	0.75 ( 0.203 )
Change at C3 D1 (n=157,143,224,67,153,224)	0.05 ( 0.194 )	-0.10 ( 0.199 )	0.00 ( 0.196 )	0.06 ( 0.204 )	-0.06 ( 0.246 )	-0.09 ( 0.214 )
Change at C5 D1(n=139,116,206,59,136,198)	0.04 ( 0.196 )	-0.15 ( 0.220 )	-0.04 ( 0.196 )	0.07 ( 0.218 )	-0.06 ( 0.231 )	-0.13 ( 0.227 )
Change at C7 D1 (n=116,88,187,53,125,169)	0.05 ( 0.201 )	-0.13 ( 0.189 )	-0.03 ( 0.215 )	0.06 ( 0.237 )	-0.16 ( 0.220 )	-0.14 ( 0.199 )
Change at C9 D1 (n=87,68,163,43,114,130)	0.03 ( 0.237 )	-0.15 ( 0.197 )	-0.04 ( 0.237 )	0.07 ( 0.192 )	-0.11 ( 0.202 )	-0.14 ( 0.199 )
Change at C11 D1 (n=72,50,144,33,95,105)	0.04 ( 0.197 )	-0.18 ( 0.206 )	-0.01 ( 0.238 )	0.06 ( 0.195 )	-0.16 ( 0.230 )	-0.17 ( 0.213 )
Change at C13 D1 (n=63,40,130,27,79,90)	0.05 ( 0.225 )	-0.17 ( 0.206 )	-0.02 ( 0.263 )	0.05 ( 0.254 )	-0.20 ( 0.216 )	-0.18 ( 0.208 )
Change at C15 D1 (n=61,29,101,17,69,78)	0.05 ( 0.208 )	-0.18 ( 0.203 )	-0.07 ( 0.280 )	0.05 ( 0.259 )	-0.26 ( 0.262 )	-0.20 ( 0.218 )
Change at C17 D1 (n=56,25,66,12,60,68)	0.07 ( 0.193 )	-0.14 ( 0.165 )	-0.02 ( 0.173 )	0.06 ( 0.188 )	-0.20 ( 0.332 )	-0.15 ( 0.203 )
Change at C19 D1 (n=51,22,28,9,49,60)	0.03 ( 0.239 )	-0.18 ( 0.235 )	-0.02 ( 0.214 )	0.05 ( 0.231 )	-0.11 ( 0.328 )	-0.17 ( 0.249 )
Change at C21 D1 (n=42,16,12,1,35,43)	0.07 ( 0.132 )	-0.14 ( 0.198 )	-0.04 ( 0.159 )	0.12 ( 0.174 )	-0.11 ( 99999 )	-0.14 ( 0.196 )
Change at C23 D1 (n=33,11,0,0,24,33)	0.04 ( 0.139 )	-0.11 ( 0.147 )	-0.05 ( 0.171 )	99999 ( 99999 )	99999 ( 99999 )	-0.11 ( 0.147 )
Change at C25 D1 (n=26,5,0,0,16,26)	0.07 ( 0.135 )	-0.11 ( 0.207 )	-0.17 ( 0.221 )	99999 ( 99999 )	99999 ( 99999 )	-0.11 ( 0.207 )
Change at EOT visit (n=5,3,5,4,3,9)	0.03 ( 0.081 )	-0.09 ( 0.347 )	-0.14 ( 0.103 )	-0.27 ( 0.481 )	-0.06 ( 0.061 )	-0.08 ( 0.249 )

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

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End point title

Part 1 and Part 2: Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

End point description

EORTC QLQ-C30 contains 30items, is composed of multi & single-item measures. These include 5functional scales (physical,role,emotional,cognitive&social functioning), 3symptom scales(fatigue, nausea/vomiting&pain), 6single items (dyspnea,insomnia,appetite loss,constipation,diarrhea&financial impact)&global health status/QOL scale. Employs 28-four point Likert scales with responses: "not at all" to "very much" & two 7-point Likert scales for global health & overall QOL. Responses to all items converted to 0-100 scale. For functional & global QOL scales, higher scores=better level of functioning/QOL. For symptom-oriented scales, higher score=more severe symptoms. Number of subjects analyzed=number of subjects evaluable for this endpoint. FAS included all randomized subjects. n= subjects with available data for each specified category. 99999=data could not be estimated due to low number of subjects with events. Planned to report combined result data of Part 1&Part 2 for LGX818 300mg arm.

End point type

Secondary

End point timeframe

Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	166	181	160	231	81	262
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=181,160,231,81,166,262)	66.72 ( 21.585 )	66.07 ( 21.890 )	64.74 ( 23.611 )	65.95 ( 23.028 )	67.39 ( 22.095 )	66.48 ( 21.920 )
Change at C3 D1 (n=156,135,220,69,152,225)	3.56 ( 22.463 )	-7.64 ( 21.564 )	-3.46 ( 25.235 )	4.47 ( 23.031 )	-4.95 ( 20.378 )	-6.81 ( 21.199 )
Change at C5 D1 (n=138,111,205,60,134,198)	1.55 ( 23.441 )	-9.24 ( 21.611 )	-4.05 ( 23.700 )	5.61 ( 19.396 )	-4.72 ( 22.776 )	-7.87 ( 22.011 )
Change at C7 D1 (n=114,85,188,53,125,167)	1.53 ( 23.220 )	-9.21 ( 23.528 )	-3.04 ( 28.197 )	5.01 ( 24.000 )	-7.08 ( 20.955 )	-8.53 ( 22.701 )
Change at C9 D1 (n=88,66,157,42,107,130)	-0.55 ( 25.500 )	-12.03 ( 19.771 )	-6.94 ( 21.512 )	4.94 ( 20.258 )	-8.73 ( 18.945 )	-10.96 ( 19.496 )
Change at C11 D1 (n=71,46,147,31,93,102)	0.81 ( 21.670 )	-11.27 ( 20.611 )	-3.80 ( 22.202 )	4.76 ( 21.212 )	-7.53 ( 19.288 )	-10.13 ( 20.197 )
Change at C13 D1 (n=64,37,126,26,79,90)	0.42 ( 22.642 )	-8.59 ( 22.516 )	-2.93 ( 20.621 )	5.89 ( 23.642 )	-9.29 ( 24.645 )	-8.80 ( 23.013 )
Change at C15 D1 (n=58,29,101,17,68,75)	5.02 ( 19.108 )	-9.91 ( 23.490 )	-10.34 ( 29.852 )	6.11 ( 21.695 )	-12.75 ( 21.270 )	-10.56 ( 22.897 )
Change at C17 D1 (n=55,24,64,14,61,69)	0.41 ( 21.807 )	-8.03 ( 17.784 )	-6.94 ( 20.214 )	5.86 ( 21.806 )	-7.14 ( 20.111 )	-7.85 ( 18.127 )
Change at C19 D1 (n=50,22,27,9,49,59)	-0.51 ( 17.547 )	-9.33 ( 19.169 )	-1.89 ( 20.401 )	1.23 ( 18.155 )	-0.93 ( 12.805 )	-8.05 ( 18.503 )
Change at C21 D1 (n=43,16,11,1,34,44)	0.74 ( 16.838 )	-11.05 ( 21.725 )	-8.85 ( 11.968 )	3.03 ( 19.816 )	0.00 ( 99999 )	-10.80 ( 21.535 )
Change at C23 D1 (n=34,12,0,0,24,34)	-1.39 ( 13.157 )	-5.64 ( 19.754 )	-3.47 ( 18.278 )	99999 ( 99999 )	99999 ( 99999 )	-5.64 ( 19.754 )
Change at C25 D1 (n=26,7,0,0,17,26)	1.96 ( 13.349 )	-7.05 ( 18.057 )	-2.38 ( 19.670 )	99999 ( 99999 )	99999 ( 99999 )	-7.05 ( 18.057 )
Change at EOT visit (n=7,4,4,2,2,9)	0.00 ( 11.785 )	4.76 ( 28.810 )	-4.17 ( 10.758 )	-6.25 ( 18.478 )	4.17 ( 29.463 )	4.63 ( 27.039 )

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Change From Baseline in Emotional Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

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End point title

Part 1 and Part 2: Change From Baseline in Emotional Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	166	181	160	231	83	264
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=181,160,231,83,166,264)	74.68 ( 21.233 )	74.46 ( 22.367 )	72.31 ( 24.695 )	73.04 ( 24.450 )	74.20 ( 21.488 )	74.38 ( 22.054 )
Change at C3 D1 (n=156,136,220,70,152,226)	3.23 ( 20.588 )	-0.34 ( 22.138 )	1.88 ( 20.610 )	7.29 ( 20.011 )	1.79 ( 19.958 )	0.32 ( 21.465 )
Change at C5 D1 (n=139,111,205,62,134,201)	5.37 ( 19.243 )	1.54 ( 22.418 )	2.03 ( 20.662 )	6.15 ( 21.401 )	2.96 ( 20.473 )	1.98 ( 21.796 )
Change at C7 D1 (n=115,85,188,53,125,168)	5.42 ( 20.027 )	0.34 ( 23.104 )	2.71 ( 20.875 )	9.37 ( 21.088 )	-3.62 ( 19.441 )	-0.91 ( 22.033 )
Change at C9 D1 (n=88,67,157,42,107,130)	4.47 ( 24.341 )	2.15 ( 19.735 )	-0.17 ( 24.283 )	9.22 ( 21.940 )	-0.60 ( 16.296 )	1.26 ( 18.674 )
Change at C11 D1 (n=71,46,147,31,93,102)	4.81 ( 22.102 )	0.12 ( 22.205 )	4.53 ( 18.148 )	10.56 ( 20.850 )	-2.69 ( 17.793 )	-0.74 ( 20.915 )
Change at C13 D1 (n=64,37,126,26,79,90)	3.52 ( 23.715 )	3.78 ( 19.694 )	-2.25 ( 22.192 )	8.66 ( 21.894 )	-6.41 ( 17.998 )	0.83 ( 19.675 )
Change at C15 D1 (n=58,29,101,17,68,75)	7.35 ( 21.813 )	2.30 ( 20.755 )	-5.46 ( 26.190 )	10.59 ( 19.609 )	-2.12 ( 13.232 )	1.30 ( 19.317 )
Change at C17 D1 (n=55,24,64,14,61,69)	5.33 ( 20.584 )	3.64 ( 21.502 )	-1.39 ( 15.862 )	10.33 ( 20.415 )	1.79 ( 15.736 )	3.26 ( 20.373 )
Change at C19 D1 (n=50,22,27,9,49,59)	4.25 ( 19.552 )	1.00 ( 24.493 )	0.38 ( 16.158 )	8.33 ( 22.997 )	2.78 ( 16.667 )	1.27 ( 23.357 )
Change at C21 D1 (n=43,16,11,1,34,44)	4.17 ( 19.811 )	-1.16 ( 23.751 )	-3.13 ( 16.908 )	13.13 ( 15.619 )	16.67 ( 99999 )	-0.76 ( 23.626 )
Change at C23 D1 (n=34,12,0,0,24,34)	-1.74 ( 21.420 )	2.94 ( 22.556 )	-0.69 ( 23.693 )	99999 ( 99999 )	99999 ( 99999 )	2.94 ( 22.556 )
Change at C25 D1 (n=26,7,0,0,17,26)	3.92 ( 11.456 )	-0.32 ( 24.093 )	-1.19 ( 34.503 )	99999 ( 99999 )	99999 ( 99999 )	-0.32 ( 24.093 )
Change at EOT visit (n=7,4,4,3,2,10)	41.67 ( 11.785 )	-3.57 ( 25.394 )	12.50 ( 28.464 )	-4.17 ( 14.434 )	5.56 ( 4.811 )	-0.83 ( 21.318 )

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Change From Baseline in Physical Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

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End point title

Part 1 and Part 2: Change From Baseline in Physical Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	167	180	159	235	83	263
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=180,159,235,83,167,263)	82.10 ( 19.593 )	83.18 ( 20.266 )	80.71 ( 22.182 )	80.67 ( 21.889 )	81.45 ( 21.890 )	82.63 ( 20.766 )
Change at C3 D1 (n=157,135,222,70,153,227)	0.20 ( 18.033 )	-13.79 ( 20.396 )	-2.90 ( 20.319 )	2.94 ( 16.831 )	-13.63 ( 22.428 )	-13.74 ( 20.994 )
Change at C5 D1 (n=138,111,208,62,135,200)	0.15 ( 18.388 )	-17.14 ( 22.276 )	-7.45 ( 17.792 )	2.73 ( 17.748 )	-12.63 ( 21.570 )	-15.74 ( 22.104 )
Change at C7 D1 (n=115,84,191,53,127,168)	-1.93 ( 18.071 )	-16.26 ( 21.719 )	-6.98 ( 19.605 )	1.22 ( 17.469 )	-17.01 ( 20.200 )	-16.49 ( 21.194 )
Change at C9 D1 (n=88,66,160,42,110,130)	-0.45 ( 20.511 )	-19.43 ( 20.755 )	-6.82 ( 21.881 )	3.03 ( 16.525 )	-15.83 ( 16.269 )	-18.27 ( 19.429 )
Change at C11 D1 (n=71,45,148,31,94,102)	-0.85 ( 18.767 )	-22.65 ( 20.867 )	-4.11 ( 18.680 )	0.50 ( 17.734 )	-13.49 ( 13.665 )	-19.87 ( 19.369 )
Change at C13 D1 (n=64,36,127,26,80,90)	-1.25 ( 19.705 )	-20.00 ( 20.874 )	-6.30 ( 22.534 )	0.47 ( 18.290 )	-13.85 ( 17.781 )	-18.22 ( 20.127 )
Change at C15 D1 (n=58,30,101,17,69,75)	0.29 ( 17.356 )	-20.26 ( 21.030 )	-6.22 ( 21.580 )	-0.40 ( 22.466 )	-24.31 ( 22.845 )	-21.18 ( 21.364 )
Change at C17 D1 (n=55,25,66,14,63,69)	-0.03 ( 17.862 )	-18.88 ( 20.072 )	-3.27 ( 19.817 )	-0.88 ( 16.432 )	-19.05 ( 23.367 )	-18.91 ( 20.599 )
Change at C19 D1 (n=49,21,28,9,49,58)	-1.22 ( 16.140 )	-20.07 ( 21.417 )	-1.90 ( 20.237 )	-5.71 ( 16.301 )	-14.07 ( 14.699 )	-19.14 ( 20.527 )
Change at C21 D1 (n=43,16,11,1,35,44)	-0.95 ( 13.150 )	-16.86 ( 19.694 )	-4.90 ( 19.355 )	-8.48 ( 23.303 )	-13.33 ( 99999 )	-16.78 ( 19.471 )
Change at C23 D1 (n=34,12,0,0,24,34)	-5.00 ( 13.656 )	-14.46 ( 18.298 )	-2.22 ( 19.557 )	99999 ( 99999 )	99999 ( 99999 )	-14.46 ( 18.298 )
Change at C25 D1 (n=25,7,0,0,17,25)	-5.49 ( 14.575 )	-15.93 ( 17.092 )	-4.76 ( 23.637 )	99999 ( 99999 )	99999 ( 99999 )	-15.93 ( 17.092 )
Change at EOT visit (n=7,4,4,3,2,10)	33.33 ( 47.140 )	-0.95 ( 22.910 )	-15.00 ( 19.149 )	-5.00 ( 10.000 )	-4.44 ( 3.849 )	-2.00 ( 18.869 )

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Change From Baseline in Social Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

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End point title

Part 1 and Part 2: Change From Baseline in Social Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

End point description

End point type

Secondary

End point timeframe

Baseline (Day 1 of Cycle 1), Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and end of treatment visit (within14 days after the last dose of study drug)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	164	179	160	229	83	262
Units: units on a scale
arithmetic mean (standard deviation)
Baseline (n=179,160,229,83,164,262)	80.69 ( 24.696 )	80.91 ( 23.841 )	78.54 ( 26.854 )	81.37 ( 25.262 )	78.31 ( 28.600 )	80.09 ( 25.418 )
Change at C3 D1 (n=155,136,218,70,152,225)	-0.66 ( 27.854 )	-10.86 ( 28.967 )	-4.90 ( 30.097 )	4.05 ( 22.461 )	-10.00 ( 26.829 )	-10.59 ( 28.262 )
Change at C5 D1 (n=137,111,203,62,133,199)	3.26 ( 27.559 )	-11.92 ( 32.145 )	-7.21 ( 27.026 )	3.37 ( 20.604 )	-5.11 ( 28.244 )	-9.80 ( 31.073 )
Change at C7 D1 (n=114,85,186,54,124,168)	2.82 ( 28.807 )	-9.80 ( 28.979 )	-2.75 ( 31.586 )	3.05 ( 22.185 )	-13.89 ( 27.992 )	-11.11 ( 28.646 )
Change at C9 D1 (n=87,67,155,42,106,129)	1.57 ( 31.834 )	-15.71 ( 26.579 )	-1.99 ( 30.084 )	3.66 ( 21.002 )	-9.52 ( 14.790 )	-13.70 ( 23.520 )
Change at C11 D1 (n=70,46,145,31,92101)	-2.72 ( 29.160 )	-12.62 ( 27.428 )	-0.36 ( 28.865 )	1.95 ( 23.032 )	-12.37 ( 23.161 )	-12.54 ( 26.077 )
Change at C13 D1 (n=63,37,124,26,78,89)	-4.27 ( 28.228 )	-11.38 ( 28.053 )	-0.45 ( 27.635 )	1.75 ( 24.585 )	-5.77 ( 18.822 )	-9.74 ( 25.723 )
Change at C15 D1 (n=58,29,99,17,67,75)	3.73 ( 25.921 )	-10.63 ( 27.695 )	-6.32 ( 34.622 )	2.86 ( 22.340 )	-15.69 ( 16.106 )	-11.78 ( 25.524 )
Change at C17 D1 (n=54,24,63,14,60,68)	1.11 ( 27.251 )	-11.42 ( 25.865 )	1.39 ( 25.020 )	1.59 ( 22.543 )	-7.14 ( 28.280 )	-10.54 ( 26.219 )
Change at C19 D1 (n=50,22,27,9,48,59)	-1.04 ( 30.248 )	-12.33 ( 30.826 )	3.79 ( 26.192 )	1.23 ( 22.133 )	-12.96 ( 34.134 )	-12.43 ( 31.041 )
Change at C21 D1 (n=43,16,11,1,33,44	-1.52 ( 32.103 )	-14.73 ( 30.257 )	-3.13 ( 22.948 )	4.55 ( 18.395 )	-33.33 ( 99999 )	-15.15 ( 30.034 )
Change at C23 D1 (34,12,0,0,23,34)	-12.32 ( 28.077 )	-6.37 ( 20.521 )	1.39 ( 15.006 )	99999 ( 99999 )	99999 ( 99999 )	-6.37 ( 20.521 )
Change at C25 D1 (n=26,7,0,0,16,26)	-5.21 ( 23.348 )	-7.05 ( 24.117 )	4.76 ( 20.893 )	99999 ( 99999 )	99999 ( 99999 )	-7.05 ( 24.117 )
Change at EOT visit (n=7,4,4,3,2,10)	25.00 ( 35.355 )	-19.05 ( 26.227 )	-8.33 ( 9.623 )	-16.67 ( 30.429 )	0.00 ( 33.333 )	-13.33 ( 28.109 )

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Number of Subjects With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS)

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End point title

Part 1 and Part 2: Number of Subjects With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS)

End point description

ECOG: subject's performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity but ambulatory and able to carry out work of a light and sedentary nature; 2= ambulatory and capable of all self-care, but unable to carry out any work activities, up and about more than 50% of waking hours; 3= capable of only limited self-care, confined to bed/chair >50% of waking hours; 4= completely disabled, cannot carry on any self-care, totally confined to bed/chair. Safety analysis set. It was planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm. 99999=data could not be estimated due to low number of subjects with events. Number of subjects analyzed=number of subjects evaluable for this endpoint. n= subjects with available data for each specified category. Data is reported only for categories with non-zero values.

End point type

Secondary

End point timeframe

Part 1 and Part 2: Baseline, Day 1 of each cycle (Cycle 2 to Cycle 119 including 30 days[D] safety follow up [fup]) (each cycle=28 days)

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	192	192	186	257	84	276
Units: subjects
Baseline: ECOG score0 (n=192,186,257,84,192,276)	136	139	135	189	60	199
Baseline: ECOG score1 (n=192,186,257,84,192,276)	56	53	51	68	24	77
C2 D1: ECOG score 0 (n=182,181,256,80,188,262)	142	98	113	193	44	142
C2 D1: ECOG score 1 (n=182,181,256,80,188,262)	44	79	64	62	32	111
C2 D1: ECOG score 2 (n=182,181,256,80,188,262)	1	3	4	1	4	7
C2 D1: ECOG score 3 (n=182,181,256,80,188,262)	0	2	0	0	0	2
C2 D1: ECOG score 4 (n=182,181,256,80,188,262)	1	0	0	0	0	0
C3 D1: ECOG score 0 (n=175,176,253,74,185,249)	131	90	107	197	40	130
C3 D1: ECOG score 1 (n=175,176,253,74,185,249)	53	81	64	55	32	113
C3 D1: ECOG score 2 (n=175,176,253,74,185,249)	1	4	4	1	2	6
C4 D1: ECOG score 0 (n=164,158,250,68,179,232)	128	93	98	189	35	128
C4 D1: ECOG score 1 (n=164,158,250,68,179,232)	50	66	52	56	30	96
C4 D1: ECOG score 2 (n=164,158,250,68,179,232)	1	4	4	4	3	7
C4 D1: ECOG score 3 (n=164,158,250,68,179,232)	0	1	4	1	0	1
C5 D1: ECOG score 0 (n=158,143,239,66,174,224)	127	85	82	181	33	118
C5 D1: ECOG score 1 (n=158,143,239,66,174,224)	43	69	52	55	31	100
C5 D1: ECOG score 2 (n=158,143,239,66,174,224)	3	4	7	2	2	6
C5 D1: ECOG score 3 (n=158,143,239,66,174,224)	1	0	1	1	0	0
C5 D1: ECOG score 4 (n=158,143,239,66,174,224)	0	0	1	0	0	0
C6 D1: ECOG score 0 (n=137,126,231,58,169,195)	124	68	78	168	29	97
C6 D1: ECOG score 1 (n=137,126,231,58,169,195)	45	65	46	58	25	90
C6 D1: ECOG score 2 (n=137,126,231,58,169,195)	0	3	1	3	3	6
C6 D1: ECOG score 3 (n=137,126,231,58,169,195)	0	0	1	1	1	1
C6 D1: ECOG score 4 (n=137,126,231,58,169,195)	0	1	0	1	0	1
C7 D1: ECOG score 0 (n=129,111,218,55,159,184)	112	68	74	158	27	95
C7 D1: ECOG score 1 (n=129,111,218,55,159,184)	46	60	35	58	27	87
C7 D1: ECOG score 2 (n=129,111,218,55,159,184)	1	1	2	2	1	2
C8 D1: ECOG score 0 (n=108,95,200,46,148,154)	112	55	58	140	22	77
C8 D1: ECOG score 1 (n=108,95,200,46,148,154)	33	49	33	58	21	70
C8 D1: ECOG score 2 (n=108,95,200,46,148,154)	2	3	4	1	3	6
C8 D1: ECOG score 3 (n=108,95,200,46,148,154)	1	1	0	1	0	1
C9 D1: ECOG score 0 (n=98,90,188,43,144,141)	102	50	55	135	22	72
C9 D1: ECOG score 1 (n=98,90,188,43,144,141)	36	47	30	52	20	67
C9 D1: ECOG score 2 (n=98,90,188,43,144,141)	4	1	4	0	0	1
C9 D1: ECOG score 3 (n=98,90,188,43,144,141)	0	0	1	0	1	1
C9 D1: ECOG score 4 (n=98,90,188,43,144,141)	1	0	0	1	0	0
C10 D1: ECOG score 0 (n=88,73,171,37,129,125)	94	52	44	121	18	70
C10 D1: ECOG score 1 (n=88,73,171,37,129,125)	32	35	26	46	18	53
C10 D1: ECOG score 2 (n=88,73,171,37,129,125)	3	1	2	3	1	2
C10 D1: ECOG score 3 (n=88,73,171,37,129,125)	0	0	1	1	0	0
C11 D1: ECOG score 0 (n=85,62,158,36,121,121)	89	44	39	116	17	61
C11 D1: ECOG score 1 (n=85,62,158,36,121,121)	30	40	20	42	16	56
C11 D1: ECOG score 2 (n=85,62,158,36,121,121)	2	1	2	0	3	4
C11 D1: ECOG score 3 (n=85,62,158,36,121,121)	0	0	1	0	0	0
C12 D1: ECOG score 0 (n=77,50,152,30,110,107)	84	44	31	113	11	55
C12 D1: ECOG score 1 (n=77,50,152,30,110,107)	25	31	16	38	18	49
C12 D1: ECOG score 2 (n=77,50,152,30,110,107)	1	1	2	0	1	2
C12 D1: ECOG score 3 (n=77,50,152,30,110,107)	0	1	1	0	0	1
C12 D1: ECOG score 4 (n=77,50,152,30,110,107)	0	0	0	1	0	0
C13 D1: ECOG score 0 (n=73,47,143,31,100,104)	77	41	27	102	14	55
C13 D1: ECOG score 1 (n=73,47,143,31,100,104)	22	31	18	39	15	46
C13 D1: ECOG score 2 (n=73,47,143,31,100,104)	1	1	2	1	2	3
C13 D1: ECOG score 4 (n=73,47,143,31,100,104)	0	0	0	1	0	0
C14 D1: ECOG score 0 (n=75,46,136,27,97,102)	74	47	25	100	15	62
C14 D1: ECOG score 1 (n=75,46,136,27,97,102)	23	27	19	33	10	37
C14 D1: ECOG score 2 (n=75,46,136,27,97,102)	0	0	2	2	2	2
C14 D1: ECOG score 3 (n=75,46,136,27,97,102)	0	0	0	1	0	0
C14 D1: ECOG score 4 (n=75,46,136,27,97,102)	0	1	0	0	0	1
C15 D1: ECOG score 0 (n=72,41,126,25,94,97)	72	41	22	93	15	56
C15 D1: ECOG score 1 (n=72,41,126,25,94,97)	20	30	18	31	8	38
C15 D1: ECOG score 2 (n=72,41,126,25,94,97)	1	1	1	1	2	3
C15 D1: ECOG score 3 (n=72,41,126,25,94,97)	1	0	0	0	0	0
C15 D1: ECOG score 4 (n=72,41,126,25,94,97)	0	0	0	1	0	0
C16 D1: ECOG score 0 (n=67,35,116,24,90,91)	65	41	24	82	13	54
C16 D1: ECOG score 1 (n=67,35,116,24,90,91)	24	23	10	33	10	33
C16 D1: ECOG score 2 (n=67,35,116,24,90,91)	1	3	1	0	1	4
C16 D1: ECOG score 3 (n=67,35,116,24,90,91)	0	0	0	1	0	0
C17 D1: ECOG score 0 (n=67,33,111,23,86,90)	68	39	21	80	12	51
C17 D1: ECOG score 1 (n=67,33,111,23,86,90)	17	27	11	30	10	37
C17 D1: ECOG score 2 (n=67,33,111,23,86,90)	1	1	1	1	1	2
C18 D1: ECOG score 0 (n=60,33,104,23,85,83)	68	36	18	75	11	47
C18 D1: ECOG score 1 (n=60,33,104,23,85,83)	16	24	13	28	11	35
C18 D1: ECOG score 2 (n=60,33,104,23,85,83)	1	0	1	1	1	1
C18 D1: ECOG score 3 (n=60,33,104,23,85,83)	0	0	1	0	0	0
C19 D1: ECOG score 0 (n=59,34,98,22,80,81)	66	38	21	70	9	47
C19 D1: ECOG score 1 (n=59,34,98,22,80,81)	12	20	11	26	12	32
C19 D1: ECOG score 2 (n=59,34,98,22,80,81)	2	1	2	1	1	2
C20 D1: ECOG score 0 (n=52,32,94,23,80,75)	70	31	20	68	11	42
C20 D1: ECOG score 1 (n=52,32,94,23,80,75)	9	19	11	25	11	30
C20 D1: ECOG score 2 (n=52,32,94,23,80,75)	0	2	1	0	1	3
C20 D1: ECOG score 3 (n=52,32,94,23,80,75)	1	0	0	1	0	0
C21 D1: ECOG score 0 (n=49,29,92,23,75,72)	62	29	17	69	10	39
C21 D1: ECOG score 1 (n=49,29,92,23,75,72)	13	19	11	23	12	31
C21 D1: ECOG score 2 (n=49,29,92,23,75,72)	0	1	1	0	1	2
C22 D1: ECOG score 0 (n=46,27,86,21,72,67)	60	28	17	63	11	39
C22 D1: ECOG score 1 (n=46,27,86,21,72,67)	12	16	9	22	8	24
C22 D1: ECOG score 3 (n=46,27,86,21,72,67)	0	1	0	0	0	1
C22 D1: ECOG score 4 (n=46,27,86,21,72,67)	0	1	0	0	0	2
C23 D1: ECOG score 0 (n=40,26,81,19,67,59)	56	28	16	60	8	36
C23 D1: ECOG score 1 (n=40,26,81,19,67,59)	10	12	7	20	9	21
C23 D1: ECOG score 2 (n=40,26,81,19,67,59)	1	0	3	1	2	2
C24 D1: ECOG score 0 (n=38,27,80,19,68,57)	55	28	15	61	9	37
C24 D1: ECOG score 1 (n=38,27,80,19,68,57)	13	10	11	19	8	18
C24 D1: ECOG score 2 (n=38,27,80,19,68,57)	0	0	1	0	2	2
C25 D1: ECOG score 0 (n=38,25,80,19,64,57)	55	28	17	60	9	37
C25 D1: ECOG score 1 (n=38,25,80,19,64,57)	8	10	8	20	8	18
C25 D1: ECOG score 2 (n=38,25,80,19,64,57)	1	0	0	0	2	2
C26 D1: ECOG score 0 (n=37,25,80,19,61,56)	51	27	16	60	9	36
C26 D1: ECOG score 1 (n=37,25,80,19,61,56)	9	10	8	20	8	18
C26 D1: ECOG score 2 (n=37,25,80,19,61,56)	1	0	1	0	2	2
C27 D1: ECOG score 0 (n=36,23,76,19,58,55)	48	28	13	57	9	37
C27 D1: ECOG score 1 (n=36,23,76,19,58,55)	9	8	9	18	8	16
C27 D1: ECOG score 2 (n=36,23,76,19,58,55)	1	0	1	1	2	2
C28 D1: ECOG score 0 (n=34,22,70,18,56,52)	50	25	14	52	7	32
C28 D1: ECOG score 1 (n=34,22,70,18,56,52)	6	9	7	18	9	18
C28 D1: ECOG score 2 (n=34,22,70,18,56,52)	0	0	1	0	2	2
C29 D1: ECOG score 0 (n=34,21,67,16,56,50)	45	22	13	51	6	28
C29 D1: ECOG score 1 (n=34,21,67,16,56,50)	10	12	8	16	8	20
C29 D1: ECOG score 2 (n=34,21,67,16,56,50)	0	0	0	0	2	2
C29 D1: ECOG score 3 (n=34,21,67,16,56,50)	1	0	0	0	0	0
C30 D1: ECOG score 0 (n=32,21,69,15,55,47)	55	23	13	50	6	29
C30 D1: ECOG score 1 (n=32,21,69,15,55,47)	40	9	8	18	7	16
C30 D1: ECOG score 2 (n=32,21,69,15,55,47)	0	0	0	1	2	2
C30 D1: ECOG score 4 (n=32,21,69,15,55,47)	1	0	0	0	0	0
C31 D1: ECOG score 0 (n=32,21,62,15,55,47)	45	24	12	48	5	29
C31 D1: ECOG score 1 (n=32,21,62,15,55,47)	8	8	9	13	8	16
C31 D1: ECOG score 2 (n=32,21,62,15,55,47)	1	0	0	1	2	2
C31 D1: ECOG score 4 (n=32,21,62,15,55,47)	1	0	0	0	0	0
C32 D1: ECOG score 0 (n=30,20,63,14,52,44)	43	21	12	49	6	27
C32 D1: ECOG score 1 (n=30,20,63,14,52,44)	9	8	8	14	6	14
C32 D1: ECOG score 2 (n=30,20,63,14,52,44)	0	1	0	0	2	3
C33 D1: ECOG score 0 (n=27,20,61,15,52,42)	47	21	14	47	7	28
C33 D1: ECOG score 1 (n=27,20,61,15,52,42)	5	6	6	13	6	12
C33 D1: ECOG score 2 (n=27,20,61,15,52,42)	0	0	0	1	2	2
C34 D1: ECOG score 0 (n=26,19,61,15,52,41)	46	18	13	47	6	24
C34 D1: ECOG score 1 (n=26,19,61,15,52,41)	6	8	6	13	7	15
C34 D1: ECOG score 2 (n=26,19,61,15,52,41)	0	0	0	1	2	2
C35 D1: ECOG score 0 (n=27,19,61,15,52,42)	42	19	13	45	7	26
C35 D1: ECOG score 1 (n=27,19,61,15,52,42)	10	7	6	15	6	13
C35 D1: ECOG score 2 (n=27,19,61,15,52,42)	0	0	0	1	2	2
C36 D1: ECOG score 0 (n=25,18,60,15,51,40)	45	20	12	44	6	26
C36 D1: ECOG score 1 (n=25,18,60,15,51,40)	6	5	6	15	7	12
C36 D1: ECOG score 2 (n=25,18,60,15,51,40)	0	0	0	1	2	2
C37 D1: ECOG score 0 (n=25,17,58,14,47,39)	39	18	9	43	5	23
C37 D1: ECOG score 1 (n=25,17,58,14,47,39)	8	7	8	15	7	14
C37 D1: ECOG score 2 (n=25,17,58,14,47,39)	0	0	0	0	2	2
C38 D1: ECOG score 0 (n=25,17,59,13,48,38)	42	17	10	43	5	22
C38 D1: ECOG score 1 (n=25,17,59,13,48,38)	5	8	7	15	6	14
C38 D1: ECOG score 2 (n=25,17,59,13,48,38)	0	0	0	1	2	2
C38 D1: ECOG score 3 (n=25,17,59,13,48,38)	1	0	0	0	0	0
C39 D1: ECOG score 0 (n=25,16,57,14,47,39)	40	20	9	42	5	25
C39 D1: ECOG score 1 (n=25,16,57,14,47,39)	6	5	7	14	7	12
C39 D1: ECOG score 2 (n=25,16,57,14,47,39)	1	0	0	1	2	2
C40 D1: ECOG score 0 (n=24,16,55,12,45,36)	38	17	10	40	3	20
C40 D1: ECOG score 1 (n=24,16,55,12,45,36)	6	7	6	14	7	14
C40 D1: ECOG score 2 (n=24,16,55,12,45,36)	1	0	0	1	2	2
C41 D1: ECOG score 0 (n=23,15,56,13,44,36)	37	17	7	41	5	22
C41 D1: ECOG score 1 (n=23,15,56,13,44,36)	7	6	7	15	6	12
C41 D1: ECOG score 2 (n=23,15,56,13,44,36)	0	0	1	0	2	2
C42 D1: ECOG score 0 (n=23,14,55,13,41,36)	38	18	8	40	4	22
C42 D1: ECOG score 1 (n=23,14,55,13,41,36)	3	5	6	15	7	12
C42 D1: ECOG score 2 (n=23,14,55,13,41,36)	0	0	0	0	2	2
C43 D1: ECOG score 0 (n=23,14,54,13,39,36)	35	18	8	39	4	22
C43 D1: ECOG score 1 (n=23,14,54,13,39,36)	4	5	6	15	7	12
C43 D1: ECOG score 2 (n=23,14,54,13,39,36)	0	0	0	0	2	2
C44 D1: ECOG score 0 (n=23,14,54,13,41,36)	38	17	7	39	5	22
C44 D1: ECOG score 1 (n=23,14,54,13,41,36)	3	6	7	15	6	12
C44 D1: ECOG score 2 (n=23,14,54,13,41,36)	0	0	0	0	2	2
C45 D1: ECOG score 0 (n=23,14,52,10,40,33)	37	17	8	35	4	21
C45 D1: ECOG score 1 (n=23,14,52,10,40,33)	3	6	6	17	6	12
C46 D1: ECOG score 0 (n=21,11,49,10,40,31)	34	17	6	37	4	21
C46 D1: ECOG score 1 (n=21,11,49,10,40,31)	6	4	5	12	6	10
C47 D1: ECOG score 0 (n=23,10,49,10,40,33)	32	18	5	36	4	22
C47 D1: ECOG score 1 (n=23,10,49,10,40,33)	8	5	5	13	6	11
C48 D1: ECOG score 0 (n=22,11,50,9,38,31)	34	17	6	36	3	20
C48 D1: ECOG score 1 (n=22,11,50,9,38,31)	4	5	5	13	6	11
C48 D1: ECOG score 3 (n=22,11,50,9,38,31)	0	0	0	1	0	0
C49 D1: ECOG score 0 (n=21,10,47,9,38,30)	35	14	6	35	3	17
C49 D1: ECOG score 1 (n=21,10,47,9,38,30)	3	7	4	9	6	13
C49 D1: ECOG score 2 (n=21,10,47,9,38,30)	0	0	0	2	0	0
C49 D1: ECOG score 3 (n=21,10,47,9,38,30)	0	0	0	1	0	0
C50 D1: ECOG score 0 (n=21,10,46,8,39,29)	36	16	5	35	3	19
C50 D1: ECOG score 1 (n=21,10,46,8,39,29)	3	5	5	10	5	10
C50 D1: ECOG score 2 (n=21,10,46,8,39,29)	0	0	0	1	0	0
C51 D1: ECOG score 0 (n=19,10,43,8,38,27)	34	16	5	29	2	18
C51 D1: ECOG score 1 (n=19,10,43,8,38,27)	4	3	5	13	5	8
C51 D1: ECOG score 2 (n=19,10,43,8,38,27)	0	0	0	1	1	1
C52 D1: ECOG score 0 (n=20,10,44,8,38,28)	32	14	5	31	1	15
C52 D1: ECOG score 1 (n=20,10,44,8,38,28)	6	6	5	12	7	3
C52 D1: ECOG score 2 (n=20,10,44,8,38,28)	0	0	0	1	0	0
C53 D1: ECOG score 0 (n=20,10,42,7,37,27)	32	14	5	32	2	16
C53 D1: ECOG score 1 (n=20,10,42,7,37,27)	5	6	5	9	5	11
C53 D1: ECOG score 2 (n=20,10,42,7,37,27)	0	0	0	1	0	0
C54 D1: ECOG score 0 (n=20,10,42,8,33,28)	26	14	5	30	2	16
C54 D1: ECOG score 1 (n=20,10,42,8,33,28)	7	6	5	11	6	12
C54 D1: ECOG score 2 (n=20,10,42,8,33,28)	0	0	0	1	0	0
C55 D1: ECOG score 0 (n=20,10,41,7,36,27)	30	15	5	30	4	19
C55 D1: ECOG score 1 (n=20,10,41,7,36,27)	6	5	5	10	3	8
C55 D1: ECOG score 2 (n=20,10,41,7,36,27)	0	0	0	1	0	0
C56 D1: ECOG score 0 (n=20,9,40,7,36,27)	29	13	4	29	3	16
C56 D1: ECOG score 1 (n=20,9,40,7,36,27)	7	7	5	10	4	11
C56 D1: ECOG score 2 (n=20,9,40,7,36,27)	0	0	0	1	0	0
C57 D1: ECOG score 0 (n=19,8,39,7,35,26)	27	15	3	29	3	18
C57 D1: ECOG score 1 (n=19,8,39,7,35,26)	8	4	5	9	4	8
C57 D1: ECOG score 2 (n=19,8,39,7,35,26)	0	0	0	1	0	0
C58 D1: ECOG score 0 (n=19,10,37,7,34,26)	29	14	6	26	4	18
C58 D1: ECOG score 1 (n=19,10,37,7,34,26)	5	5	4	10	3	8
C58 D1: ECOG score 2 (n=19,10,37,7,34,26)	0	0	0	1	0	0
C59 D1: ECOG score 0 (n=18,8,36,6,33,24)	27	13	6	25	3	16
C59 D1: ECOG score 1 (n=18,8,36,6,33,24)	6	5	2	10	3	8
C59 D1: ECOG score 2 (n=18,8,36,6,33,24)	0	0	0	1	0	0
C60 D1: ECOG score 0 (n=17,8,38,5,32,22)	28	13	5	26	3	16
C60 D1: ECOG score 1 (n=17,8,38,5,32,22)	3	4	3	11	2	6
C60 D1: ECOG score 2 (n=17,8,38,5,32,22)	1	0	0	1	0	0
C61 D1: ECOG score 0 (n=18,8,35,5,30,23)	26	13	5	24	3	16
C61 D1: ECOG score 1 (n=18,8,35,5,30,23)	4	5	2	10	2	7
C61 D1: ECOG score 2 (n=18,8,35,5,30,23)	0	0	0	1	0	0
C61 D1: ECOG score 3 (n=18,8,35,5,30,23)	0	0	1	0	0	0
C62 D1: ECOG score 0 (n=17,7,35,5,29,22)	24	13	5	24	3	16
C62 D1: ECOG score 1 (n=17,7,35,5,29,22)	5	4	2	10	2	6
C62 D1: ECOG score 2 (n=17,7,35,5,29,22)	0	0	0	1	0	0
C63 D1: ECOG score 0 (n=17,7,33,5,28,22)	22	13	5	24	3	16
C63 D1: ECOG score 1 (n=17,7,33,5,28,22)	6	4	2	8	2	6
C63 D1: ECOG score 2 (n=17,7,33,5,28,22)	0	0	0	1	0	0
C64 D1: ECOG score 0 (n=17,7,32,5,28,22)	23	11	5	25	2	13
C64 D1: ECOG score 1 (n=17,7,32,5,28,22)	5	6	2	6	3	9
C64 D1: ECOG score 2 (n=17,7,32,5,28,22)	0	0	0	1	0	0
C65 D1: ECOG score 0 (n=16,7,29,4,28,20)	21	13	5	18	2	15
C65 D1: ECOG score 1 (n=16,7,29,4,28,20)	7	3	2	10	2	5
C65 D1: ECOG score 2 (n=16,7,29,4,28,20)	0	0	0	1	0	0
C66 D1: ECOG score 0 (n=17,7,32,4,28,21)	24	12	5	21	2	14
C66 D1: ECOG score 1 (n=17,7,32,4,28,21)	4	5	2	10	2	7
C66 D1: ECOG score 2 (n=17,7,32,4,28,21)	0	0	0	1	0	0
C67 D1: ECOG score 0 (n=15,7,29,5,28,20)	24	13	5	19	3	16
C67 D1: ECOG score 1 (n=15,7,29,5,28,20)	4	2	2	9	2	4
C67 D1: ECOG score 2 (n=15,7,29,5,28,20)	0	0	0	1	0	0
C68 D1: ECOG score 0 (n=15,6,29,5,28,20)	24	13	4	19	2	15
C68 D1: ECOG score 1 (n=15,6,29,5,28,20)	4	2	2	9	3	5
C68 D1: ECOG score 2 (n=15,6,29,5,28,20)	0	0	0	1	0	0
C69 D1: ECOG score 0 (n=14,6,30,5,26,19)	21	12	5	20	1	13
C69 D1: ECOG score 1 (n=14,6,30,5,26,19)	5	2	1	9	3	5
C69 D1: ECOG score 2 (n=14,6,30,5,26,19)	0	0	0	1	1	1
C70 D1: ECOG score 0 (n=14,6,29,5,27,19)	22	11	4	20	2	13
C70 D1: ECOG score 1 (n=14,6,29,5,27,19)	5	3	2	8	3	6
C70 D1: ECOG score 2 (n=14,6,29,5,27,19)	0	0	0	1	0	0
C71 D1: ECOG score 0 (n=14,6,24,4,26,18)	21	12	4	15	1	13
C71 D1: ECOG score 1 (n=14,6,24,4,26,18)	5	2	2	8	3	5
C71 D1: ECOG score 2 (n=14,6,24,4,26,18)	0	0	0	1	0	0
C72 D1: ECOG score 0 (n=14,5,32,4,28,18)	23	11	4	21	2	13
C72 D1: ECOG score 1 (n=14,5,32,4,28,18)	5	3	1	10	2	5
C72 D1: ECOG score 2 (n=14,5,32,4,28,18)	0	0	0	1	0	0
C73 D1: ECOG score 0 (n=13,5,24,4,25,17)	24	12	4	15	1	13
C73 D1: ECOG score 1 (n=13,5,24,4,25,17)	1	1	1	8	3	4
C73 D1: ECOG score 2 (n=13,5,24,4,25,17)	0	0	0	1	0	0
C74 D1: ECOG score 0 (n=14,5,25,5,26,19)	22	13	3	16	2	15
C74 D1: ECOG score 1 (n=14,5,25,5,26,19)	4	1	2	8	3	4
C74 D1: ECOG score 2 (n=14,5,25,5,26,19)	0	0	0	1	0	0
C75 D1: ECOG score 0 (n=13,5,29,3,25,16)	22	12	3	21	1	13
C75 D1: ECOG score 1 (n=13,5,29,3,25,16)	2	1	2	8	2	3
C75 D1: ECOG score 2 (n=13,5,29,3,25,16)	1	0	0	0	0	0
C76 D1: ECOG score 0 (n=14,3,24,4,24,18)	21	13	2	17	1	14
C76 D1: ECOG score 1 (n=14,3,24,4,24,18)	2	1	1	6	3	4
C76 D1: ECOG score 2 (n=14,3,24,4,24,18)	1	0	0	1	0	0
C77 D1: ECOG score 0 (n=12,3,21,4,20,16)	18	11	2	13	0	11
C77 D1: ECOG score 1 (n=12,3,21,4,20,16)	2	1	1	8	4	5
C78 D1: ECOG score 0 (n=13,3,31,2,19,15)	17	12	2	21	0	12
C78 D1: ECOG score 1 (n=13,3,31,2,19,15)	2	1	1	9	2	3
C78 D1: ECOG score 2 (n=13,3,31,2,19,15)	0	0	0	1	0	0
C79 D1: ECOG score 0 (n=14,2,22,2,21,16)	18	12	1	16	0	12
C79 D1: ECOG score 1 (n=14,2,22,2,21,16)	3	2	1	5	2	4
C79 D1: ECOG score 2 (n=14,2,22,2,21,16)	0	0	0	1	0	0
C80 D1: ECOG score 0 (n=11,2,24,2,15,13)	14	10	1	17	0	10
C80 D1: ECOG score 1 (n=11,2,24,2,15,13)	1	1	1	5	2	3
C80 D1: ECOG score 2 (n=11,2,24,2,15,13)	0	0	0	2	0	0
C81 D1: ECOG score 0 (n=11,3,28,3,21,14)	19	10	2	21	0	10
C81 D1: ECOG score 1 (n=11,3,28,3,21,14)	2	1	1	6	3	4
C81 D1: ECOG score 2 (n=11,3,28,3,21,14)	0	0	0	1	0	0
C82 D1: ECOG score 0 (n=13,2,22,2,18,15)	16	11	1	16	0	11
C82 D1: ECOG score 1 (n=13,2,22,2,18,15)	2	2	1	5	2	4
C82 D1: ECOG score 2 (n=13,2,22,2,18,15)	0	0	0	1	0	0
C83 D1: ECOG score 0 (n=10,1,21,2,20,12)	17	8	0	16	0	8
C83 D1: ECOG score 1 (n=10,1,21,2,20,12)	3	2	1	5	2	4
C84 D1: ECOG score 0 (n=12,1,27,3,14,15)	13	11	1	21	0	11
C84 D1: ECOG score 1 (n=12,1,27,3,14,15)	1	1	0	5	3	4
C84 D1: ECOG score 2 (n=12,1,27,3,14,15)	0	0	0	1	0	0
C85 D1: ECOG score 0 (n=11,1,19,2,16,13)	14	11	0	14	0	11
C85 D1: ECOG score 1 (n=11,1,19,2,16,13)	2	0	0	5	2	2
C86 D1: ECOG score 0 (n=10,0,20,3,12,13)	11	9	99999	15	0	9
C86 D1: ECOG score 1 (n=10,0,20,3,12,13)	1	1	99999	4	3	4
C86 D1: ECOG score 2 (n=10,0,20,3,12,13)	0	0	99999	1	0	0
C87 D1: ECOG score 0 (n=10,2,28,2,16,12)	15	9	1	21	0	9
C87 D1: ECOG score 1 (n=10,2,28,2,16,12)	1	1	1	5	2	3
C87 D1: ECOG score 2 (n=10,2,28,2,16,12)	0	0	0	1	0	0
C87 D1: ECOG score 4 (n=10,2,28,2,16,12)	0	0	0	1	0	0
C88 D1: ECOG score 0 (n=8,0,18,3,13,11)	10	6	99999	14	0	6
C88 D1: ECOG score 1 (n=8,0,18,3,13,11)	3	2	99999	4	2	4
C88 D1: ECOG score 2 (n=8,0,18,3,13,11)	0	0	99999	0	1	1
C89 D1: ECOG score 0 (n=7,1,19,2,14,9)	13	6	0	15	0	6
C89 D1: ECOG score 1 (n=7,1,19,2,14,9)	1	1	1	4	2	3
C90 D1: ECOG score 0 (n=10,1,24,3,15,13)	14	8	1	18	0	8
C90 D1: ECOG score 1 (n=10,1,24,3,15,13)	1	2	0	5	2	4
C90 D1: ECOG score 2 (n=10,1,24,3,15,13)	0	0	0	1	1	1
C91 D1: ECOG score 0 (n=8,1,20,2,15,10)	12	7	0	15	0	7
C91 D1: ECOG score 1 (n=8,1,20,2,15,10)	3	1	1	5	2	3
C92 D1: ECOG score 0 (n=5,0,17,3,12,8)	10	5	99999	12	0	5
C92 D1: ECOG score 1 (n=5,0,17,3,12,8)	2	0	99999	5	2	2
C92 D1: ECOG score 2 (n=5,0,17,3,12,8)	0	0	99999	0	1	1
C93 D1: ECOG score 0 (n=7,2,24,2,16,9)	15	6	1	19	0	6
C93 D1: ECOG score 1 (n=7,2,24,2,16,9)	1	1	1	3	2	3
C93 D1: ECOG score 2 (n=7,2,24,2,16,9)	0	0	0	2	0	0
C94 D1: ECOG score 0 (n=8,0,18,2,14,10)	11	7	99999	14	0	7
C94 D1: ECOG score 1 (n=8,0,18,2,14,10)	3	1	99999	3	1	2
C94 D1: ECOG score 2 (n=8,0,18,2,14,10)	0	0	99999	1	1	1
C95 D1: ECOG score 0 (n=5,1,18,1,12,6)	11	4	0	13	0	4
C95 D1: ECOG score 1 (n=5,1,18,1,12,6)	1	1	1	3	1	2
C95 D1: ECOG score 2 (n=5,1,18,1,12,6)	0	0	0	2	0	0
C96 D1: ECOG score 0 (n=6,1,21,2,15,8)	14	6	0	16	0	6
C96 D1: ECOG score 1 (n=6,1,21,2,15,8)	1	0	1	4	1	1
C96 D1: ECOG score 2 (n=6,1,21,2,15,8)	0	0	0	1	1	1
C97 D1: ECOG score 0 (n=8,1,18,1,12,9)	9	8	0	16	0	8
C97 D1: ECOG score 1 (n=8,1,18,1,12,9)	3	0	1	1	1	1
C97 D1: ECOG score 2 (n=8,1,18,1,12,9)	0	0	0	1	0	0
C98 D1: ECOG score 0 (n=4,0,12,1,10,5)	7	4	99999	10	0	4
C98 D1: ECOG score 1 (n=4,0,12,1,10,5)	3	0	99999	1	1	1
C98 D1: ECOG score 2 (n=4,0,12,1,10,5)	0	0	99999	1	0	0
C99 D1: ECOG score 0 (n=6,2,17,2,14,8)	13	6	0	16	0	6
C99 D1: ECOG score 1 (n=6,2,17,2,14,8)	1	0	2	0	1	1
C99 D1: ECOG score 2 (n=6,2,17,2,14,8)	0	0	0	1	1	1
C100 D1: ECOG score 0 (n=6,0,12,1,12,7)	10	6	99999	11	0	6
C100 D1: ECOG score 1 (n=6,0,12,1,12,7)	2	0	99999	0	1	1
C100 D1: ECOG score 2 (n=6,0,12,1,12,7)	0	0	99999	1	0	0
C101 D1: ECOG score 0 (n=4,1,8,2,11,6)	9	4	0	8	0	4
C101 D1: ECOG score 1 (n=4,1,8,2,11,6)	2	0	1	0	1	1
C101 D1: ECOG score 2 (n=4,1,8,2,11,6)	0	0	0	0	1	1
C102 D1: ECOG score 0 (n=6,1,8,1,10,7)	8	6	0	8	0	6
C102 D1: ECOG score 1 (n=6,1,8,1,10,7)	1	0	1	0	1	1
C102 D1: ECOG score 2 (n=6,1,8,1,10,7)	1	0	0	0	0	0
C103 D1: ECOG score 0 (n=6,1,4,1,8,7)	6	6	0	4	0	6
C103 D1: ECOG score 1 (n=6,1,4,1,8,7)	2	0	1	0	1	1
C104 D1: ECOG score 0 (n=3,0,1,0,9,3)	9	2	99999	1	99999	2
C104 D1: ECOG score 1 (n=3,0,1,0,9,3)	0	1	99999	0	99999	1
C105 D1: ECOG score 0 (n=4,2,1,0,10,4)	10	4	0	1	99999	4
C105 D1: ECOG score 1 (n=4,2,1,0,10,4)	0	0	2	0	99999	0
C106 D1: ECOG score 0 (n=5,0,0,0,9,5)	6	5	99999	99999	99999	5
C106 D1: ECOG score 1 (n=5,0,0,0,9,5)	3	0	99999	99999	99999	0
C107 D1: ECOG score 0 (n=3,1,0,0,7,3)	6	3	0	99999	99999	3
C107 D1: ECOG score 1 (n=3,1,0,0,7,3)	1	0	1	99999	99999	0
C108 D1: ECOG score 0 (n=3,1,0,0,8,3)	8	3	0	99999	99999	3
C108 D1: ECOG score 1 (n=3,1,0,0,8,3)	0	0	1	99999	99999	0
C109 D1: ECOG score 0 (n=4,1,0,0,8,4)	7	4	0	99999	99999	4
C109 D1: ECOG score 1 (n=4,1,0,0,8,4)	1	0	1	99999	99999	0
C110 D1: ECOG score 0 (n=2,0,0,0,7,2)	7	2	99999	99999	99999	2
C111 D1: ECOG score 0 (n=3,1,0,0,6,3)	6	3	0	99999	99999	3
C111 D1: ECOG score 1 (n=3,1,0,0,6,3)	0	0	1	99999	99999	0
C112 D1: ECOG score 0 (n=1,0,0,0,4,1)	4	1	99999	99999	99999	1
C113 D1: ECOG score 0 (n=1,1,0,0,4,1)	3	1	0	99999	99999	1
C113 D1: ECOG score 1 (n=1,1,0,0,4,1)	1	0	1	99999	99999	0
C114 D1: ECOG score 0 (n=0,0,0,0,4,0)	3	99999	99999	99999	99999	99999
C114 D1: ECOG score 1 (n=0,0,0,0,4,0)	1	99999	99999	99999	99999	99999
C115 D1: ECOG score 0 (n=0,1,0,0,2,0)	1	99999	0	99999	99999	99999
C115 D1: ECOG score 1 (n=0,1,0,0,2,0)	1	99999	1	99999	99999	99999
C116 D1: ECOG score 0 (n=1,0,0,0,2,1)	2	1	99999	99999	99999	1
C117 D1: ECOG score 0 (n=0,1,0,0,2,0)	2	99999	0	99999	99999	99999
C117 D1: ECOG score 1 (n=0,1,0,0,2,0)	0	99999	1	99999	99999	99999
C118 D1: ECOG score 0 (n=0,0,0,0,1,0)	1	99999	99999	99999	99999	99999
C119 D1: ECOG score 0 (n=0,0,0,0,1,1)	0	99999	99999	99999	99999	99999
30D safety fup ECOG score 0(n=76,60,75,30,64,106)	31	43	34	42	13	56
30D safety fup ECOG score 1(n=76,60,75,30,64,106)	26	27	21	27	11	38
30D safety fup ECOG score 2(n=76,60,75,30,64,106)	5	5	4	4	5	10
30D safety fup ECOG score 3(n=76,60,75,30,64,106)	1	0	1	2	1	1
30D safety fup ECOG score 4 (n=76,60,75,30,64,106)	1	1	0	0	0	1
C19 D1: ECOG score 4 (n=59,34,98,22,80,81)	0	0	0	1	0	0
C22 D1: ECOG score 2 (n=46,27,86,21,72,67)	0	0	0	1	1	1

No statistical analyses for this end point

Secondary: Part 1: Plasma Concentrations of LGX 818

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End point title

Part 1: Plasma Concentrations of LGX 818 ^[22]

End point description

Pharmacokinetic analysis set included all subjects who received at least one dose of LGX818 or MEK162 and had at least one evaluable post-baseline LGX818 or MEK162 concentration measurement. Here, Number of subjects analyzed signifies the number of subjects evaluable for this endpoint and n= subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: pre-dose, 0.5, 1.5, anytime between 4 to 8 hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg
Number of subjects analysed	175	172
Units: nanogram per milliliter (ng/ml)
arithmetic mean (standard deviation)
C1 D1: pre-dose (n=172,175)	18.6 ( 125 )	58.1 ( 513 )
C1 D1: 0.5 hours post dose (n=145,159)	1640 ( 2400 )	1190 ( 1790 )
C1 D1: 1.5 hours post dose (n=116,122)	6860 ( 3680 )	4090 ( 2100 )
C1 D1: 4 to 8 hours post dose (n=142,147)	3400 ( 2010 )	1850 ( 925 )
C2 D1: pre-dose (73,119)	119 ( 468 )	73.6 ( 405 )
C3 D1: pre-dose (n=74,98)	150 ( 697 )	53.8 ( 256 )

No statistical analyses for this end point

Secondary: Part 2: Plasma Concentrations of LGX 818

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End point title

Part 2: Plasma Concentrations of LGX 818 ^[23]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1: pre-dose, 0.5, 1.5, anytime between 4 to 8 hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 2: LGX818 300 mg	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	242	80	252
Units: ng/ml
arithmetic mean (standard deviation)
C1 D1: pre-dose (n=242,80,252)	5.02 ( 77.8 )	0.0145 ( 0.130 )	39.7 ( 424 )
C1 D1: 0.5 hours post dose (n=207,68,213)	1360 ( 2000 )	1370 ( 2170 )	1250 ( 1910 )
C1 D1: 1.5 hours post dose (n=220,73,189)	4390 ( 2380 )	4310 ( 2570 )	4170 ( 2290 )
C1 D1: 4 to 8 hours post dose (n=185,66,208)	2420 ( 1270 )	2250 ( 1170 )	1980 ( 1020 )
C2 D1: pre-dose (175,32,105)	121 ( 483 )	29.5 ( 99.9 )	60.1 ( 342 )
C3 D1: pre-dose (n=151,27,101)	74.1 ( 322 )	79.5 ( 291 )	60.6 ( 265 )

No statistical analyses for this end point

Secondary: Part 1: Plasma Concentrations of MEK162

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End point title

Part 1: Plasma Concentrations of MEK162 ^[24]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1: pre-dose, 0.5, 1.5, anytime between 4 to 8 hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)
Number of subjects analysed	167
Units: ng/ml
arithmetic mean (standard deviation)
C1 D1: pre-dose (n=167)	2.95 ( 30.7 )
C1 D1: 0.5 hours post dose (n=151)	426 ( 410 )
C1 D1: 1.5 hours post dose (n=117)	832 ( 527 )
C1 D1: 4 to 8 hours post dose (n=138)	330 ( 226 )
C2 D1: pre-dose (n=77)	81.0 ( 106 )
C3 D1: pre-dose (n=65)	68.1 ( 101 )

No statistical analyses for this end point

Secondary: Part 2: Plasma Concentrations of MEK162

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End point title

Part 2: Plasma Concentrations of MEK162 ^[25]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1: pre-dose, 0.5, 1.5, anytime between 4 to 8 hours post dose; Cycle 2 Day 1: pre-dose; Cycle 3 Day 1: pre-dose

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)
Number of subjects analysed	215
Units: ng/ml
arithmetic mean (standard deviation)
C1 D1: pre-dose (n=215)	1.68 ( 24.3 )
C1 D1: 0.5 hours post dose (n=191)	366 ( 347 )
C1 D1: 1.5 hours post dose (n=196)	642 ( 337 )
C1 D1: 4 to 8 hours post dose (n=169)	287 ( 175 )
C2 D1: pre-dose (n=98)	72.3 ( 62.6 )
C3 D1: pre-dose (n=94)	73.2 ( 89.0 )

No statistical analyses for this end point

Secondary: Part 1 and Part 2: Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS)

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End point title

Part 1 and Part 2: Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group Performance Status (ECOG PS) ^[26]

End point description

ECOG: subjects performance status was measured on a 6-point scale: 0= fully active/able to carry on all pre-disease activities without restriction; 1=restricted in physically strenuous activity but ambulatory & able to carry out work of a light & sedentary nature; 2=ambulatory &= capable of all self-care, but unable to carry out any work activities, up & about more than 50 percent (%) of waking hours; 3= capable of only limited self-care, confined to bed/chair >50% of waking hours; 4=completely disabled, cannot carry on any self-care, totally confined to bed/chair: 5= dead. Definitive deterioration was defined as death due to any cause/decrease in ECOG PS by at least one category from baseline score with no subsequent improvement. Safety analysis set. Number of subjects analyzed =number of subjects evaluable for this endpoint. 99999=data could not be estimated due to low number of subjects with events. Planned to report combined result data of Part 1 and Part 2 for LGX818 300 mg arm.

End point type

Secondary

End point timeframe

Baseline up to 30 days from last dose of study drug (up to maximum of 417.7, 471.4 and 415.4 weeks of treatment for Combo 300, LGX818 300 and Part 1 and 2 arms, respectively)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 1 + Part 2: LGX818 300 mg
Number of subjects analysed	192	186	257	270
Units: months
median (confidence interval 95%)	99999 (53.4 to 99999)	20.9 (11.1 to 99999)	83.4 (52.4 to 99999)	24.8 (14.8 to 50.1)

No statistical analyses for this end point

Other pre-specified: Part 1: PFS by BIRC in Combo 450 Group as Compared to LGX818 Group: Final OS and Follow-up Efficacy and Safety Data as of End of Study

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End point title

Part 1: PFS by BIRC in Combo 450 Group as Compared to LGX818 Group: Final OS and Follow-up Efficacy and Safety Data as of End of Study ^[27]

End point description

PFS was defined as the time from the date of randomization to the date of the first documented PD or death due to any cause, whichever occurred first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC and survival information. If a subject did not have an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm^2. FAS included all randomized subjects.

End point type

Other pre-specified

End point timeframe

From randomization until documented PD, initiation of new anti-cancer therapy, censoring date or death, whichever occurred first (up to maximum of 471.7 and 465.4 weeks of treatment for Combo 3450 and vemurafenib, respectively)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: LGX818 300 mg
Number of subjects analysed	192	194
Units: months
median (confidence interval 95%)	14.9 (11.0 to 20.2)	9.6 (7.4 to 14.8)

No statistical analyses for this end point

Other pre-specified: Part 1: PFS by BIRC in Combo 450 Group as Compared to Vemurafenib Group: Final OS and Follow-up Efficacy and Safety Data as of End of Study

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End point title

Part 1: PFS by BIRC in Combo 450 Group as Compared to Vemurafenib Group: Final OS and Follow-up Efficacy and Safety Data as of End of Study ^[28]

End point description

PFS was defined as the time from the date of randomization to the date of the first documented PD or death due to any cause, whichever occured first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria) as per BIRC/central review and survival information. If a subject did not have an event at the time of the analysis cut-off or at the start of any new anti-cancer therapy, data was censored at the date of last adequate tumor assessment. PD was defined as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 square millimeter (mm^2). Full analysis set (FAS) included all randomized subjects.

End point type

Other pre-specified

End point timeframe

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was summarized for specified reporting arms only.

End point values	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 1: Vemurafenib 960 mg BID
Number of subjects analysed	192	191
Units: months
median (confidence interval 95%)	14.9 (11.0 to 20.2)	7.3 (5.6 to 7.9)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Part 1: Baseline up to 30 days from last dose of study drug (up to maximum of 417.7, 465.4, 471.4, 471.4 and 415.4 weeks of treatment for LGX818 300, vemurafenib, combo 300, combo 450 and Part 1 and 2 arms, respectively)

Adverse event reporting additional description

Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 subject and as non-serious in another subject or 1 subject may have experienced both serious and non-serious event during study. Safety analysis population evaluated.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Part 1: Vemurafenib 960 mg BID

Reporting group description

Subjects received 960 mg of LGX818 according to the locally approved prescribing information twice daily for each 28 day treatment cycle until PD as confirmed by BIRC, withdrawal of consent, intolerable toxicity, study discontinuation, lost to follow-up or death.

Reporting group title

Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)

Reporting group description

Subjects received 300 mg of LGX818 orally once daily along with 45 mg of MEK162 twice daily for each 28 day treatment cycle until PD as confirmed by BIRC, withdrawal of consent, intolerable toxicity, study discontinuation, lost to follow-up or death.

Reporting group title

Part 1: LGX818 300 mg

Reporting group description

Subjects received 300 mg of LGX818 orally once daily for each 28 day treatment cycle until PD as confirmed by BIRC, withdrawal of consent, intolerable toxicity, study discontinuation, lost to follow-up or death.

Reporting group title

Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)

Reporting group description

Subjects received 450 milligram (mg) of LGX818 orally once daily (QD) along with 45 mg of MEK162 twice daily (BID) for each 28 day treatment cycle until progressive disease (PD) as confirmed by Blinded Independent Review Committee (BIRC), withdrawal of consent, intolerable toxicity, study discontinuation, lost to follow-up or death.

Reporting group title

Part 2: LGX818 300 mg

Reporting group description

Serious adverse events	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 1: LGX818 300 mg	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 2: LGX818 300 mg
Total subjects affected by serious adverse events
subjects affected / exposed	78 / 186 (41.94%)	98 / 257 (38.13%)	71 / 192 (36.98%)	85 / 192 (44.27%)	31 / 84 (36.90%)
number of deaths (all causes)	145	171	125	136	60
number of deaths resulting from adverse events	6	14	8	10	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intracranial Tumour Haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	2 / 257 (0.78%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
Metastases To Bone
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases To Central Nervous System
subjects affected / exposed	3 / 186 (1.61%)	4 / 257 (1.56%)	3 / 192 (1.56%)	3 / 192 (1.56%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 3	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0
Metastases To Meninges
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
Rectal Adenocarcinoma
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Malignant Melanoma In Situ
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cancer Pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatofibrosarcoma Protuberans
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant Melanoma
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	2 / 192 (1.04%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal Cell Carcinoma
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	4 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour Haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transitional Cell Carcinoma
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Superficial Spreading Melanoma Stage Unspecified
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	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
Squamous Cell Carcinoma
subjects affected / exposed	3 / 186 (1.61%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasm
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic Malignant Melanoma
subjects affected / exposed	2 / 186 (1.08%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastasis
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases To Adrenals
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases To Spine
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases To Bladder
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour Associated Fever
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour Pain
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Plasma Cell Myeloma
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign neoplasm
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign bone neoplasm
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Myeloproliferative neoplasm
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lung
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial cancer
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Breast cancer
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Vascular disorders
Superficial vein thrombosis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Deep Vein Thrombosis
subjects affected / exposed	0 / 186 (0.00%)	2 / 257 (0.78%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Circulatory Collapse
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Giant cell arteritis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	2 / 192 (1.04%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	2 / 192 (1.04%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 2	0 / 0
General Physical Health Deterioration
subjects affected / exposed	6 / 186 (3.23%)	4 / 257 (1.56%)	2 / 192 (1.04%)	3 / 192 (1.56%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	2 / 6	0 / 4	0 / 2	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	2 / 186 (1.08%)	2 / 257 (0.78%)	3 / 192 (1.56%)	7 / 192 (3.65%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 2	4 / 4	1 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Multiple Organ Dysfunction Syndrome
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Pain
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	4 / 192 (2.08%)	1 / 192 (0.52%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema Peripheral
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Performance Status Decreased
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Immune system disorders
Contrast Media Allergy
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug Hypersensitivity
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Breast Pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism
subjects affected / exposed	3 / 186 (1.61%)	2 / 257 (0.78%)	1 / 192 (0.52%)	3 / 192 (1.56%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	1 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Alveolar Haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Arrest
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural Effusion
subjects affected / exposed	2 / 186 (1.08%)	0 / 257 (0.00%)	1 / 192 (0.52%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	3 / 186 (1.61%)	0 / 257 (0.00%)	1 / 192 (0.52%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	1 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Mediastinal Shift
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Epistaxis
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung Infiltration
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Failure
subjects affected / exposed	0 / 186 (0.00%)	2 / 257 (0.78%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional State
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental Status Changes
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression Suicidal
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Completed Suicide
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
Depression
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post-Traumatic Stress Disorder
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Agitation
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device Failure
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood Creatinine Increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Intraocular Pressure Increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic Enzyme Increased
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-Glutamyltransferase Increased
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
C-Reactive Protein Increased
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase Increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
White Blood Cell Count Increased
subjects affected / exposed	2 / 186 (1.08%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial Necrosis Marker Increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymph Node Palpable
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Troponin Increased
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Radiation Necrosis
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	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
Multiple Injuries
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur Fracture
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acetabulum Fracture
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Compression Fracture
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Compression Fracture
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Fracture
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seroma
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Face injury
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest injury
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin abrasion
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Jaw fracture
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Procedural pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated incisional hernia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Intestinal anastomosis complication
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hydrocele
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Myocardial Infarction
subjects affected / exposed	0 / 186 (0.00%)	3 / 257 (1.17%)	0 / 192 (0.00%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute Coronary Syndrome
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bundle Branch Block Left
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular Block First Degree
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Acute Myocardial Infarction
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial Effusion
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial Ischaemia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Left Ventricular Failure
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac Failure
subjects affected / exposed	2 / 186 (1.08%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-Respiratory Arrest
subjects affected / exposed	0 / 186 (0.00%)	2 / 257 (0.78%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
Cardiac Tamponade
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachyarrhythmia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Congestive cardiomyopathy
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Cardiac hypertrophy
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Nervous system disorders
Cerebral Haemorrhage
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	2 / 192 (1.04%)	3 / 192 (1.56%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 1
Balance Disorder
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Hemiparesis
subjects affected / exposed	3 / 186 (1.61%)	2 / 257 (0.78%)	2 / 192 (1.04%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 2	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 186 (0.54%)	2 / 257 (0.78%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 186 (0.54%)	4 / 257 (1.56%)	1 / 192 (0.52%)	1 / 192 (0.52%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Dysarthria
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Coma
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Cervicobrachial Syndrome
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Transient Ischaemic Attack
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Cord Compression
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Facial Paralysis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	2 / 192 (1.04%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain Stem Syndrome
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Brain Oedema
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 186 (0.00%)	3 / 257 (1.17%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glial Scar
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intercostal Neuralgia
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial Pressure Increased
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous System Disorder
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Facial Paresis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	2 / 192 (1.04%)	0 / 192 (0.00%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 186 (0.54%)	5 / 257 (1.95%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 7	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Restless Legs Syndrome
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraparesis
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depressed Level Of Consciousness
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cerebellar Ischaemia
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aphasia
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Facial Nerve Disorder
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paresis Cranial Nerve
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertebral Artery Dissection
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Ischaemic Stroke
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Speech Disorder
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive Encephalopathy
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Guillain-Barre Syndrome
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid Haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Monoplegia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular Accident
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diplegia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Motor Dysfunction
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bell's palsy
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Hemihypoaesthesia
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 186 (1.08%)	6 / 257 (2.33%)	2 / 192 (1.04%)	5 / 192 (2.60%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 2	3 / 6	1 / 2	2 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Lymphopenia
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymph node pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Normal Tension Glaucoma
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Detachment
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Central serous chorioretinopathy
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Retinal Artery Occlusion
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhegmatogenous retinal detachment
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uveitis
subjects affected / exposed	0 / 186 (0.00%)	2 / 257 (0.78%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retinal Vein Occlusion
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angle closure glaucoma
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Visual impairment
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vision blurred
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vogt-Koyanagi-Hara da disease
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	2 / 192 (1.04%)	5 / 192 (2.60%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 2	2 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	2 / 186 (1.08%)	0 / 257 (0.00%)	6 / 192 (3.13%)	3 / 192 (1.56%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	3 / 6	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric Ulcer Haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Diverticulum
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Diarrhoea
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 186 (0.00%)	2 / 257 (0.78%)	6 / 192 (3.13%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	3 / 6	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain Upper
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	2 / 192 (1.04%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal Haemorrhage
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 186 (0.54%)	2 / 257 (0.78%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Anal Incontinence
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal Fistula
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Distension
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal Haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Pancreatitis Acute
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Inguinal Hernia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	2 / 192 (1.04%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea Haemorrhagic
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large Intestine Perforation
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Obstruction
subjects affected / exposed	2 / 186 (1.08%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	2 / 257 (0.78%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Pancreatic fistula
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal stenosis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Jaundice
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Cholecystitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Cholecystitis acute
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Rash Erythematous
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Granuloma Annulare
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erythema Nodosum
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug Eruption
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis Bullous
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dermatitis Allergic
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cutaneous Vasculitis
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	3 / 186 (1.61%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute Kidney Injury
subjects affected / exposed	1 / 186 (0.54%)	5 / 257 (1.95%)	1 / 192 (0.52%)	4 / 192 (2.08%)	3 / 84 (3.57%)
occurrences causally related to treatment / all	1 / 1	2 / 5	0 / 1	1 / 4	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Calculus Urethral
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Renal Failure
subjects affected / exposed	2 / 186 (1.08%)	0 / 257 (0.00%)	2 / 192 (1.04%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Renal Impairment
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Urinary Incontinence
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ureteric Obstruction
subjects affected / exposed	2 / 186 (1.08%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Disorder
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Ureterolithiasis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Retention
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal vasculitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Glomerulonephritis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain In Extremity
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	1 / 192 (0.52%)	1 / 192 (0.52%)	2 / 84 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Intervertebral Disc Disorder
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Fracture Pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Groin Pain
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mobility Decreased
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal Pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	3 / 192 (1.56%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	2 / 2	3 / 4	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal Pain
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back Pain
subjects affected / exposed	3 / 186 (1.61%)	1 / 257 (0.39%)	4 / 192 (2.08%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	2 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	3 / 186 (1.61%)	1 / 257 (0.39%)	3 / 192 (1.56%)	0 / 192 (0.00%)	3 / 84 (3.57%)
occurrences causally related to treatment / all	3 / 3	2 / 2	0 / 3	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Rheumatoid Arthritis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polymyalgia Rheumatica
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular Weakness
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Osteoarthritis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis Streptococcal
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chorioretinitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Pneumonia
subjects affected / exposed	3 / 186 (1.61%)	4 / 257 (1.56%)	0 / 192 (0.00%)	3 / 192 (1.56%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
Cellulitis
subjects affected / exposed	1 / 186 (0.54%)	2 / 257 (0.78%)	0 / 192 (0.00%)	2 / 192 (1.04%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 2	1 / 4	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 186 (0.00%)	4 / 257 (1.56%)	1 / 192 (0.52%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary Tract Infection
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	3 / 192 (1.56%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Campylobacter Gastroenteritis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Herpes Zoster
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Gastroenteritis
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	2 / 192 (1.04%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal Sepsis
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Infected Seroma
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia Sepsis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Diverticulitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Peritonsillar Abscess
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal Sepsis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal Infection
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 186 (0.54%)	3 / 257 (1.17%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Tract Infection
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium Difficile Colitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myelitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal Abscess
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasopharyngitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin Infection
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver Abscess
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Zika virus infection
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	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
Pyelonephritis acute
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 186 (0.54%)	2 / 257 (0.78%)	2 / 192 (1.04%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 4	3 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
Decreased Appetite
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Hyperlipidaemia
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 186 (0.00%)	0 / 257 (0.00%)	3 / 192 (1.56%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 186 (0.54%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	0 / 192 (0.00%)	0 / 192 (0.00%)	0 / 84 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	1 / 84 (1.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1: Vemurafenib 960 mg BID	Part 2: LGX818 300 mg QD+MEK162 45 mg BID (Combo 300)	Part 1: LGX818 300 mg	Part 1: LGX818 450 mg QD+MEK162 45 mg BID (Combo 450)	Part 2: LGX818 300 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	185 / 186 (99.46%)	152 / 257 (59.14%)	190 / 192 (98.96%)	189 / 192 (98.44%)	82 / 84 (97.62%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	32 / 186 (17.20%)	18 / 257 (7.00%)	21 / 192 (10.94%)	16 / 192 (8.33%)	13 / 84 (15.48%)
occurrences all number	46	22	27	18	13
Seborrhoeic keratosis
subjects affected / exposed	13 / 186 (6.99%)	6 / 257 (2.33%)	13 / 192 (6.77%)	12 / 192 (6.25%)	5 / 84 (5.95%)
occurrences all number	16	8	14	18	6
Keratoacanthoma
subjects affected / exposed	22 / 186 (11.83%)	5 / 257 (1.95%)	15 / 192 (7.81%)	8 / 192 (4.17%)	10 / 84 (11.90%)
occurrences all number	25	6	17	11	14
Melanocytic naevus
subjects affected / exposed	7 / 186 (3.76%)	6 / 257 (2.33%)	18 / 192 (9.38%)	6 / 192 (3.13%)	6 / 84 (7.14%)
occurrences all number	10	6	31	7	6
Squamous cell carcinoma
subjects affected / exposed	10 / 186 (5.38%)	0 / 257 (0.00%)	3 / 192 (1.56%)	3 / 192 (1.56%)	0 / 84 (0.00%)
occurrences all number	18	0	3	3	0
Vascular disorders
Hypertension
subjects affected / exposed	24 / 186 (12.90%)	38 / 257 (14.79%)	12 / 192 (6.25%)	36 / 192 (18.75%)	5 / 84 (5.95%)
occurrences all number	44	71	19	53	5
General disorders and administration site conditions
Fatigue
subjects affected / exposed	56 / 186 (30.11%)	67 / 257 (26.07%)	51 / 192 (26.56%)	57 / 192 (29.69%)	26 / 84 (30.95%)
occurrences all number	90	92	77	100	37
Asthenia
subjects affected / exposed	35 / 186 (18.82%)	45 / 257 (17.51%)	42 / 192 (21.88%)	44 / 192 (22.92%)	16 / 84 (19.05%)
occurrences all number	72	81	74	103	22
Pyrexia
subjects affected / exposed	54 / 186 (29.03%)	50 / 257 (19.46%)	32 / 192 (16.67%)	36 / 192 (18.75%)	13 / 84 (15.48%)
occurrences all number	68	87	48	63	31
Oedema peripheral
subjects affected / exposed	20 / 186 (10.75%)	36 / 257 (14.01%)	18 / 192 (9.38%)	25 / 192 (13.02%)	5 / 84 (5.95%)
occurrences all number	28	42	22	40	8
Influenza like illness
subjects affected / exposed	3 / 186 (1.61%)	14 / 257 (5.45%)	15 / 192 (7.81%)	12 / 192 (6.25%)	2 / 84 (2.38%)
occurrences all number	5	17	17	20	2
Xerosis
subjects affected / exposed	8 / 186 (4.30%)	2 / 257 (0.78%)	17 / 192 (8.85%)	5 / 192 (2.60%)	1 / 84 (1.19%)
occurrences all number	11	2	23	7	1
Chills
subjects affected / exposed	10 / 186 (5.38%)	16 / 257 (6.23%)	13 / 192 (6.77%)	9 / 192 (4.69%)	3 / 84 (3.57%)
occurrences all number	13	19	14	9	5
Pain
subjects affected / exposed	0 / 186 (0.00%)	9 / 257 (3.50%)	0 / 192 (0.00%)	0 / 192 (0.00%)	7 / 84 (8.33%)
occurrences all number	0	10	0	0	8
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	15 / 186 (8.06%)	21 / 257 (8.17%)	24 / 192 (12.50%)	24 / 192 (12.50%)	5 / 84 (5.95%)
occurrences all number	17	27	34	32	8
Dyspnoea
subjects affected / exposed	14 / 186 (7.53%)	12 / 257 (4.67%)	10 / 192 (5.21%)	20 / 192 (10.42%)	7 / 84 (8.33%)
occurrences all number	18	16	10	28	7
Oropharyngeal pain
subjects affected / exposed	12 / 186 (6.45%)	6 / 257 (2.33%)	10 / 192 (5.21%)	7 / 192 (3.65%)	5 / 84 (5.95%)
occurrences all number	16	8	10	8	5
Psychiatric disorders
Anxiety
subjects affected / exposed	4 / 186 (2.15%)	11 / 257 (4.28%)	8 / 192 (4.17%)	18 / 192 (9.38%)	7 / 84 (8.33%)
occurrences all number	4	12	8	21	8
Insomnia
subjects affected / exposed	15 / 186 (8.06%)	20 / 257 (7.78%)	37 / 192 (19.27%)	23 / 192 (11.98%)	14 / 84 (16.67%)
occurrences all number	17	21	50	35	18
Depression
subjects affected / exposed	3 / 186 (1.61%)	5 / 257 (1.95%)	10 / 192 (5.21%)	6 / 192 (3.13%)	1 / 84 (1.19%)
occurrences all number	3	5	11	7	1
Investigations
Blood creatinine increased
subjects affected / exposed	12 / 186 (6.45%)	14 / 257 (5.45%)	4 / 192 (2.08%)	14 / 192 (7.29%)	1 / 84 (1.19%)
occurrences all number	18	23	4	28	2
Blood creatine phosphokinase increased
subjects affected / exposed	4 / 186 (2.15%)	67 / 257 (26.07%)	4 / 192 (2.08%)	52 / 192 (27.08%)	0 / 84 (0.00%)
occurrences all number	5	228	4	142	0
Gamma-glutamyltransferase increased
subjects affected / exposed	20 / 186 (10.75%)	44 / 257 (17.12%)	22 / 192 (11.46%)	30 / 192 (15.63%)	7 / 84 (8.33%)
occurrences all number	27	100	41	68	11
Alanine aminotransferase increased
subjects affected / exposed	15 / 186 (8.06%)	36 / 257 (14.01%)	11 / 192 (5.73%)	23 / 192 (11.98%)	1 / 84 (1.19%)
occurrences all number	20	66	16	41	1
Aspartate aminotransferase increased
subjects affected / exposed	15 / 186 (8.06%)	27 / 257 (10.51%)	9 / 192 (4.69%)	19 / 192 (9.90%)	1 / 84 (1.19%)
occurrences all number	17	52	10	27	1
Blood alkaline phosphatase increased
subjects affected / exposed	10 / 186 (5.38%)	16 / 257 (6.23%)	6 / 192 (3.13%)	16 / 192 (8.33%)	2 / 84 (2.38%)
occurrences all number	12	25	7	17	3
Ejection fraction decreased
subjects affected / exposed	1 / 186 (0.54%)	0 / 257 (0.00%)	4 / 192 (2.08%)	12 / 192 (6.25%)	0 / 84 (0.00%)
occurrences all number	1	0	4	22	0
Weight decreased
subjects affected / exposed	20 / 186 (10.75%)	10 / 257 (3.89%)	30 / 192 (15.63%)	7 / 192 (3.65%)	8 / 84 (9.52%)
occurrences all number	31	13	39	12	9
Blood bilirubin increased
subjects affected / exposed	14 / 186 (7.53%)	0 / 257 (0.00%)	0 / 192 (0.00%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences all number	29	0	0	2	0
Injury, poisoning and procedural complications
Sunburn
subjects affected / exposed	20 / 186 (10.75%)	0 / 257 (0.00%)	1 / 192 (0.52%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences all number	40	0	1	2	0
Fall
subjects affected / exposed	1 / 186 (0.54%)	13 / 257 (5.06%)	4 / 192 (2.08%)	11 / 192 (5.73%)	2 / 84 (2.38%)
occurrences all number	1	18	4	14	2
Nervous system disorders
Headache
subjects affected / exposed	38 / 186 (20.43%)	50 / 257 (19.46%)	56 / 192 (29.17%)	52 / 192 (27.08%)	24 / 84 (28.57%)
occurrences all number	56	79	77	79	38
Dizziness
subjects affected / exposed	8 / 186 (4.30%)	28 / 257 (10.89%)	11 / 192 (5.73%)	32 / 192 (16.67%)	5 / 84 (5.95%)
occurrences all number	11	40	17	46	7
Dysgeusia
subjects affected / exposed	16 / 186 (8.60%)	10 / 257 (3.89%)	22 / 192 (11.46%)	11 / 192 (5.73%)	6 / 84 (7.14%)
occurrences all number	20	12	25	15	6
Paraesthesia
subjects affected / exposed	12 / 186 (6.45%)	9 / 257 (3.50%)	18 / 192 (9.38%)	19 / 192 (9.90%)	8 / 84 (9.52%)
occurrences all number	16	9	20	28	9
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	19 / 186 (10.22%)	35 / 257 (13.62%)	15 / 192 (7.81%)	39 / 192 (20.31%)	6 / 84 (7.14%)
occurrences all number	46	61	53	100	13
Neutropenia
subjects affected / exposed	3 / 186 (1.61%)	14 / 257 (5.45%)	3 / 192 (1.56%)	10 / 192 (5.21%)	0 / 84 (0.00%)
occurrences all number	3	23	3	20	0
Eye disorders
Cataract
subjects affected / exposed	8 / 186 (4.30%)	16 / 257 (6.23%)	7 / 192 (3.65%)	17 / 192 (8.85%)	2 / 84 (2.38%)
occurrences all number	9	17	9	21	2
Retinal detachment
subjects affected / exposed	0 / 186 (0.00%)	15 / 257 (5.84%)	2 / 192 (1.04%)	14 / 192 (7.29%)	0 / 84 (0.00%)
occurrences all number	0	25	6	41	0
Vision blurred
subjects affected / exposed	4 / 186 (2.15%)	29 / 257 (11.28%)	4 / 192 (2.08%)	30 / 192 (15.63%)	2 / 84 (2.38%)
occurrences all number	5	36	4	39	2
Macular oedema
subjects affected / exposed	2 / 186 (1.08%)	0 / 257 (0.00%)	0 / 192 (0.00%)	13 / 192 (6.77%)	0 / 84 (0.00%)
occurrences all number	2	0	0	22	0
Dry eye
subjects affected / exposed	13 / 186 (6.99%)	12 / 257 (4.67%)	14 / 192 (7.29%)	16 / 192 (8.33%)	1 / 84 (1.19%)
occurrences all number	14	12	17	20	1
Blepharitis
subjects affected / exposed	11 / 186 (5.91%)	10 / 257 (3.89%)	10 / 192 (5.21%)	11 / 192 (5.73%)	4 / 84 (4.76%)
occurrences all number	12	13	13	13	4
Lacrimation increased
subjects affected / exposed	0 / 186 (0.00%)	1 / 257 (0.39%)	0 / 192 (0.00%)	0 / 192 (0.00%)	5 / 84 (5.95%)
occurrences all number	0	1	0	0	5
Visual impairment
subjects affected / exposed	4 / 186 (2.15%)	0 / 257 (0.00%)	8 / 192 (4.17%)	10 / 192 (5.21%)	0 / 84 (0.00%)
occurrences all number	4	0	11	13	0
Visual field defect
subjects affected / exposed	3 / 186 (1.61%)	13 / 257 (5.06%)	5 / 192 (2.60%)	18 / 192 (9.38%)	1 / 84 (1.19%)
occurrences all number	3	13	8	27	1
Gastrointestinal disorders
Vomiting
subjects affected / exposed	29 / 186 (15.59%)	53 / 257 (20.62%)	51 / 192 (26.56%)	65 / 192 (33.85%)	19 / 84 (22.62%)
occurrences all number	40	90	71	134	27
Constipation
subjects affected / exposed	13 / 186 (6.99%)	53 / 257 (20.62%)	32 / 192 (16.67%)	50 / 192 (26.04%)	11 / 84 (13.10%)
occurrences all number	14	64	43	70	13
Abdominal pain
subjects affected / exposed	13 / 186 (6.99%)	32 / 257 (12.45%)	14 / 192 (7.29%)	35 / 192 (18.23%)	5 / 84 (5.95%)
occurrences all number	19	45	20	57	7
Abdominal pain upper
subjects affected / exposed	20 / 186 (10.75%)	40 / 257 (15.56%)	18 / 192 (9.38%)	25 / 192 (13.02%)	5 / 84 (5.95%)
occurrences all number	25	50	20	39	7
Dyspepsia
subjects affected / exposed	8 / 186 (4.30%)	0 / 257 (0.00%)	9 / 192 (4.69%)	17 / 192 (8.85%)	0 / 84 (0.00%)
occurrences all number	8	0	12	21	0
Stomatitis
subjects affected / exposed	11 / 186 (5.91%)	9 / 257 (3.50%)	17 / 192 (8.85%)	8 / 192 (4.17%)	4 / 84 (4.76%)
occurrences all number	12	9	25	11	5
Dysphagia
subjects affected / exposed	10 / 186 (5.38%)	0 / 257 (0.00%)	7 / 192 (3.65%)	4 / 192 (2.08%)	0 / 84 (0.00%)
occurrences all number	11	0	7	4	0
Diarrhoea
subjects affected / exposed	64 / 186 (34.41%)	92 / 257 (35.80%)	29 / 192 (15.10%)	75 / 192 (39.06%)	8 / 84 (9.52%)
occurrences all number	135	184	33	213	14
Nausea
subjects affected / exposed	65 / 186 (34.95%)	73 / 257 (28.40%)	69 / 192 (35.94%)	84 / 192 (43.75%)	27 / 84 (32.14%)
occurrences all number	78	113	96	184	34
Skin and subcutaneous tissue disorders
Keratosis pilaris
subjects affected / exposed	43 / 186 (23.12%)	8 / 257 (3.11%)	33 / 192 (17.19%)	9 / 192 (4.69%)	10 / 84 (11.90%)
occurrences all number	52	8	40	13	10
Dry skin
subjects affected / exposed	43 / 186 (23.12%)	26 / 257 (10.12%)	58 / 192 (30.21%)	34 / 192 (17.71%)	19 / 84 (22.62%)
occurrences all number	49	30	83	42	20
Hyperkeratosis
subjects affected / exposed	54 / 186 (29.03%)	29 / 257 (11.28%)	76 / 192 (39.58%)	29 / 192 (15.10%)	36 / 84 (42.86%)
occurrences all number	91	34	148	46	76
Rash
subjects affected / exposed	67 / 186 (36.02%)	30 / 257 (11.67%)	49 / 192 (25.52%)	36 / 192 (18.75%)	27 / 84 (32.14%)
occurrences all number	107	43	70	46	38
Alopecia
subjects affected / exposed	70 / 186 (37.63%)	36 / 257 (14.01%)	108 / 192 (56.25%)	29 / 192 (15.10%)	29 / 84 (34.52%)
occurrences all number	76	38	142	33	41
Pruritus
subjects affected / exposed	41 / 186 (22.04%)	28 / 257 (10.89%)	59 / 192 (30.73%)	28 / 192 (14.58%)	19 / 84 (22.62%)
occurrences all number	47	43	80	45	22
Palmoplantar keratoderma
subjects affected / exposed	33 / 186 (17.74%)	20 / 257 (7.78%)	51 / 192 (26.56%)	19 / 192 (9.90%)	17 / 84 (20.24%)
occurrences all number	49	26	98	30	27
Erythema
subjects affected / exposed	33 / 186 (17.74%)	19 / 257 (7.39%)	32 / 192 (16.67%)	17 / 192 (8.85%)	13 / 84 (15.48%)
occurrences all number	59	25	38	22	17
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	26 / 186 (13.98%)	13 / 257 (5.06%)	99 / 192 (51.56%)	16 / 192 (8.33%)	32 / 84 (38.10%)
occurrences all number	34	19	300	22	95
Skin hyperpigmentation
subjects affected / exposed	3 / 186 (1.61%)	3 / 257 (1.17%)	16 / 192 (8.33%)	4 / 192 (2.08%)	4 / 84 (4.76%)
occurrences all number	3	3	19	4	4
Rash maculo-papular
subjects affected / exposed	27 / 186 (14.52%)	12 / 257 (4.67%)	18 / 192 (9.38%)	6 / 192 (3.13%)	3 / 84 (3.57%)
occurrences all number	50	19	22	7	5
Actinic keratosis
subjects affected / exposed	10 / 186 (5.38%)	0 / 257 (0.00%)	6 / 192 (3.13%)	10 / 192 (5.21%)	0 / 84 (0.00%)
occurrences all number	14	0	7	11	0
Photosensitivity reaction
subjects affected / exposed	47 / 186 (25.27%)	0 / 257 (0.00%)	7 / 192 (3.65%)	7 / 192 (3.65%)	0 / 84 (0.00%)
occurrences all number	71	0	7	9	0
Rash papular
subjects affected / exposed	7 / 186 (3.76%)	4 / 257 (1.56%)	12 / 192 (6.25%)	5 / 192 (2.60%)	2 / 84 (2.38%)
occurrences all number	7	6	12	8	3
Vitiligo
subjects affected / exposed	0 / 186 (0.00%)	11 / 257 (4.28%)	0 / 192 (0.00%)	0 / 192 (0.00%)	5 / 84 (5.95%)
occurrences all number	0	13	0	0	6
Solar dermatitis
subjects affected / exposed	17 / 186 (9.14%)	0 / 257 (0.00%)	1 / 192 (0.52%)	1 / 192 (0.52%)	0 / 84 (0.00%)
occurrences all number	23	0	1	1	0
Skin lesion
subjects affected / exposed	14 / 186 (7.53%)	0 / 257 (0.00%)	8 / 192 (4.17%)	5 / 192 (2.60%)	0 / 84 (0.00%)
occurrences all number	16	0	8	5	0
Skin exfoliation
subjects affected / exposed	4 / 186 (2.15%)	1 / 257 (0.39%)	11 / 192 (5.73%)	2 / 192 (1.04%)	0 / 84 (0.00%)
occurrences all number	4	1	12	2	0
Papule
subjects affected / exposed	0 / 186 (0.00%)	4 / 257 (1.56%)	0 / 192 (0.00%)	0 / 192 (0.00%)	5 / 84 (5.95%)
occurrences all number	0	5	0	0	5
Hair texture abnormal
subjects affected / exposed	7 / 186 (3.76%)	7 / 257 (2.72%)	10 / 192 (5.21%)	7 / 192 (3.65%)	2 / 84 (2.38%)
occurrences all number	7	7	10	7	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	86 / 186 (46.24%)	74 / 257 (28.79%)	96 / 192 (50.00%)	64 / 192 (33.33%)	39 / 84 (46.43%)
occurrences all number	162	121	227	123	68
Myalgia
subjects affected / exposed	34 / 186 (18.28%)	38 / 257 (14.79%)	55 / 192 (28.65%)	32 / 192 (16.67%)	22 / 84 (26.19%)
occurrences all number	47	47	105	47	38
Pain in extremity
subjects affected / exposed	27 / 186 (14.52%)	38 / 257 (14.79%)	44 / 192 (22.92%)	24 / 192 (12.50%)	14 / 84 (16.67%)
occurrences all number	42	53	78	39	38
Back pain
subjects affected / exposed	10 / 186 (5.38%)	51 / 257 (19.84%)	33 / 192 (17.19%)	30 / 192 (15.63%)	8 / 84 (9.52%)
occurrences all number	11	67	40	44	11
Muscle spasms
subjects affected / exposed	4 / 186 (2.15%)	25 / 257 (9.73%)	7 / 192 (3.65%)	26 / 192 (13.54%)	1 / 84 (1.19%)
occurrences all number	8	37	11	35	1
Musculoskeletal pain
subjects affected / exposed	4 / 186 (2.15%)	5 / 257 (1.95%)	12 / 192 (6.25%)	11 / 192 (5.73%)	6 / 84 (7.14%)
occurrences all number	5	7	19	14	10
Muscular weakness
subjects affected / exposed	4 / 186 (2.15%)	5 / 257 (1.95%)	7 / 192 (3.65%)	11 / 192 (5.73%)	5 / 84 (5.95%)
occurrences all number	5	5	9	13	8
Infections and infestations
Nasopharyngitis
subjects affected / exposed	20 / 186 (10.75%)	35 / 257 (13.62%)	15 / 192 (7.81%)	28 / 192 (14.58%)	7 / 84 (8.33%)
occurrences all number	33	63	33	56	11
Upper respiratory tract infection
subjects affected / exposed	7 / 186 (3.76%)	19 / 257 (7.39%)	8 / 192 (4.17%)	19 / 192 (9.90%)	3 / 84 (3.57%)
occurrences all number	7	34	19	28	3
Influenza
subjects affected / exposed	10 / 186 (5.38%)	0 / 257 (0.00%)	9 / 192 (4.69%)	12 / 192 (6.25%)	0 / 84 (0.00%)
occurrences all number	12	0	10	15	0
Folliculitis
subjects affected / exposed	10 / 186 (5.38%)	0 / 257 (0.00%)	8 / 192 (4.17%)	7 / 192 (3.65%)	0 / 84 (0.00%)
occurrences all number	11	0	11	7	0
Conjunctivitis
subjects affected / exposed	15 / 186 (8.06%)	9 / 257 (3.50%)	9 / 192 (4.69%)	8 / 192 (4.17%)	6 / 84 (7.14%)
occurrences all number	19	9	11	9	7
Oral candidiasis
subjects affected / exposed	0 / 186 (0.00%)	6 / 257 (2.33%)	0 / 192 (0.00%)	0 / 192 (0.00%)	5 / 84 (5.95%)
occurrences all number	0	8	0	0	6
Urinary tract infection
subjects affected / exposed	5 / 186 (2.69%)	21 / 257 (8.17%)	8 / 192 (4.17%)	14 / 192 (7.29%)	6 / 84 (7.14%)
occurrences all number	5	32	11	20	8
Gastroenteritis
subjects affected / exposed	3 / 186 (1.61%)	0 / 257 (0.00%)	2 / 192 (1.04%)	10 / 192 (5.21%)	0 / 84 (0.00%)
occurrences all number	4	0	2	11	0
Bronchitis
subjects affected / exposed	6 / 186 (3.23%)	0 / 257 (0.00%)	7 / 192 (3.65%)	10 / 192 (5.21%)	0 / 84 (0.00%)
occurrences all number	6	0	9	12	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	36 / 186 (19.35%)	30 / 257 (11.67%)	41 / 192 (21.35%)	21 / 192 (10.94%)	12 / 84 (14.29%)
occurrences all number	43	42	50	26	18
Hyperglycaemia
subjects affected / exposed	2 / 186 (1.08%)	14 / 257 (5.45%)	6 / 192 (3.13%)	14 / 192 (7.29%)	2 / 84 (2.38%)
occurrences all number	8	34	9	35	2

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A 2-part Phase III Randomized, Open Label, Multicenter Study of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) in Combo 450 Group as Compared to Vemurafenib Group

Primary: Part 1: Progression Free Survival (PFS) by Blinded Independent Review Committee (BIRC) in Combo 450 Group as Compared to Vemurafenib Group

Primary: Part 1: PFS by BIRC in Combo 450 Group as Compared to LGX818 Group

Primary: Part 1: PFS by BIRC in Combo 450 Group as Compared to LGX818 Group

Secondary: Part 2: PFS by BIRC in Combo 300 Group as Compared to LGX818 Group

Secondary: Part 2: PFS by BIRC in Combo 300 Group as Compared to LGX818 Group

Secondary: Part 1: Percentage of Subject With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Part 1: Percentage of Subject With Adverse Events (AEs) and Serious Adverse Events (SAEs) as Graded by National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Part 1: Overall Survival (OS)

Secondary: Part 1: Overall Survival (OS)

Secondary: Part 1: Number of Subjects With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.03

Secondary: Part 1: Number of Subjects With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.03

Secondary: Part 1: Number of Subjects With Newly Occurring Notable Abnormal Vital Signs

Secondary: Part 1: Number of Subjects With Newly Occurring Notable Abnormal Vital Signs

Secondary: Part 1: Number of Subjects With Newly Occurring Notable Electrocardiogram (ECG) Values

Secondary: Part 1: Number of Subjects With Newly Occurring Notable Electrocardiogram (ECG) Values

Secondary: Part 1: Number of Subjects With Worst Post-baseline Left Ventricular Dysfunction Events (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade

Secondary: Part 1: Number of Subjects With Worst Post-baseline Left Ventricular Dysfunction Events (LVEF) Values by Multigated Acquisition (MUGA) Scans or Transthoracic Echocardiograms (ECHO), by CTCAE Grade

Secondary: Part 1: Number of Subjects With Dermatologic-Related Adverse Events of Special Interest (AESI) Graded According to the NCI-CTCAE Version 4.03

Secondary: Part 1: Number of Subjects With Dermatologic-Related Adverse Events of Special Interest (AESI) Graded According to the NCI-CTCAE Version 4.03

Secondary: Part 2: Percentage of Subjects With AEs and SAEs as Graded by NCI-CTCAE Version 4.03

Secondary: Part 2: Percentage of Subjects With AEs and SAEs as Graded by NCI-CTCAE Version 4.03

Secondary: Part 1: Number of Subjects With Ocular-Related AESI Graded According to the NCI-CTCAE Version 4.03

Secondary: Part 1: Number of Subjects With Ocular-Related AESI Graded According to the NCI-CTCAE Version 4.03

Secondary: Part 2: Number of Subjects With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.0

Secondary: Part 2: Number of Subjects With Clinically Notable Shift From Baseline in Laboratory Parameter Values Based on NCI-CTCAE Grade, Version 4.0

Secondary: Part 2: Number of Subjects With Newly Occurring Notable Abnormal Vital Signs

Secondary: Part 2: Number of Subjects With Newly Occurring Notable Abnormal Vital Signs

Secondary: Part 2: Number of Subjects With Newly Occurring Notable ECG Values

Secondary: Part 2: Number of Subjects With Newly Occurring Notable ECG Values

Secondary: Part 2: Number of Subjects With Worst Post-baseline LVEF Values by MUGA Scans or Transthoracic ECHO, by CTCAE Grade

Secondary: Part 2: Number of Subjects With Worst Post-baseline LVEF Values by MUGA Scans or Transthoracic ECHO, by CTCAE Grade

Secondary: Part 2: Number of Subjects With Dermatologic-Related AESI Graded According to the NCI-CTCAE Version 4.03

Secondary: Part 2: Number of Subjects With Dermatologic-Related AESI Graded According to the NCI-CTCAE Version 4.03

Secondary: Part 2: Number of Subjects With Ocular-Related AESI Graded According to the NCI-CTCAE Version 4.03

Secondary: Part 2: Number of Subjects With Ocular-Related AESI Graded According to the NCI-CTCAE Version 4.03

Secondary: Part 2: Overall Survival (OS)

Secondary: Part 2: Overall Survival (OS)

Secondary: Part 1 and Part 2: Objective Response Rate (ORR)

Secondary: Part 1 and Part 2: Objective Response Rate (ORR)

Secondary: Part 1 and Part 2: Disease Control Rate (DCR)

Secondary: Part 1 and Part 2: Disease Control Rate (DCR)

Secondary: Part 1 and Part 2: Time to Objective Response (TTR)

Secondary: Part 1 and Part 2: Time to Objective Response (TTR)

Secondary: Part 1 and Part 2: Duration of Response (DOR)

Secondary: Part 1 and Part 2: Duration of Response (DOR)

Secondary: Part 1 and Part 2: Time to Definitive 10% Deterioration in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale

Secondary: Part 1 and Part 2: Time to Definitive 10% Deterioration in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale

Secondary: Part 1 and Part 2: Change From Baseline in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in the Function Assessment Cancer Therapy-melanoma (FACT-M) Subscale at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Time to Definitive 10% Deterioration in the Global Health Status Score of the European Organization for Research and Treatment of Cancer’s Core quality of Life Questionnaire (EORTC QLQ-C30)

Secondary: Part 1 and Part 2: Time to Definitive 10% Deterioration in the Global Health Status Score of the European Organization for Research and Treatment of Cancer’s Core quality of Life Questionnaire (EORTC QLQ-C30)

Secondary: Part 1 and Part 2: Change From Baseline in EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Index Score at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in EuroQoL-5 Dimension-5 Level (EQ-5D-5L) Index Score at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in Emotional Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in Emotional Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in Physical Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in Physical Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in Social Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Change From Baseline in Social Functioning Scale Score of the EORTC QLQ-C30 at Day 1 of Cycle 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 and End of Treatment Visit

Secondary: Part 1 and Part 2: Number of Subjects With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS)

Secondary: Part 1 and Part 2: Number of Subjects With Change From Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS)

Secondary: Part 1: Plasma Concentrations of LGX 818

Secondary: Part 1: Plasma Concentrations of LGX 818

Secondary: Part 2: Plasma Concentrations of LGX 818

Secondary: Part 2: Plasma Concentrations of LGX 818

Secondary: Part 1: Plasma Concentrations of MEK162

Secondary: Part 1: Plasma Concentrations of MEK162

Clinical Trial Results:
A 2-part Phase III Randomized, Open Label, Multicenter Study of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma