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Clinical Trial Results:
A Phase Ib/II, multicenter, open-label study of EGF816 in combination with INC280 in adult subjects with EGFR mutated non-small cell lung cancer

Summary
EudraCT number	2014-000726-37
Trial protocol	DE ES FR IT
Global end of trial date	11 May 2022

Results information
Results version number	v2(current)
This version publication date	05 Mar 2023
First version publication date	26 Jan 2023
Other versions	v1
Version creation reason	Correction of full data set Alignement with Clinicaltrials.gov information

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

CINC280X2105C

ISRCTN number

US NCT number

NCT02335944

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis Campus, Basel, Switzerland,

Public contact

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

Scientific contact

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

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

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

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

Analysis stage

Final

Date of interim/final analysis

10 Nov 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 May 2022

Was the trial ended prematurely?

Yes

Main objective of the trial

The purpose of this study was to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of nazartinib in combination with capmatinib and to estimate the preliminary anti-tumor activity of nazartinib in combination with capmatinib in participants with advanced non-small cell lung cancer with documented EGFR mutation.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jan 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 8

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Germany: 17

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

Korea, Republic of: 14

Country: Number of subjects enrolled

Norway: 4

Country: Number of subjects enrolled

Singapore: 31

Country: Number of subjects enrolled

Spain: 38

Country: Number of subjects enrolled

Taiwan: 25

Country: Number of subjects enrolled

United States: 6

Worldwide total number of subjects

177

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

112

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in 19 investigative sites in 11 countries. Due to early study termination, Group 5 (Phase II part) was never opened

Screening details

The screening period began once patients had signed the study informed consent. All screening/baseline evaluations were performed ≤ 28 days before Cycle 1 Day 1.

Period 1 title

Treatment Phase (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase IB part- INC280 200mg BID/ EGF816 50mg QD

Arm description

Combination of INC280 200mg twice daily (BID) and EGF816 50mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 200 mg, in fasted state.

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 50 mg, in fasted state

Phase IB part- INC280 200mg BID/ EGF816 100mg QD

Arm description

Combination of INC280 200mg twice daily (BID) and EGF816 100mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 200 mg, in fasted state.

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 100 mg, in fasted state

Phase IB part- INC280 400mg BID/ EGF816 75mg QD

Arm description

Combination of INC280 400mg twice daily (BID) and EGF816 75mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Arm type

Experimental

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 75 mg, in fasted state

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 400 mg, in fasted state.

Phase IB part- INC280 400mg BID/ EGF816 100mg QD

Arm description

Combination of INC280 400mg twice daily (BID) and EGF816 100mg once daily (QD) in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 400 mg, in fasted state.

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 100 mg, in fasted state

Phase IB part- INC280 400mg BID/ EGF816 150mg QD

Arm description

Combination of INC280 400mg twice daily (BID) and EGF816 150mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Arm type

Experimental

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 150 mg, in fasted state

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 400 mg, in fasted state.

Phase II- Group 1

Arm description

NSCLC participants with previously documented activating EGFR mutation, with any T790M and MET dysregulation status, who received 1 to 3 lines of systemic antineoplastic therapy prior to study entry including one line maximum of 1st or 2nd generation EGFR TKI. Participants were treated with 400 mg twice daily for INC280 and 100 mg once daily for EGF816 in fasted state

Arm type

Experimental

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 100 mg, in fasted state

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 400 mg, in fasted state.

Phase II- Group 2

Arm description

NSCLC participants harboring T790M mutation in de novo setting, irrespective of the activating mutation status who received none to 2 lines of systemic antineoplastic therapy prior to study entry, but no therapy known to inhibit EGFR. Participants were treated with 400 mg twice daily for INC280 and 100 mg once daily for EGF816 in fasted state

Arm type

Experimental

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 100 mg, in fasted state

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 400 mg, in fasted state.

Phase II- Group 3

Arm description

NSCLC participants with previously documented EGFR activating mutation, T790M negative, and any MET status who never received any prior line of systemic antineoplastic therapy. Participants were treated with 400 mg twice daily for INC280 and 100 mg once daily for EGF816 in fasted state

Arm type

Experimental

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 100 mg, in fasted state

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 400 mg, in fasted state.

Phase II- Group 4

Arm description

NSCLC participants with previously documented EGFR activating mutations and any T790M and MET status who received none to 2 prior lines of systemic antineoplastic therapy prior to study entry. Participants were treated with 400 mg twice daily for INC280 and 100 mg once daily for EGF816 in fed state.

Arm type

Experimental

Investigational medicinal product name

Nazartinib

Investigational medicinal product code

EGF816

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Nazartinib was administered orally, once a day, at a dose of 100 mg, in fed state

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Capmatinib was administered orally, twice per day, at a dose of 400 mg, in fed state.

Number of subjects in period 1	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3	Phase II- Group 4
Started	4	5	3	16	5	52	3	47	42
Completed	0	0	0	1	0	2	0	5	6
Not completed	4	5	3	15	5	50	3	42	36
Physician decision	-	-	-	1	-	6	1	2	1
Adverse event, non-fatal	2	-	-	2	1	15	-	5	7
Study Terminated By Sponsor	-	-	-	1	-	3	-	1	1
Progressive Disease	2	5	2	11	4	25	2	30	27
Subject/Guardian Decision	-	-	1	-	-	1	-	4	-

Baseline characteristics

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Reporting group title

Phase IB part- INC280 200mg BID/ EGF816 50mg QD

Reporting group description

Combination of INC280 200mg twice daily (BID) and EGF816 50mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 200mg BID/ EGF816 100mg QD

Reporting group description

Combination of INC280 200mg twice daily (BID) and EGF816 100mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 75mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 75mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 100mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 100mg once daily (QD) in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 150mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 150mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase II- Group 1

Reporting group description

Reporting group title

Phase II- Group 2

Reporting group description

Reporting group title

Phase II- Group 3

Reporting group description

Reporting group title

Phase II- Group 4

Reporting group description

Reporting group values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3	Phase II- Group 4	Total
Number of subjects	4	5	3	16	5	52	3	47	42	177
Age Categorical
Units: Participants
<=18 years	0	0	0	0	0	0	0	0	0	0
Between 18 and 65 years	3	5	2	11	3	33	1	30	24	112
>=65 years	1	0	1	5	2	19	2	17	18	65
Sex: Female, Male
Units: Participants
Female	4	3	1	9	4	38	2	33	24	118
Male	0	2	2	7	1	14	1	14	18	59
Race/Ethnicity, Customized
Units: Subjects
Asian	2	3	1	10	4	26	2	30	20	98
Caucasian	2	2	1	4	1	22	1	16	21	70
Missing	0	0	1	2	0	3	0	1	1	8
Black	0	0	0	0	0	1	0	0	0	1

End points

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Reporting group title

Phase IB part- INC280 200mg BID/ EGF816 50mg QD

Reporting group description

Combination of INC280 200mg twice daily (BID) and EGF816 50mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 200mg BID/ EGF816 100mg QD

Reporting group description

Combination of INC280 200mg twice daily (BID) and EGF816 100mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 75mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 75mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 100mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 100mg once daily (QD) in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 150mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 150mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase II- Group 1

Reporting group description

Reporting group title

Phase II- Group 2

Reporting group description

Reporting group title

Phase II- Group 3

Reporting group description

Reporting group title

Phase II- Group 4

Reporting group description

Primary: Phase Ib: Number of participants with dose limiting toxicities (DLTs)

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End point title

Phase Ib: Number of participants with dose limiting toxicities (DLTs) ^[1] ^[2]

End point description

Number of participants with DLTs in the Phase Ib part. A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment with EGF816 in combination with INC280 during the escalation part of the study (Phase Ib)

End point type

Primary

End point timeframe

Up to first 28 days of treatment

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: No statistical analyses were planned for this endpoint
[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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	1	13	5
Units: Participants	1	0	0	1	2

No statistical analyses for this end point

Primary: Phase II Group 1, 2 and 3: Overall Response Rate (ORR) by investigator's assessment per RECIST 1.1

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End point title

Phase II Group 1, 2 and 3: Overall Response Rate (ORR) by investigator's assessment per RECIST 1.1 ^[3] ^[4]

End point description

ORR is defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) determined by investigator's assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). ORR was assessed in Group 1, 2 and 3 (Phase II part). 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 diameters of all target lesions, taking as reference the baseline sum of diameters.

End point type

Primary

End point timeframe

Up to approximately 4 years

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: No statistical analyses were planned for this endpoint
[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 is only applicable for Phase II Groups 1, 2 and 3

End point values	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3
Number of subjects analysed	52	3	47
Units: Percentage of participants
number (confidence interval 95%)	28.8 (17.1 to 43.10)	33.3 (0.8 to 90.6)	61.7 (46.4 to 75.5)

No statistical analyses for this end point

Primary: Phase II Group 4: Number of participants with Adverse Events (AEs) and Serious AEs (SAEs)

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End point title

Phase II Group 4: Number of participants with Adverse Events (AEs) and Serious AEs (SAEs) ^[5] ^[6]

End point description

Number of participants in Group 4 (Phase II part) with AEs and SAEs. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward event resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.

End point type

Primary

End point timeframe

From start of treatment up to 30 days after last dose of study treatment, assessed up to 3.7 years

Notes
[5] - 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: No statistical analyses were planned for this endpoint
[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 is only applicable for Phase II Group 4

End point values	Phase II- Group 4
Number of subjects analysed	42
Units: Participants
AEs	42
SAEs	26

No statistical analyses for this end point

Primary: Phase II Group 4: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

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End point title

Phase II Group 4: Number of participants with dose reductions and dose interruptions of INC280 and EGF618 ^[7] ^[8]

End point description

Number of participants with at least one dose reduction of INC280, at least one dose interruption of INC280, at least one dose reduction of EGF816 and at least one dose interruption of EGF816 in the Group 4 (Phase II part).

End point type

Primary

End point timeframe

From start of treatment until end of treatment, assessed up to 3.6 years

Notes
[7] - 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: No statistical analyses were planned for this endpoint
[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 is only applicable for Phase II Group 4

End point values	Phase II- Group 4
Number of subjects analysed	42
Units: Participants
Dose Reduction of INC280	30
Dose Interruption of INC280	31
Dose Reduction of EGF816	12
Dose Interruption of EGF816	35

No statistical analyses for this end point

Primary: Phase II Group 4: Dose intensity

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End point title

Phase II Group 4: Dose intensity ^[9] ^[10]

End point description

Dose intensity, defined as the ratio of total dose received and actual duration, for participants in Group 4 (Phase II part)

End point type

Primary

End point timeframe

From start of treatment until end of treatment, assessed up to 3.6 years

Notes
[9] - 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: No statistical analyses were planned for this endpoint
[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 is only applicable for Phase II Group 4

End point values	Phase II- Group 4
Number of subjects analysed	42
Units: milligram/day
arithmetic mean (standard deviation)
INC280	666.2 ( 148.97 )
EGF816	87.4 ( 14.82 )

No statistical analyses for this end point

Secondary: Phase Ib: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

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End point title

Phase Ib: Number of participants with dose reductions and dose interruptions of INC280 and EGF618 ^[11]

End point description

Number of participants in Phase Ib with at least one dose reduction of INC280, at least one dose interruption of INC280, at least one dose reduction of EGF816 and at least one dose interruption of EGF816 .

End point type

Secondary

End point timeframe

From start of treatment until end of treatment, assessed up to approximately 5 years

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	16	5
Units: Participants
Dose Reduction of INC280	2	4	2	10	5
Dose Interruption of INC280	2	2	2	12	5
Dose Reduction of EGF816	2	1	1	5	3
Dose Interruption of EGF816	2	2	2	11	5

No statistical analyses for this end point

Secondary: Phase II Group 1, 2 and 3: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

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End point title

Phase II Group 1, 2 and 3: Number of participants with dose reductions and dose interruptions of INC280 and EGF618 ^[12]

End point description

Number of participants in Groups 1, 2 and 3 (Phase II part) with at least one dose reduction of INC280, at least one dose interruption of INC280, at least one dose reduction of EGF816 and at least one dose interruption of EGF816 .

End point type

Secondary

End point timeframe

From start of treatment until end of treatment, assessed up to approximately 4 years

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 is only applicable for Phase II Groups 1, 2 and 3

End point values	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3
Number of subjects analysed	52	3	47
Units: Participants
Dose Reduction of INC280	33	3	34
Dose Interruption of INC280	31	3	39
Dose Reduction of EGF816	17	2	23
Dose Interruption of EGF816	34	3	40

No statistical analyses for this end point

Secondary: Phase Ib: Dose intensity

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End point title

Phase Ib: Dose intensity ^[13]

End point description

Dose intensity, defined as the ratio of total dose received and actual duration, in Phase Ib participants

End point type

Secondary

End point timeframe

From start of treatment until end of treatment, assessed up to approximately 5 years

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	16	5
Units: milligram/day
arithmetic mean (standard deviation)
INC280	319.1 ( 101.09 )	356.9 ( 71.14 )	596.3 ( 200.24 )	658.2 ( 158.18 )	463.4 ( 212.52 )
EGF816	40.0 ( 12.60 )	89.6 ( 17.93 )	60.0 ( 13.36 )	85.2 ( 17.28 )	97.7 ( 36.43 )

No statistical analyses for this end point

Secondary: Phase II Group 1, 2 and 3: Dose intensity

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End point title

Phase II Group 1, 2 and 3: Dose intensity ^[14]

End point description

Dose intensity, defined as the ratio of total dose received and actual duration, in Group 1, 2 and 3 (Phase II)

End point type

Secondary

End point timeframe

From start of treatment until end of treatment, assessed up to approximately 4 years

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 is only applicable for Phase II Groups 1, 2 and 3

End point values	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3
Number of subjects analysed	52	3	47
Units: milligram/day
arithmetic mean (standard deviation)
INC280	662.9 ( 160.73 )	562.9 ( 38.36 )	634.7 ( 172.33 )
EGF816	85.2 ( 18.21 )	76.3 ( 15.31 )	84.8 ( 15.53 )

No statistical analyses for this end point

Secondary: Phase Ib: Overall Response Rate (ORR) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase Ib: Overall Response Rate (ORR) per RECIST 1.1 based on investigator’s assessment ^[15]

End point description

ORR is defined as percentage of participants with best overall response of PR+CR determined by Investigator's assessment in accordance to RECIST 1.1. ORR was assessed in Phase Ib participants. 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 diameters of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

Up to approximately 5 years

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	16	5
Units: Percentage of participants
number (confidence interval 95%)	0 (0.0 to 60.2)	40.0 (5.3 to 85.3)	33.3 (0.8 to 90.6)	50.0 (24.7 to 75.3)	60.0 (14.7 to 94.7)

No statistical analyses for this end point

Secondary: Phase II Group 4: Overall Response Rate (ORR) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase II Group 4: Overall Response Rate (ORR) per RECIST 1.1 based on investigator’s assessment ^[16]

End point description

ORR is defined as percentage of participants with best overall response of PR+CR determined by Investigator's assessment in accordance to RECIST 1.1. ORR was assessed in Group 4 (Phase II) 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 diameters of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

Up to approximately 4 years

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 is only applicable for Phase II Group 4

End point values	Phase II- Group 4
Number of subjects analysed	42
Units: Percentage of participants
number (confidence interval 95%)	42.9 (27.7 to 59.0)

No statistical analyses for this end point

Secondary: Phase Ib: Progression Free Survival (PFS) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase Ib: Progression Free Survival (PFS) per RECIST 1.1 based on investigator’s assessment ^[17]

End point description

PFS is defined as time from date of first dose of study treatment to date of first documented disease progression determined by Investigator assessment in accordance to RECIST 1.1.or death due to any cause. The PFS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, PFS is censored at the date of last adequate tumor assessment. PFS was assessed in Phase Ib participants

End point type

Secondary

End point timeframe

From date of first dose to first documented disease progression or death, assessed up to approximately 5 years

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	16	5
Units: Months
median (confidence interval 95%)	5.6 (3.5 to 999999)	7.4 (1.6 to 999999)	3.5 (0.8 to 999999)	5.7 (1.9 to 42.1)	14.5 (7.3 to 999999)

No statistical analyses for this end point

Secondary: Phase II Groups 1, 2, 3 and 4: Progression Free Survival (PFS) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase II Groups 1, 2, 3 and 4: Progression Free Survival (PFS) per RECIST 1.1 based on investigator’s assessment ^[18]

End point description

End point type

Secondary

End point timeframe

From date of first dose to first documented disease progression or death, assessed up to approximately 4 years

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 is only applicable for Phase II Groups 1, 2, 3 and 4

End point values	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	52	3	47	42
Units: Months
median (confidence interval 95%)	5.6 (3.7 to 7.4)	3.8 (3.7 to 999999)	10.1 (7.6 to 13.8)	10.9 (5.6 to 19.2)

No statistical analyses for this end point

Secondary: Phase Ib: Time to Response (TTR) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase Ib: Time to Response (TTR) per RECIST 1.1 based on investigator’s assessment ^[19]

End point description

TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to RECIST 1.1. The TTR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, duration was censored at the date of last adequate tumor assessment. TTR was assessed in Phase Ib participants. 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 diameters of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

From the date of the first dose to the date of first documented response, up to approximately 5 years

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	16	5
Units: Months
median (confidence interval 95%)	999999 (999999 to 999999)	999999 (1.8 to 999999)	999999 (1.7 to 999999)	3.5 (1.6 to 999999)	4.5 (1.9 to 999999)

No statistical analyses for this end point

Secondary: Phase II Groups 1, 2, 3 and 4: Time to Response (TTR) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase II Groups 1, 2, 3 and 4: Time to Response (TTR) per RECIST 1.1 based on investigator’s assessment ^[20]

End point description

TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to RECIST 1.1. The TTR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, duration was censored at the date of last adequate tumor assessment. TTR was assessed in Group 1, 2, 3 and 4 (Phase II) 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 diameters of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

From the date of the first dose to the date of first documented response, up to approximately 4 years

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 is only applicable for Phase II Groups 1, 2, 3 and 4

End point values	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	52	3	47	42
Units: Months
median (confidence interval 95%)	9999 (5.4 to 999999)	999999 (1.8 to 999999)	1.9 (1.8 to 5.9)	999999 (3.6 to 999999)

No statistical analyses for this end point

Secondary: Phase Ib: Duration of Response (DOR) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase Ib: Duration of Response (DOR) per RECIST 1.1 based on investigator’s assessment ^[21]

End point description

DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression determined by Investigator assessment in accordance to RECIST 1.1 or death due to underlying cancer. The DOR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, duration was censored at the date of last adequate tumor assessment. DOR was assessed in Phase Ib participants 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 diameters of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

From date of first documented response to first documented disease progression or death, assessed up to approximately 5 years

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	0 ^[22]	2	1	8	3
Units: Months
median (confidence interval 95%)	( to )	8.8 (5.6 to 999999)	14.8 (-999999 to 999999)	25.3 (3.6 to 47.9)	8.0 (5.4 to 999999)

Notes
[22] - No participants had a documented response (CR or PR)

No statistical analyses for this end point

Secondary: Phase II Groups 1, 2, 3 and 4: Duration of Response (DOR) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase II Groups 1, 2, 3 and 4: Duration of Response (DOR) per RECIST 1.1 based on investigator’s assessment ^[23]

End point description

DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression determined by Investigator assessment in accordance to RECIST 1.1 or death due to underlying cancer. The DOR distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant has not had an event, duration was censored at the date of last adequate tumor assessment. DOR was assessed in Group 1, 2, 3 and 4 (Phase II) 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 diameters of all target lesions, taking as reference the baseline sum of diameters.

End point type

Secondary

End point timeframe

From date of first documented response to first documented disease progression or deaths, assessed up to approximately 4 years

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 is only applicable for Phase II Groups 1, 2, 3 and 4

End point values	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	15	1	29	18
Units: Months
median (confidence interval 95%)	6.5 (3.7 to 10.8)	12.0 (-999999 to 999999)	11.6 (6.6 to 17.5)	14.5 (9.2 to 999999)

No statistical analyses for this end point

Secondary: Phase Ib: Disease Control Rate (DCR) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase Ib: Disease Control Rate (DCR) per RECIST 1.1 based on investigator’s assessment ^[24]

End point description

DCR is defined as the percentage of participants with best overall response of CR, PR, or stable disease (SD) determined by Investigator assessment in accordance to RECIST 1.1. DCR was assessed in Phase Ib participants 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 diameters of all target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression.

End point type

Secondary

End point timeframe

Up to approximately 5 years

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	16	5
Units: Percentage of participants
number (confidence interval 95%)	100 (39.8 to 100)	60.0 (14.7 to 94.7)	33.3 (0.8 to 90.6)	62.5 (35.4 to 84.8)	80.0 (28.4 to 99.5)

No statistical analyses for this end point

Secondary: Phase II Group 1, 2 3 and 4: Disease Control Rate (DCR) per RECIST 1.1 based on investigator’s assessment

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End point title

Phase II Group 1, 2 3 and 4: Disease Control Rate (DCR) per RECIST 1.1 based on investigator’s assessment ^[25]

End point description

DCR is defined as the percentage of participants with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to RECIST 1.1. DCR was assessed in Group 1, 2, 3 and 4 (Phase II) 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 diameters of all target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression.

End point type

Secondary

End point timeframe

Up to approximately 4 years

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 is only applicable for Phase II Groups 1, 2, 3 and 4

End point values	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	52	3	47	42
Units: Percentage of participants
number (confidence interval 95%)	59.6 (45.1 to 73.0)	100 (29.2 to 100)	93.6 (82.5 to 98.7)	81.0 (65.9 to 91.4)

No statistical analyses for this end point

Secondary: Phase Ib: Overall Survival (OS)

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End point title

Phase Ib: Overall Survival (OS) ^[26]

End point description

OS is defined as the time from first dose of the study treatment to the date of death due to any cause. The OS distribution was estimated using the Kaplan-Meier method and associated 95% confidence intervals were calculated. If a participant was not known to have died, survival was censored at the date of last contact. OS was assessed in Phase Ib participants

End point type

Secondary

End point timeframe

From date of first dose to death, assessed up to approximately 5 years

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	16	5
Units: Months
median (confidence interval 95%)	10.1 (8.1 to 999999)	56.5 (6.5 to 999999)	7.0 (1.1 to 999999)	17.2 (5.7 to 58.7)	31.5 (16.6 to 999999)

No statistical analyses for this end point

Secondary: Phase II Groups 1, 2, 3 and 4: Overall Survival (OS)

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End point title

Phase II Groups 1, 2, 3 and 4: Overall Survival (OS) ^[27]

End point description

End point type

Secondary

End point timeframe

From date of first dose to death, assessed up to approximately 4 years

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 is only applicable for Phase II Groups 1, 2 3 and 4

End point values	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	52	3	47	42
Units: Months
median (confidence interval 95%)	18.8 (14.9 to 26.0)	5.6 (3.7 to 999999)	25.6 (18.8 to 33.0)	28.9 (20.5 to 999999)

No statistical analyses for this end point

Secondary: Phase Ib: Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) of INC280

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End point title

Phase Ib: Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) of INC280 ^[28]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)

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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	1	12	3
Units: hoursnanogram/mililiter (hrng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n= 3 / 5 / 1 / 12 / 3)	12300 ( 4710 )	10500 ( 4320 )	38300 ( 999999 )	22200 ( 10700 )	23000 ( 11600 )
Cycle 1 Day 15 (n= 3 / 5 / 1 / 11 / 2)	11600 ( 3400 )	11800 ( 3360 )	48800 ( 999999 )	28900 ( 12700 )	23000 ( 3440 )
Cycle 2 Day 1 (n= 3 / 5 / 0 / 9 / 2)	11300 ( 4050 )	11100 ( 1770 )	999999 ( 999999 )	21600 ( 7370 )	24900 ( 5190 )

No statistical analyses for this end point

Secondary: Phase Ib: Peak plasma concentration (Cmax) of INC280

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End point title

Phase Ib: Peak plasma concentration (Cmax) of INC280 ^[29]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[29] - 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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	1	12	3
Units: nanogram/mililiter (ng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n= 4 / 5 / 1 / 12 / 3)	3630 ( 588 )	2530 ( 1080 )	8000 ( 999999 )	5100 ( 2550 )	5930 ( 1330 )
Cycle 1 Day 15 (n= 3 / 5 / 1 / 11 / 2)	3070 ( 1120 )	2840 ( 1350 )	12000 ( 999999 )	5780 ( 2640 )	4350 ( 933 )
Cycle 2 Day 1 (N= 3 / 5 / 0 / 10 / 2)	3590 ( 1620 )	2800 ( 797 )	999999 ( 999999 )	4830 ( 1390 )	6370 ( 1060 )

No statistical analyses for this end point

Secondary: Phase Ib: Time to reach maximum concentration (Tmax) of INC280

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End point title

Phase Ib: Time to reach maximum concentration (Tmax) of INC280 ^[30]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[30] - 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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	1	12	3
Units: Hours
median (full range (min-max))
Cycle 1 Day 1 (n= 4 / 5 / 1 / 12 / 3)	1.07 (1.00 to 2.00)	2.00 (1.00 to 4.00)	2.00 (2.00 to 2.00)	2.01 (1.00 to 7.67)	2.00 (1.02 to 2.13)
Cycle 1 Day 15 (n= 3 / 5 / 1 / 11 / 2)	1.12 (1.03 to 2.05)	2.00 (0.883 to 7.98)	1.17 (1.17 to 1.17)	1.97 (0.950 to 4.00)	1.50 (1.00 to 2.00)
Cycle 2 Day 1 (n= 3 / 5 / 0 / 10 / 2)	1.00 (1.00 to 2.00)	2.00 (1.00 to 3.83)	999999 (999999 to 999999)	1.94 (0.983 to 4.00)	1.51 (1.02 to 2.00)

No statistical analyses for this end point

Secondary: Phase II Groups 3 and 4: Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) of INC280

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End point title

Phase II Groups 3 and 4: Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) of INC280 ^[31]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[31] - 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 is only applicable for Phase II Groups 3 and 4

End point values	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	9	15
Units: hoursnanogram/mililiter (hrng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n= 8 / 12)	22000 ( 8000 )	16900 ( 7360 )
Cycle 2 Day 1 (n= 8 / 15)	19700 ( 11200 )	20500 ( 7440 )

No statistical analyses for this end point

Secondary: Phase II Groups 3 and 4: Peak plasma concentration (Cmax) of INC280

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End point title

Phase II Groups 3 and 4: Peak plasma concentration (Cmax) of INC280 ^[32]

End point description

Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[32] - 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 is only applicable for Phase II Groups 3 and 4

End point values	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	9	15
Units: nanogram/mililiter (ng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n= 8 / 12)	4770 ( 1460 )	3420 ( 1550 )
Cycle 2 Day 1 (n= 8 / 15)	4360 ( 2060 )	3940 ( 1660 )

No statistical analyses for this end point

Secondary: Phase II Groups 3 and 4: Time to reach maximum concentration (Tmax) of INC280

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End point title

Phase II Groups 3 and 4: Time to reach maximum concentration (Tmax) of INC280 ^[33]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[33] - 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 is only applicable for Phase II Groups 3 and 4

End point values	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	9	15
Units: Hours
median (full range (min-max))
Cycle 1 Day 1 (n= 8 / 12)	1.99 (1.00 to 4.00)	2.08 (1.85 to 8.00)
Cycle 2 Day 1 (n= 8 / 15)	1.47 (1.00 to 7.08)	3.82 (1.00 to 4.10)

No statistical analyses for this end point

Secondary: Phase Ib: Area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) of EGF816

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End point title

Phase Ib: Area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) of EGF816 ^[34]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[34] - 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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	13	3
Units: hoursnanogram/mililiter (hrng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n= 3 / 5 / 2 / 11 / 2)	3920 ( 1450 )	5850 ( 4380 )	4010 ( 534 )	5930 ( 3600 )	10500 ( 3400 )
Cycle 1 Day 15 (n= 4 / 5 / 2 / 12 / 2)	5200 ( 2010 )	9630 ( 4060 )	7330 ( 108 )	11100 ( 5340 )	16400 ( 5670 )
Cycle 2 Day 1 (n= 3 / 4 / 0 / 11 / 2)	4080 ( 1130 )	7460 ( 2340 )	999999 ( 999999 )	10500 ( 7480 )	11400 ( 2360 )

No statistical analyses for this end point

Secondary: Phase Ib: Peak plasma concentration (Cmax) of EGF816

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End point title

Phase Ib: Peak plasma concentration (Cmax) of EGF816 ^[35]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[35] - 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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	13	3
Units: nanogram/mililiter (ng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n= 4 / 5 / 2 / 13 / 3)	258 ( 104 )	465 ( 323 )	302 ( 8.49 )	381 ( 231 )	777 ( 281 )
Cycle 1 Day 15 (n= 3 / 5 / 3 / 12 / 2)	361 ( 165 )	677 ( 321 )	517 ( 180 )	595 ( 261 )	1010 ( 354 )
Cycle 2 Day 1 (n= 3 / 5 / 0 / 11 / 2)	269 ( 90.8 )	583 ( 261 )	999999 ( 999999 )	604 ( 365 )	814 ( 137 )

No statistical analyses for this end point

Secondary: Phase Ib: Time to reach maximum concentration (Tmax) of EGF816

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End point title

Phase Ib: Time to reach maximum concentration (Tmax) of EGF816 ^[36]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods. Actual time of sample collection was used (not the nominal time point as per scheduled assessment)

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[36] - 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 is only applicable for Phase Ib arms

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD
Number of subjects analysed	4	5	3	13	3
Units: Hours (hr)
median (full range (min-max))
Cycle 1 Day 1 (n= 4 / 5 / 2 / 13 / 3)	3.03 (1.08 to 4.02)	3.90 (2.00 to 4.00)	3.00 (2.00 to 4.00)	4.00 (2.00 to 8.99)	4.00 (2.03 to 4.02)
Cycle 1 Day 15 (n= 3 / 5 / 3 / 12 / 2)	2.07 (2.00 to 4.05)	3.95 (2.00 to 4.00)	4.00 (2.17 to 4.05)	5.90 (2.17 to 11.9)	3.93 (3.83 to 4.02)
Cycle 2 Day 1 (n= 3 / 5 / 0 / 11 / 2)	4.00 (3.95 to 4.00)	4.00 (2.00 to 4.00)	999999 (999999 to 999999)	4.00 (1.98 to 7.00)	3.05 (2.10 to 4.00)

No statistical analyses for this end point

Secondary: Phase II Groups 3 and 4: Area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) of EGF816

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End point title

Phase II Groups 3 and 4: Area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) of EGF816 ^[37]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[37] - 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 is only applicable for Phase II Groups 3 and 4

End point values	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	7	15
Units: hoursnanogram/mililiter (hrng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n= 6 / 12)	6390 ( 2460 )	3420 ( 1700 )
Cycle 2 Day 1 (n= 5 / 15)	11100 ( 2000 )	7670 ( 3330 )

No statistical analyses for this end point

Secondary: Phase II Groups 3 and 4: Peak plasma concentration (Cmax) of EGF816

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End point title

Phase II Groups 3 and 4: Peak plasma concentration (Cmax) of EGF816 ^[38]

End point description

Pharmacokinetic (PK) parameters were calculated based on EGF816 plasma concentrations by using non-compartmental methods.

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[38] - 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 is only applicable for Phase II Groups 3 and 4

End point values	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	7	15
Units: nanogram/mililiter (ng/mL)
arithmetic mean (standard deviation)
Cycle 1 Day 1 (n= 6 / 12)	448 ( 184 )	239 ( 107 )
Cycle 2 Day 1 (n= 6 / 15)	658 ( 117 )	447 ( 175 )

No statistical analyses for this end point

Secondary: Phase II Groups 3 and 4: Time to reach maximum concentration (Tmax) of EGF816

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End point title

Phase II Groups 3 and 4: Time to reach maximum concentration (Tmax) of EGF816 ^[39]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5 hours (hr) and 1 hr, 2 hr, 4 hr, 8 hr and 12 hr and 24 hr post-dose on Cycle 1 Day 1 and Cycle 2 Day 1 (Cycle=28 days)

Notes
[39] - 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 is only applicable for Phase II Groups 3 and 4

End point values	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	7	15
Units: Hours (hr)
median (full range (min-max))
Cycle 1 Day 1 (n= 6 / 12)	4.00 (1.12 to 8.00)	4.00 (1.85 to 8.00)
Cycle 2 Day 1 (n= 6 / 15)	4.00 (2.00 to 4.13)	4.00 (3.82 to 8.00)

No statistical analyses for this end point

Post-hoc: All collected deaths

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End point title

All collected deaths

End point description

On-treatment deaths were collected from first dose of study medication to 30 days after the last dose of study medication for a maximum duration of approximately 5 years (Phase Ib) and 4 years (Phase II). Post-treatment deaths were collected after 30 days post-treatment, for a maximum duration of approximately 5 years (Phase Ib) and 4 years (Phase II). All deaths refer to the sum of on-treatment and post-treatment deaths

End point type

Post-hoc

End point timeframe

On-treatment: up to approximately 5 years (Phase Ib) and 4 years (Phase II). Post-treatment: Up to approximately 5 years (Phase Ib) and 4 years (Phase II).

End point values	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD	Phase II- Group 1	Phase II- Group 2	Phase II- Group 3	Phase II- Group 4
Number of subjects analysed	4	5	3	16	5	52	3	47	42
Units: Participants
On-treatment deaths	0	0	1	2	0	9	2	5	1
Post-treatment deaths	4	3	2	9	3	26	1	25	22
All deaths	4	3	3	11	3	35	3	30	23

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study treatment until last dose of study treatment plus 30 days, up to approximately 5 years (Phase Ib) and 4 years (Phase II).

Adverse event reporting additional description

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

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Phase IB part- INC280 200mg BID/ EGF816 50mg QD

Reporting group description

Combination of INC280 200mg twice daily (BID) and EGF816 50mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 150mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 150mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 100mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 100mg once daily (QD) in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 400mg BID/ EGF816 75mg QD

Reporting group description

Combination of INC280 400mg twice daily (BID) and EGF816 75mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

Phase IB part- INC280 200mg BID/ EGF816 100mg QD

Reporting group description

Combination of INC280 200mg twice daily (BID) and EGF816 100mg once daily (QD) in fasted state in NSCLC participants with previously documented EGFR mutation, who progressed on EGFR TKI treatment

Reporting group title

All Participants

Reporting group description

All Participants

Reporting group title

Phase II- Group 4

Reporting group description

Reporting group title

Phase II- Group 3

Reporting group description

Reporting group title

Phase II- Group 2

Reporting group description

Reporting group title

Phase II- Group 1

Reporting group description

Serious adverse events	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	All Participants	Phase II- Group 4	Phase II- Group 3	Phase II- Group 2	Phase II- Group 1
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 4 (75.00%)	4 / 5 (80.00%)	11 / 16 (68.75%)	3 / 3 (100.00%)	2 / 5 (40.00%)	113 / 177 (63.84%)	26 / 42 (61.90%)	33 / 47 (70.21%)	2 / 3 (66.67%)	29 / 52 (55.77%)
number of deaths (all causes)	0	0	2	1	0	20	1	5	2	9
number of deaths resulting from adverse events	0	0	0	0	0	2	0	1	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Embolism
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 4	0 / 1	1 / 1	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	8 / 177 (4.52%)	2 / 42 (4.76%)	4 / 47 (8.51%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	4 / 8	2 / 2	1 / 4	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	8 / 177 (4.52%)	2 / 42 (4.76%)	1 / 47 (2.13%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	1 / 9	0 / 2	1 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
Aspiration
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersensitivity pneumonitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	10 / 177 (5.65%)	3 / 42 (7.14%)	4 / 47 (8.51%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	3 / 12	1 / 3	2 / 6	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	3 / 42 (7.14%)	0 / 47 (0.00%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	5 / 5	3 / 3	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
Pulmonary embolism
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	1 / 3 (33.33%)	0 / 5 (0.00%)	7 / 177 (3.95%)	0 / 42 (0.00%)	1 / 47 (2.13%)	1 / 3 (33.33%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1	0 / 0	0 / 7	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	6 / 177 (3.39%)	0 / 42 (0.00%)	3 / 47 (6.38%)	1 / 3 (33.33%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 7	0 / 0	0 / 3	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 1	0 / 1	0 / 1
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Apathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	2 / 2	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Amylase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Weight decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Cardio-respiratory arrest
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Pericardial effusion
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysarthria
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive hydrocephalus
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
Neurological decompensation
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 5 (0.00%)	7 / 177 (3.95%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 8	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Speech disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wernicke's encephalopathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Disseminated intravascular coagulation
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Visual impairment
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Ascites
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	1 / 42 (2.38%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0	3 / 5	0 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 4	1 / 3	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis allergic
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erythema multiforme
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug eruption
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Purpura
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash macular
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	7 / 7	1 / 1	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urticaria
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neck pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	1 / 5 (20.00%)	9 / 177 (5.08%)	3 / 42 (7.14%)	2 / 47 (4.26%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	1 / 2	5 / 12	2 / 4	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Herpes zoster meningitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Necrotising fasciitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	10 / 177 (5.65%)	4 / 42 (9.52%)	0 / 47 (0.00%)	0 / 3 (0.00%)	5 / 52 (9.62%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 10	0 / 4	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pleural infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia chlamydial
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 5	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 1	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte imbalance
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	1 / 3	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase IB part- INC280 200mg BID/ EGF816 50mg QD	Phase IB part- INC280 400mg BID/ EGF816 150mg QD	Phase IB part- INC280 400mg BID/ EGF816 100mg QD	Phase IB part- INC280 400mg BID/ EGF816 75mg QD	Phase IB part- INC280 200mg BID/ EGF816 100mg QD	All Participants	Phase II- Group 4	Phase II- Group 3	Phase II- Group 2	Phase II- Group 1
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 4 (100.00%)	5 / 5 (100.00%)	16 / 16 (100.00%)	3 / 3 (100.00%)	5 / 5 (100.00%)	176 / 177 (99.44%)	42 / 42 (100.00%)	47 / 47 (100.00%)	3 / 3 (100.00%)	51 / 52 (98.08%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	3	0	2	0	0
Hypotension
subjects affected / exposed	1 / 4 (25.00%)	2 / 5 (40.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	10 / 177 (5.65%)	1 / 42 (2.38%)	4 / 47 (8.51%)	1 / 3 (33.33%)	1 / 52 (1.92%)
occurrences all number	1	2	0	0	0	12	2	5	1	1
Pallor
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	2	0
Thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Asthenia
subjects affected / exposed	2 / 4 (50.00%)	0 / 5 (0.00%)	4 / 16 (25.00%)	1 / 3 (33.33%)	2 / 5 (40.00%)	44 / 177 (24.86%)	10 / 42 (23.81%)	18 / 47 (38.30%)	1 / 3 (33.33%)	6 / 52 (11.54%)
occurrences all number	2	0	5	2	3	62	14	22	2	12
Chills
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	1	0	1	0	0	8	0	3	0	3
Fatigue
subjects affected / exposed	2 / 4 (50.00%)	2 / 5 (40.00%)	6 / 16 (37.50%)	2 / 3 (66.67%)	0 / 5 (0.00%)	46 / 177 (25.99%)	9 / 42 (21.43%)	9 / 47 (19.15%)	2 / 3 (66.67%)	14 / 52 (26.92%)
occurrences all number	3	2	10	3	0	57	11	10	3	15
Face oedema
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	3 / 16 (18.75%)	0 / 3 (0.00%)	0 / 5 (0.00%)	9 / 177 (5.08%)	1 / 42 (2.38%)	2 / 47 (4.26%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	1	3	0	0	9	1	2	0	2
Gait disturbance
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	2	1	0	0	0
Influenza like illness
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	10 / 177 (5.65%)	5 / 42 (11.90%)	2 / 47 (4.26%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	0	0	0	0	15	8	3	0	4
Non-cardiac chest pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 5 (0.00%)	23 / 177 (12.99%)	6 / 42 (14.29%)	6 / 47 (12.77%)	1 / 3 (33.33%)	8 / 52 (15.38%)
occurrences all number	0	0	1	1	0	26	6	8	1	9
Oedema peripheral
subjects affected / exposed	1 / 4 (25.00%)	4 / 5 (80.00%)	8 / 16 (50.00%)	2 / 3 (66.67%)	1 / 5 (20.00%)	103 / 177 (58.19%)	26 / 42 (61.90%)	31 / 47 (65.96%)	3 / 3 (100.00%)	27 / 52 (51.92%)
occurrences all number	3	8	17	2	5	226	42	93	3	53
Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	6 / 177 (3.39%)	1 / 42 (2.38%)	2 / 47 (4.26%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	0	0	0	0	7	1	3	0	3
Peripheral swelling
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	3 / 42 (7.14%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	2	3	0	0	10	4	1	0	0
Pyrexia
subjects affected / exposed	1 / 4 (25.00%)	3 / 5 (60.00%)	7 / 16 (43.75%)	0 / 3 (0.00%)	1 / 5 (20.00%)	43 / 177 (24.29%)	12 / 42 (28.57%)	11 / 47 (23.40%)	0 / 3 (0.00%)	8 / 52 (15.38%)
occurrences all number	1	3	11	0	1	55	14	13	0	12
Immune system disorders
Anaphylactoid reaction
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Hypersensitivity
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	0	0	2	5	0	0	0	3
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Perineal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0
Prostatomegaly
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	5 / 16 (31.25%)	2 / 3 (66.67%)	2 / 5 (40.00%)	47 / 177 (26.55%)	14 / 42 (33.33%)	11 / 47 (23.40%)	1 / 3 (33.33%)	10 / 52 (19.23%)
occurrences all number	1	1	10	2	2	75	23	13	3	20
Dry throat
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0
Dysphonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	5 / 177 (2.82%)	1 / 42 (2.38%)	1 / 47 (2.13%)	1 / 3 (33.33%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	1	5	1	1	1	1
Dyspnoea
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	4 / 16 (25.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	40 / 177 (22.60%)	7 / 42 (16.67%)	13 / 47 (27.66%)	1 / 3 (33.33%)	11 / 52 (21.15%)
occurrences all number	2	1	8	1	1	48	7	13	1	14
Dyspnoea exertional
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	2	0	0	2	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	0 / 42 (0.00%)	4 / 47 (8.51%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	0	5	0	4	0	1
Haemoptysis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	4 / 177 (2.26%)	2 / 42 (4.76%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	1	0	5	3	0	0	1
Nasal discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	2	0	0	2	0	0	0	0
Hypoxia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	0	0	0	0	4	0	0	0	4
Nasal dryness
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	8 / 177 (4.52%)	5 / 42 (11.90%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	1	0	0	8	5	1	0	1
Pleural effusion
subjects affected / exposed	2 / 4 (50.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	9 / 177 (5.08%)	3 / 42 (7.14%)	2 / 47 (4.26%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	2	0	1	0	0	9	3	2	0	1
Pneumothorax
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	1	0	0	0	3	0	1	0	1
Productive cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	0 / 42 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	1	0	0	7	0	5	0	1
Pulmonary embolism
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	1	0	0	3	0	1	0	1
Rhinorrhoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	3 / 16 (18.75%)	1 / 3 (33.33%)	0 / 5 (0.00%)	13 / 177 (7.34%)	5 / 42 (11.90%)	2 / 47 (4.26%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	6	1	0	17	5	2	0	3
Throat irritation
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	6 / 177 (3.39%)	0 / 42 (0.00%)	4 / 47 (8.51%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	0	0	0	6	0	4	0	2
Confusional state
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	3	0	2	0	0
Sleep disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	1	0	0	0	3	0	0	0	2
Depression
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	2	1	0	0	0
Insomnia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	12 / 177 (6.78%)	4 / 42 (9.52%)	3 / 47 (6.38%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	2	0	0	0	14	5	3	0	4
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 4 (50.00%)	2 / 5 (40.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	41 / 177 (23.16%)	13 / 42 (30.95%)	13 / 47 (27.66%)	2 / 3 (66.67%)	7 / 52 (13.46%)
occurrences all number	4	3	2	0	0	54	17	19	2	7
Amylase increased
subjects affected / exposed	2 / 4 (50.00%)	2 / 5 (40.00%)	8 / 16 (50.00%)	1 / 3 (33.33%)	2 / 5 (40.00%)	45 / 177 (25.42%)	7 / 42 (16.67%)	11 / 47 (23.40%)	1 / 3 (33.33%)	11 / 52 (21.15%)
occurrences all number	4	2	13	1	5	103	17	23	3	35
Aspartate aminotransferase increased
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	34 / 177 (19.21%)	11 / 42 (26.19%)	13 / 47 (27.66%)	2 / 3 (66.67%)	4 / 52 (7.69%)
occurrences all number	2	2	2	0	0	47	15	20	2	4
Blood albumin decreased
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	1	8	1	0	0	12	1	1	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 5 (0.00%)	12 / 177 (6.78%)	2 / 42 (4.76%)	6 / 47 (12.77%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	1	0	3	1	0	18	2	10	0	1
Blood bilirubin increased
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	6 / 177 (3.39%)	1 / 42 (2.38%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	1	0	0	0	0	10	1	6	0	2
Blood creatine increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	3	2	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	4 / 16 (25.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	22 / 177 (12.43%)	6 / 42 (14.29%)	5 / 47 (10.64%)	0 / 3 (0.00%)	5 / 52 (9.62%)
occurrences all number	0	0	7	1	6	42	10	6	0	12
Blood creatinine increased
subjects affected / exposed	2 / 4 (50.00%)	2 / 5 (40.00%)	8 / 16 (50.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	56 / 177 (31.64%)	15 / 42 (35.71%)	16 / 47 (34.04%)	1 / 3 (33.33%)	10 / 52 (19.23%)
occurrences all number	3	7	12	0	3	108	35	30	4	14
Blood glucose increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	2	0	0	2	0	0	0	0
Blood potassium increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0
Blood triglycerides increased
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0
Blood urea increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	2 / 42 (4.76%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	4	2	1	0	0
Blood uric acid increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	0	2	0	0	1	1
C-reactive protein increased
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	3 / 42 (7.14%)	1 / 47 (2.13%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	1	0	0	0	0	13	9	1	0	2
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	16 / 177 (9.04%)	5 / 42 (11.90%)	5 / 47 (10.64%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	1	2	3	0	0	23	9	6	0	2
Haemoglobin decreased
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	4	0	0	0	0	4	0	0	0	0
Lipase increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	4 / 16 (25.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	33 / 177 (18.64%)	8 / 42 (19.05%)	7 / 47 (14.89%)	0 / 3 (0.00%)	12 / 52 (23.08%)
occurrences all number	0	2	6	0	3	81	11	19	0	40
Lymphocyte count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	6	0	0	7	1	0	0	0
Protein total decreased
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	8 / 177 (4.52%)	3 / 42 (7.14%)	0 / 47 (0.00%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	1	0	0	0	8	3	0	0	4
Weight decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	3 / 16 (18.75%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	2 / 42 (4.76%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	3	0	0	7	2	1	0	1
Weight increased
subjects affected / exposed	0 / 4 (0.00%)	2 / 5 (40.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	13 / 177 (7.34%)	2 / 42 (4.76%)	4 / 47 (8.51%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	2	2	0	0	13	2	4	0	3
White blood cell count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	2	0	0	4	0	2	0	0
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	1	0	0	0	0	2	0	1	0	0
Traumatic haematoma
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	2	0	1	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	1 / 42 (2.38%)	0 / 47 (0.00%)	1 / 3 (33.33%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	0	3	1	0	1	1
Bradycardia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	2	1	0	0	0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	2	0	0	3	0	1	0	0
Dizziness
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	4 / 16 (25.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	36 / 177 (20.34%)	10 / 42 (23.81%)	11 / 47 (23.40%)	0 / 3 (0.00%)	9 / 52 (17.31%)
occurrences all number	0	1	7	2	0	45	13	12	0	10
Dysaesthesia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	1	0	3	0	0	0	2
Dysgeusia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	6 / 177 (3.39%)	1 / 42 (2.38%)	4 / 47 (8.51%)	1 / 3 (33.33%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	0	6	1	4	1	0
Epilepsy
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0
Hypoaesthesia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	8 / 177 (4.52%)	2 / 42 (4.76%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	1	2	0	0	9	2	3	0	1
Lethargy
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	2	0	0	4	1	1	0	0
Headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	7 / 16 (43.75%)	0 / 3 (0.00%)	1 / 5 (20.00%)	45 / 177 (25.42%)	12 / 42 (28.57%)	17 / 47 (36.17%)	1 / 3 (33.33%)	7 / 52 (13.46%)
occurrences all number	0	0	12	0	1	59	14	23	1	8
Neuropathy peripheral
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	1	0	0	3	0	0	0	2
Seizure
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	1 / 42 (2.38%)	3 / 47 (6.38%)	1 / 3 (33.33%)	1 / 52 (1.92%)
occurrences all number	0	0	1	0	0	9	1	4	2	1
Post herpetic neuralgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Syncope
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	2 / 3 (66.67%)	0 / 5 (0.00%)	30 / 177 (16.95%)	4 / 42 (9.52%)	11 / 47 (23.40%)	1 / 3 (33.33%)	9 / 52 (17.31%)
occurrences all number	0	2	2	2	0	39	4	17	2	10
Febrile neutropenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	1	0	2	0	0	0	1
Leukopenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	1 / 5 (20.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	3	1	6	0	2	0	0
Lymphopenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 5 (0.00%)	7 / 177 (3.95%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	0	1	1	0	11	3	2	0	4
Neutropenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	2 / 5 (40.00%)	6 / 177 (3.39%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	2	0	4	2	10	0	1	0	1
Thrombocytopenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	10 / 177 (5.65%)	2 / 42 (4.76%)	3 / 47 (6.38%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	0	0	3	0	12	2	3	0	4
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	1 / 3 (33.33%)	0 / 5 (0.00%)	5 / 177 (2.82%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	4	1	0	7	0	2	0	0
Ear pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	2	0	0	3	0	0	0	1
Deafness transitory
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Hypoacusis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	9 / 177 (5.08%)	3 / 42 (7.14%)	3 / 47 (6.38%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	1	0	0	9	3	3	0	2
Tinnitus
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	0 / 42 (0.00%)	6 / 47 (12.77%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	0	7	0	6	0	1
Eye disorders
Eye pruritus
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	1 / 42 (2.38%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	0	5	1	3	0	1
Eye swelling
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0
Eyelid oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 5 (0.00%)	3 / 177 (1.69%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	1	0	3	1	0	0	0
Vision blurred
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0
Vitreous floaters
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	13 / 177 (7.34%)	4 / 42 (9.52%)	7 / 47 (14.89%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	1	0	0	0	13	4	7	0	1
Abdominal discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	3 / 42 (7.14%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	0	4	3	0	0	1
Abdominal pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	14 / 177 (7.91%)	2 / 42 (4.76%)	5 / 47 (10.64%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	1	2	0	0	17	3	5	0	6
Abdominal pain upper
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	20 / 177 (11.30%)	7 / 42 (16.67%)	6 / 47 (12.77%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	1	0	3	0	0	22	7	7	0	4
Constipation
subjects affected / exposed	1 / 4 (25.00%)	2 / 5 (40.00%)	5 / 16 (31.25%)	1 / 3 (33.33%)	0 / 5 (0.00%)	28 / 177 (15.82%)	8 / 42 (19.05%)	6 / 47 (12.77%)	1 / 3 (33.33%)	4 / 52 (7.69%)
occurrences all number	1	2	11	3	0	42	9	9	1	6
Diarrhoea
subjects affected / exposed	1 / 4 (25.00%)	2 / 5 (40.00%)	6 / 16 (37.50%)	1 / 3 (33.33%)	1 / 5 (20.00%)	79 / 177 (44.63%)	20 / 42 (47.62%)	26 / 47 (55.32%)	2 / 3 (66.67%)	20 / 52 (38.46%)
occurrences all number	1	3	18	1	1	132	30	37	2	39
Dry mouth
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	3 / 42 (7.14%)	1 / 47 (2.13%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	1	0	0	7	3	1	0	2
Dyspepsia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	4 / 16 (25.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	30 / 177 (16.95%)	6 / 42 (14.29%)	9 / 47 (19.15%)	0 / 3 (0.00%)	10 / 52 (19.23%)
occurrences all number	0	0	6	1	0	33	6	9	0	11
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	3 / 16 (18.75%)	0 / 3 (0.00%)	0 / 5 (0.00%)	8 / 177 (4.52%)	3 / 42 (7.14%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	3	0	0	8	3	2	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	12 / 177 (6.78%)	6 / 42 (14.29%)	2 / 47 (4.26%)	1 / 3 (33.33%)	2 / 52 (3.85%)
occurrences all number	0	0	1	0	0	13	7	2	1	2
Lip blister
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	2	0	0	0	2	0	0	0	0
Lip dry
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	9 / 177 (5.08%)	4 / 42 (9.52%)	4 / 47 (8.51%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	1	0	9	4	4	0	0
Nausea
subjects affected / exposed	2 / 4 (50.00%)	5 / 5 (100.00%)	11 / 16 (68.75%)	2 / 3 (66.67%)	0 / 5 (0.00%)	97 / 177 (54.80%)	19 / 42 (45.24%)	27 / 47 (57.45%)	3 / 3 (100.00%)	28 / 52 (53.85%)
occurrences all number	2	5	27	3	0	150	31	38	3	41
Odynophagia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	3	1	1	0	0
Toothache
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	2	0	0	5	0	2	0	1
Stomatitis
subjects affected / exposed	0 / 4 (0.00%)	2 / 5 (40.00%)	3 / 16 (18.75%)	0 / 3 (0.00%)	0 / 5 (0.00%)	25 / 177 (14.12%)	3 / 42 (7.14%)	12 / 47 (25.53%)	0 / 3 (0.00%)	5 / 52 (9.62%)
occurrences all number	0	3	8	0	0	49	13	20	0	5
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	3 / 5 (60.00%)	6 / 16 (37.50%)	1 / 3 (33.33%)	0 / 5 (0.00%)	64 / 177 (36.16%)	11 / 42 (26.19%)	22 / 47 (46.81%)	1 / 3 (33.33%)	20 / 52 (38.46%)
occurrences all number	0	6	20	1	0	106	12	33	1	33
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	1 / 42 (2.38%)	3 / 47 (6.38%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	5	1	3	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	1	0	0	0	0	6	0	5	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 4 (0.00%)	2 / 5 (40.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	1 / 5 (20.00%)	21 / 177 (11.86%)	4 / 42 (9.52%)	10 / 47 (21.28%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	4	2	0	1	26	5	11	0	3
Alopecia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	1 / 3 (33.33%)	1 / 5 (20.00%)	8 / 177 (4.52%)	0 / 42 (0.00%)	4 / 47 (8.51%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	5	1	1	11	0	4	0	0
Dry skin
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	5 / 16 (31.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	23 / 177 (12.99%)	5 / 42 (11.90%)	7 / 47 (14.89%)	0 / 3 (0.00%)	5 / 52 (9.62%)
occurrences all number	0	4	7	0	0	32	5	11	0	5
Eczema
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	9 / 177 (5.08%)	6 / 42 (14.29%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	1	0	0	11	8	1	0	1
Ingrowing nail
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	2	0	1	0	0
Nail discolouration
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Night sweats
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	2	0	1	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Pruritus
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	5 / 16 (31.25%)	0 / 3 (0.00%)	1 / 5 (20.00%)	36 / 177 (20.34%)	14 / 42 (33.33%)	9 / 47 (19.15%)	0 / 3 (0.00%)	6 / 52 (11.54%)
occurrences all number	0	2	6	0	1	50	19	14	0	8
Rash
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	28 / 177 (15.82%)	9 / 42 (21.43%)	11 / 47 (23.40%)	0 / 3 (0.00%)	7 / 52 (13.46%)
occurrences all number	0	0	1	0	0	32	10	13	0	8
Rash macular
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	1 / 5 (20.00%)	9 / 177 (5.08%)	1 / 42 (2.38%)	3 / 47 (6.38%)	1 / 3 (33.33%)	0 / 52 (0.00%)
occurrences all number	0	1	1	1	1	10	1	4	1	0
Rash maculo-papular
subjects affected / exposed	0 / 4 (0.00%)	4 / 5 (80.00%)	3 / 16 (18.75%)	0 / 3 (0.00%)	2 / 5 (40.00%)	43 / 177 (24.29%)	9 / 42 (21.43%)	14 / 47 (29.79%)	1 / 3 (33.33%)	10 / 52 (19.23%)
occurrences all number	0	4	5	0	2	56	13	21	1	10
Rash papular
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	2 / 42 (4.76%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	6	3	2	0	0
Rash pruritic
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	1 / 42 (2.38%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	3	0	0	9	1	4	0	1
Skin hyperpigmentation
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	2	0	1	0	0
Urticaria
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	2 / 42 (4.76%)	2 / 47 (4.26%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	5	2	2	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	1	0	0	0	0	2	0	0	0	1
Chronic kidney disease
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Hypertonic bladder
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0
Renal failure
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	1	0	0	3	0	1	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	2 / 4 (50.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	1 / 3 (33.33%)	1 / 5 (20.00%)	26 / 177 (14.69%)	6 / 42 (14.29%)	10 / 47 (21.28%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	2	1	3	2	2	32	6	13	0	3
Back pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	18 / 177 (10.17%)	8 / 42 (19.05%)	7 / 47 (14.89%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	0	1	0	20	9	8	0	2
Bone pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	6 / 177 (3.39%)	1 / 42 (2.38%)	3 / 47 (6.38%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	0	0	0	11	1	8	0	2
Flank pain
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	1	0	1	0	0	4	0	1	0	1
Joint stiffness
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Muscular weakness
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 4 (0.00%)	2 / 5 (40.00%)	2 / 16 (12.50%)	1 / 3 (33.33%)	0 / 5 (0.00%)	35 / 177 (19.77%)	14 / 42 (33.33%)	12 / 47 (25.53%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	2	3	2	0	45	19	15	0	4
Musculoskeletal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	4 / 47 (8.51%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	0	4	0	4	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	2 / 42 (4.76%)	3 / 47 (6.38%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	0	0	0	8	2	4	0	2
Myalgia
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	1 / 3 (33.33%)	0 / 5 (0.00%)	10 / 177 (5.65%)	0 / 42 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	2	1	2	1	0	12	0	3	0	3
Neck pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	1 / 5 (20.00%)	2 / 177 (1.13%)	0 / 42 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	1	2	0	1	0	0
Pain in extremity
subjects affected / exposed	0 / 4 (0.00%)	3 / 5 (60.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	23 / 177 (12.99%)	7 / 42 (16.67%)	7 / 47 (14.89%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	6	2	0	0	28	8	8	0	4
Tendon pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	2 / 42 (4.76%)	2 / 47 (4.26%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	2	0	0	0	10	2	4	0	2
Conjunctivitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	0	0	0	0	4	1	0	0	3
Cellulitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	2 / 5 (40.00%)	12 / 177 (6.78%)	5 / 42 (11.90%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	1	0	0	3	17	8	4	0	1
Cystitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	2 / 177 (1.13%)	1 / 42 (2.38%)	0 / 47 (0.00%)	1 / 3 (33.33%)	0 / 52 (0.00%)
occurrences all number	0	0	0	0	0	2	1	0	1	0
Folliculitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	1 / 42 (2.38%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	0	5	1	3	0	1
Gastroenteritis
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	1	0	0	0	0	3	1	0	0	1
Herpes zoster
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	5 / 177 (2.82%)	3 / 42 (7.14%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	2	0	0	6	4	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	16 / 177 (9.04%)	5 / 42 (11.90%)	5 / 47 (10.64%)	0 / 3 (0.00%)	5 / 52 (9.62%)
occurrences all number	0	0	1	0	0	19	5	7	0	6
Infection
subjects affected / exposed	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0
Paronychia
subjects affected / exposed	0 / 4 (0.00%)	2 / 5 (40.00%)	5 / 16 (31.25%)	0 / 3 (0.00%)	1 / 5 (20.00%)	25 / 177 (14.12%)	7 / 42 (16.67%)	7 / 47 (14.89%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	0	3	6	0	1	33	8	8	0	7
Pharyngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	3 / 177 (1.69%)	2 / 42 (4.76%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	3	2	0	0	0
Pneumonia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	9 / 177 (5.08%)	2 / 42 (4.76%)	2 / 47 (4.26%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	1	2	0	0	9	2	2	0	2
Respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	0 / 42 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	0	0	0	5	0	4	0	1
Rhinitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	7 / 177 (3.95%)	1 / 42 (2.38%)	2 / 47 (4.26%)	1 / 3 (33.33%)	2 / 52 (3.85%)
occurrences all number	0	1	0	0	0	10	1	2	1	5
Sinobronchitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0
Skin infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	1	0	0	5	1	2	0	1
Tooth infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	4 / 16 (25.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	25 / 177 (14.12%)	6 / 42 (14.29%)	6 / 47 (12.77%)	0 / 3 (0.00%)	9 / 52 (17.31%)
occurrences all number	0	0	5	0	0	34	10	8	0	11
Urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	0 / 3 (0.00%)	0 / 5 (0.00%)	18 / 177 (10.17%)	8 / 42 (19.05%)	4 / 47 (8.51%)	0 / 3 (0.00%)	5 / 52 (9.62%)
occurrences all number	0	1	0	0	0	31	19	4	0	7
Viral infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 4 (25.00%)	1 / 5 (20.00%)	10 / 16 (62.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	50 / 177 (28.25%)	9 / 42 (21.43%)	14 / 47 (29.79%)	1 / 3 (33.33%)	14 / 52 (26.92%)
occurrences all number	1	2	17	0	0	63	11	15	1	16
Hyperglycaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	6 / 177 (3.39%)	2 / 42 (4.76%)	3 / 47 (6.38%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	0	2	0	8	2	4	0	0
Hyperkalaemia
subjects affected / exposed	2 / 4 (50.00%)	0 / 5 (0.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	8 / 177 (4.52%)	1 / 42 (2.38%)	0 / 47 (0.00%)	0 / 3 (0.00%)	3 / 52 (5.77%)
occurrences all number	3	0	2	0	0	14	1	0	0	8
Hyperlipasaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	2	0	0	2	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	5 / 16 (31.25%)	1 / 3 (33.33%)	1 / 5 (20.00%)	34 / 177 (19.21%)	7 / 42 (16.67%)	10 / 47 (21.28%)	0 / 3 (0.00%)	9 / 52 (17.31%)
occurrences all number	0	1	8	1	1	52	9	15	0	17
Hypocalcaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	1 / 3 (33.33%)	0 / 5 (0.00%)	7 / 177 (3.95%)	0 / 42 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)	2 / 52 (3.85%)
occurrences all number	0	0	2	2	0	10	0	4	0	2
Hypoglycaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	4 / 177 (2.26%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	0	1	0	0	5	1	2	0	1
Hypokalaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	0 / 3 (0.00%)	0 / 5 (0.00%)	15 / 177 (8.47%)	2 / 42 (4.76%)	4 / 47 (8.51%)	1 / 3 (33.33%)	5 / 52 (9.62%)
occurrences all number	0	1	3	0	0	20	2	5	1	8
Hyponatraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	3 / 16 (18.75%)	0 / 3 (0.00%)	0 / 5 (0.00%)	10 / 177 (5.65%)	2 / 42 (4.76%)	1 / 47 (2.13%)	0 / 3 (0.00%)	4 / 52 (7.69%)
occurrences all number	0	0	9	0	0	19	3	1	0	6
Hypomagnesaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	3 / 16 (18.75%)	0 / 3 (0.00%)	0 / 5 (0.00%)	15 / 177 (8.47%)	3 / 42 (7.14%)	3 / 47 (6.38%)	1 / 3 (33.33%)	4 / 52 (7.69%)
occurrences all number	0	1	16	0	0	33	3	5	1	7
Hypophosphataemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 16 (12.50%)	1 / 3 (33.33%)	0 / 5 (0.00%)	7 / 177 (3.95%)	2 / 42 (4.76%)	1 / 47 (2.13%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	1	15	3	0	22	2	1	0	0
Hypophagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 16 (6.25%)	0 / 3 (0.00%)	0 / 5 (0.00%)	1 / 177 (0.56%)	0 / 42 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)	0 / 52 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0
Hypoproteinaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 16 (0.00%)	1 / 3 (33.33%)	0 / 5 (0.00%)	5 / 177 (2.82%)	1 / 42 (2.38%)	1 / 47 (2.13%)	0 / 3 (0.00%)	1 / 52 (1.92%)
occurrences all number	0	1	0	3	0	7	1	1	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

28 Nov 2014

Reduced nazartinib starting dose to 50 mg qd. Clarified the subsequent escalation of nazartinib and capmatinib doses. Revised the DLT definitions by adding Grade 2 pneumonitis as dose-limiting toxicity. Provided the latest available clinical safety and PK data for nazartinib and capmatinib tablet formulation. Provided updated hypothetical scenarios in reflection of the reduced starting dose of nazartinib and the updated priors based on the updated safety information.

24 Jul 2015

Introduced a formulation change for nazartinib from capsules to tablets (viable formulation for commercialization). Recommended guidelines for management and dose modification of rash/skin toxicities were provided for the nazartinib treatment. For capmatinib treatment, updated the dose modifications guideline for hepatotoxicity in regard to discontinuing study medication(s) with concurrent elevation of ALT and/or AST > 3×ULN and total bilirubin > 2×ULN with ALP < 2×ULN, in the absence of signs of cholestasis, hemolysis, and alternative causes of the liver injury (e.g., concomitant use of hepatotoxic drug(s), alcoholic hepatitis, etc.). Specific work-up for potential Hy’s law cases had been added to the protocol. The dose modification rules and the dose limiting toxicity for liver toxicity as well as the follow-up evaluations for hepatic toxicities had also been updated accordingly. Included precautionary measures against ultraviolet exposure as capmatinib had photosensitization potential. Additionally, updated the exclusion criteria and few new exclusion criteria were added. Updated concomitant therapies, criteria for interruption and re-initiation of nazartinib and capmatinib.

01 Sep 2015

Provided detailed information about an urgent safety measure related to nazartinib. Excluded subjects with other malignancies, who underwent a bone marrow or solid organ transplant, with a known history of human immunodeficiency virus infection, or receiving immunosuppressive agents or chronic corticosteroids at study entry. Allowed subjects with either HBV surface antigen positive or HBV-DNA positive to enroll into the study if willing to take antiviral therapy 1-2 weeks prior to first dose of study treatment and continue antiviral therapy for at least 4 weeks after the last dose of study treatment. Allowed new subjects with negative hepatitis C antibody (HC Ab) or who were HC Ab positive but with an undetectable level of HCV-RNA into the study. Subjects with detectable HCV-RNA were not eligible to enroll into the study.

02 Nov 2015

Implemented a centralization of analysis for the resistance mutations EGFRT790M and MET oncogene amplification at a Novartis designated central laboratory for all subjects entering into Phase II. Introduced 50 mg dose strength of nazartinib tablets for better compliance. Optimized the subject safety and the toxicity monitoring as well as to align Novartis study protocols, the QTcF eligibility criterion and the management guidelines for pancreatic toxicity were revised. Updated the definition of the end of study to detail study continuation conditions after completion of the primary analysis until all subjects discontinued, or until another clinical trial was available for all ongoing subjects to be transferred to that clinical study and continue to receive capmatinib + nazartinib. Clarified the possibility of using bisphosphonates during the study. Detailed the use of an Interactive Response Technology system in the Phase II part of the study to specify the enrollment and the study drug dispensation tracking via the application. Modalities and conditions for subject re-screening after screen failure was introduced, together with screening assessments to be performed again during the new screening phase.

29 Jul 2016

Better defined the subject population to be enrolled in the Phase II part of the study (expansion phase). A new group was added (Group 3), and the sample size of Group 2 was revised. Implemented a requirement of ECOG performance status of 0-1 for all subjects to be enrolled in the study to ensure that subjects would be able to receive potential benefit from study treatment. Removed the exclusion criterion on fasting plasma glucose ≥ 160 mg/dL (≥ 8.9 mmol/L) in the absence of evidence of impact on the glycemia in light of the most recent available clinical data and according to the latest versions of capmatinib and nazartinib Investigator Brochures Introduced a new dose strength (150 mg) for capmatinib tablets. Introduced other rare EGFR activating sensitizing mutations that were also considered for enrollment onto the Phase II. These rare mutations, L861Q, G719X, and S768I, account for almost 10% of the cases whereas L858R point mutation and exon 19 deletions accounted for approximately 90% of the cases. Updated the overview of capmatinib and nazartinib according to last Investigator Brochure versions. Removed the restriction of proton pump inhibitors use during the course of the study. Clarified the conditions in which local laboratory assessments should be reported in the Case Report Form during the Phase 2 part of the trial. Clarified the time window for post-dose ECG during the visits with PK sampling. Clarified the definition of acquired resistance mechanisms and the definition of the 4 subgroups of subjects being enrolled in the Phase II Group 1. Clarified the biosample requirements for the optional biomarker assessments. Introduced the RP2D and the dose reduction steps starting from the RP2D.

11 Apr 2017

Added in Phase II a new group 4 of subjects (N=30) with EGFRmut, any T790M, any MET, in order to assess the safety and tolerability of the combination therapy when taken with food (unrestricted meal type). Proposed a new group 4 to administer study medication with food to improve the tolerability profile of the combination therapy, as dosing with food had been shown to improve the GI tolerability of some multi-kinase inhibitors such as imatinib (Gleevec®) and bosutinib (Bosulif®). Corrected the exclusion criterion for subjects with asymptomatic serum amylase and lipase > Grade 2, to clarify that subject now met exclusion criterion even if only one of the two parameters (asymptomatic serum amylase or lipase) was > Grade 2. Added the collection of an optional on-treatment biopsy with paired cfDNA sample to identify emergence of potential resistance markers during treatment as well as understand the correlation between tissue and plasma biomarker status. Clarified the exclusion criterion for subjects with brain metastases. Clarified the interpretation of study discontinuation after dose interruption.

20 Oct 2021

A new group 5 added per protocol amendment 7 will not be opened as Novartis made the decision to discontinue the study on 11-May-2022. Below are the key changes in amendment 7. As of 20-Oct-2021, a total of 177 participants have been enrolled in the study: 33 participants in Phase Ib and 144 in Phase II (Group 1 to Group 4). All participants from Phase Ib and Phase II Groups 1 to 4 had met one of the end of study completion criteria as considered under protocol amendment 6 and there were no participants receiving treatment. The main purpose of this amendment is to implement a new subject group, Phase II Group 5, to determine the efficacy and safety of capmatinib monotherapy. The rationale for this addition is based on the following: Based on evidence suggesting that MET gene amplification plays an important role as a mechanism of resistance to treatment with EGFR-TKIs in NSCLC patients carrying mutated EGFR. Furthermore, the fact that there are reports showing significant clinical antitumor activity in this subpopulation of patients when combining an EGFR-TKI with a specific cMET inhibitor (such as Capmatinib). Therefore, the contribution of capmatinib as a monodrug needs to be established. This information will pave the way for the optimal use of the combination in future trials.

Were there any global interruptions to the trial? No

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

Due to EudraCT system limitations, which EMA is aware of, data using 999999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.

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Clinical trials

Clinical Trial Results: A Phase Ib/II, multicenter, open-label study of EGF816 in combination with INC280 in adult subjects with EGFR mutated non-small cell lung cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase Ib: Number of participants with dose limiting toxicities (DLTs)

Primary: Phase Ib: Number of participants with dose limiting toxicities (DLTs)

Primary: Phase II Group 1, 2 and 3: Overall Response Rate (ORR) by investigator's assessment per RECIST 1.1

Primary: Phase II Group 1, 2 and 3: Overall Response Rate (ORR) by investigator's assessment per RECIST 1.1

Primary: Phase II Group 4: Number of participants with Adverse Events (AEs) and Serious AEs (SAEs)

Primary: Phase II Group 4: Number of participants with Adverse Events (AEs) and Serious AEs (SAEs)

Primary: Phase II Group 4: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

Primary: Phase II Group 4: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

Primary: Phase II Group 4: Dose intensity

Primary: Phase II Group 4: Dose intensity

Secondary: Phase Ib: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

Secondary: Phase Ib: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

Secondary: Phase II Group 1, 2 and 3: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

Secondary: Phase II Group 1, 2 and 3: Number of participants with dose reductions and dose interruptions of INC280 and EGF618

Secondary: Phase Ib: Dose intensity

Secondary: Phase Ib: Dose intensity

Secondary: Phase II Group 1, 2 and 3: Dose intensity

Secondary: Phase II Group 1, 2 and 3: Dose intensity

Secondary: Phase Ib: Overall Response Rate (ORR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Overall Response Rate (ORR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Group 4: Overall Response Rate (ORR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Group 4: Overall Response Rate (ORR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Progression Free Survival (PFS) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Progression Free Survival (PFS) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Groups 1, 2, 3 and 4: Progression Free Survival (PFS) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Groups 1, 2, 3 and 4: Progression Free Survival (PFS) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Time to Response (TTR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Time to Response (TTR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Groups 1, 2, 3 and 4: Time to Response (TTR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Groups 1, 2, 3 and 4: Time to Response (TTR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Duration of Response (DOR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Duration of Response (DOR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Groups 1, 2, 3 and 4: Duration of Response (DOR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Groups 1, 2, 3 and 4: Duration of Response (DOR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Disease Control Rate (DCR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Disease Control Rate (DCR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Group 1, 2 3 and 4: Disease Control Rate (DCR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase II Group 1, 2 3 and 4: Disease Control Rate (DCR) per RECIST 1.1 based on investigator’s assessment

Secondary: Phase Ib: Overall Survival (OS)

Secondary: Phase Ib: Overall Survival (OS)

Secondary: Phase II Groups 1, 2, 3 and 4: Overall Survival (OS)

Secondary: Phase II Groups 1, 2, 3 and 4: Overall Survival (OS)

Secondary: Phase Ib: Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) of INC280

Secondary: Phase Ib: Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) of INC280

Secondary: Phase Ib: Peak plasma concentration (Cmax) of INC280

Secondary: Phase Ib: Peak plasma concentration (Cmax) of INC280

Secondary: Phase Ib: Time to reach maximum concentration (Tmax) of INC280

Secondary: Phase Ib: Time to reach maximum concentration (Tmax) of INC280

Secondary: Phase II Groups 3 and 4: Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) of INC280

Secondary: Phase II Groups 3 and 4: Area under the plasma concentration versus time curve from time 0 to 12 hours (AUC0-12) of INC280

Secondary: Phase II Groups 3 and 4: Peak plasma concentration (Cmax) of INC280

Secondary: Phase II Groups 3 and 4: Peak plasma concentration (Cmax) of INC280

Secondary: Phase II Groups 3 and 4: Time to reach maximum concentration (Tmax) of INC280

Secondary: Phase II Groups 3 and 4: Time to reach maximum concentration (Tmax) of INC280

Secondary: Phase Ib: Area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) of EGF816

Secondary: Phase Ib: Area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) of EGF816

Secondary: Phase Ib: Peak plasma concentration (Cmax) of EGF816

Secondary: Phase Ib: Peak plasma concentration (Cmax) of EGF816

Secondary: Phase Ib: Time to reach maximum concentration (Tmax) of EGF816

Secondary: Phase Ib: Time to reach maximum concentration (Tmax) of EGF816

Secondary: Phase II Groups 3 and 4: Area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) of EGF816

Secondary: Phase II Groups 3 and 4: Area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) of EGF816

Secondary: Phase II Groups 3 and 4: Peak plasma concentration (Cmax) of EGF816

Secondary: Phase II Groups 3 and 4: Peak plasma concentration (Cmax) of EGF816

Secondary: Phase II Groups 3 and 4: Time to reach maximum concentration (Tmax) of EGF816

Secondary: Phase II Groups 3 and 4: Time to reach maximum concentration (Tmax) of EGF816

Post-hoc: All collected deaths

Post-hoc: All collected deaths

Adverse events

Adverse events

Clinical Trial Results:
A Phase Ib/II, multicenter, open-label study of EGF816 in combination with INC280 in adult subjects with EGFR mutated non-small cell lung cancer