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Clinical Trial Results:
A Phase IB/II, open-label, multicenter study of INC280 administered orally in combination with gefitinib in adult patients with EGFR mutated, cMET-amplified non-small cell lung cancer who have progressed after EGFR inhibitor treatment

Summary
EudraCT number	2011-002569-39
Trial protocol	BE IT ES DE NL FR
Global end of trial date	27 May 2020

Results information
Results version number	v2(current)
This version publication date	20 Jun 2021
First version publication date	28 Mar 2021
Other versions	v1
Version creation reason	New data added to full data set Description for adverse events updated

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CINC280X2202

ISRCTN number

-

US NCT number

NCT01610336

WHO universal trial number (UTN)

-

Sponsor organisation name

Novartis Pharmaceuticals

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

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

Scientific contact

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

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

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

27 May 2020

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

27 May 2020

Was the trial ended prematurely?

No

Main objective of the trial

Phase Ib: To estimate the MTD/RP2D of capmatinib in combination with gefitinib in NSCLC patients with cMET gene dysregulation. Phase II: To estimate overall clinical activity of capmatinib in combination with gefitinib in NSCLC patients with cMET gene dysregulation. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

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

05 Apr 2012

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 2

Country: Number of subjects enrolled

China: 67

Country: Number of subjects enrolled

Israel: 1

Country: Number of subjects enrolled

Japan: 1

Country: Number of subjects enrolled

Korea, Republic of: 36

Country: Number of subjects enrolled

New Zealand: 1

Country: Number of subjects enrolled

Singapore: 8

Country: Number of subjects enrolled

Taiwan: 14

Country: Number of subjects enrolled

Thailand: 3

Country: Number of subjects enrolled

Belgium: 6

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Netherlands: 5

Country: Number of subjects enrolled

Spain: 6

Worldwide total number of subjects

161

EEA total number of subjects

28

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

108

From 65 to 84 years

53

85 years and over

0

Subject disposition

Top of page

Recruitment details

This study was conducted at 31 centers located on: Australia, Belgium, China, France, Germany, Israel, Italy, Japan, Korea, Netherlands, New Zealand, Singapore, Spain, Taiwan and Thailand.

Screening details

All patients must had documented evidence of EGFR mutation. A locally documented result from anytime during the patients treatment cycle was acceptable.. If EGFR mutation status was unknown, patients could be tested for EGFR mutation status centrally.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

INC280 100 mg Cap QD Phase Ib

Arm description

cap=capsule; QD=once daily

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

INC280 100 mg once daily oral capsule

INC280 200 mg Cap QD Phase Ib

Arm description

cap=capsule; QD=once daily

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

INC280 200 mg once daily oral Capsule

INC280 400 mg Cap QD Phase Ib

Arm description

cap=capsule; QD=once daily

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

INC280 400 mg once daily oral capsule

INC280 800 mg Cap QD Phase Ib

Arm description

cap=capsule; QD=once daily

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

INCC280 800 mg once daily oral capsule

INC280 200 mg Cap BID Phase Ib

Arm description

cap=capsule; BID=twice daily

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

INC280 200 mg twice daily oral capsule

INC280 400 mg Cap BID Phase Ib

Arm description

cap=capsule; BID=twice daily

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

INC280 400 mg twice daily oral capsule

INC280 600 mg Cap BID Phase Ib

Arm description

cap=capsule; BID=twice daily

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

INC280 600 mg twice daily oral capsule

INC280 200 mg Tab BID Phase Ib

Arm description

tab=tablet; BID=twice daily

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

INC280 200 mg twice daily oral tablet

INC280 400 mg Tab BID Phase Ib

Arm description

tab=tablet; BID=twice daily

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

INC280 400 mg twice daily oral tablet

INC280 400 mg Cap BID Phase II

Arm description

cap=capsule; BID=twice daily

Arm type

Experimental

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

INC280 400 mg twice daily oral capsule

INC280 400 mg Tab BID Phase II

Arm description

tab=tablet; BID=twice daily

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

INC280 400 mg twice daily oral tablet

Number of subjects in period 1	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Started	5	7	6	7	4	12	5	7	8	53	47
Completed	0	0	0	0	0	0	0	0	0	0	0
Not completed	5	7	6	7	4	12	5	7	8	53	47
Adverse event, serious fatal	-	-	-	-	-	1	3	-	-	1	2
Physician decision	-	-	-	-	-	-	1	-	-	-	-
Adverse event, non-fatal	-	-	-	1	1	1	-	-	2	8	6
Protocol Deviation	-	-	-	-	-	-	-	-	-	1	-
Progressive Disease	4	6	6	5	3	10	1	6	6	40	36
Subject/Guardian decision	1	1	-	1	-	-	-	1	-	2	2
Transfer to another trial	-	-	-	-	-	-	-	-	-	-	1
Non-Compliance with study treatment	-	-	-	-	-	-	-	-	-	1	-

Baseline characteristics

Top of page

Reporting group title

INC280 100 mg Cap QD Phase Ib

Reporting group description

cap=capsule; QD=once daily

Reporting group title

INC280 200 mg Cap QD Phase Ib

Reporting group description

cap=capsule; QD=once daily

Reporting group title

INC280 400 mg Cap QD Phase Ib

Reporting group description

cap=capsule; QD=once daily

Reporting group title

INC280 800 mg Cap QD Phase Ib

Reporting group description

cap=capsule; QD=once daily

Reporting group title

INC280 200 mg Cap BID Phase Ib

Reporting group description

cap=capsule; BID=twice daily

Reporting group title

INC280 400 mg Cap BID Phase Ib

Reporting group description

cap=capsule; BID=twice daily

Reporting group title

INC280 600 mg Cap BID Phase Ib

Reporting group description

cap=capsule; BID=twice daily

Reporting group title

INC280 200 mg Tab BID Phase Ib

Reporting group description

tab=tablet; BID=twice daily

Reporting group title

INC280 400 mg Tab BID Phase Ib

Reporting group description

tab=tablet; BID=twice daily

Reporting group title

INC280 400 mg Cap BID Phase II

Reporting group description

cap=capsule; BID=twice daily

Reporting group title

INC280 400 mg Tab BID Phase II

Reporting group description

tab=tablet; BID=twice daily

Reporting group values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II	Total
Number of subjects	5	7	6	7	4	12	5	7	8	53	47	161
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	3	3	5	7	2	11	4	4	7	35	27	108
From 65-84 years	2	4	1	0	2	1	1	3	1	18	20	53
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	57.8 ± 11.05	60.4 ± 15.27	59.5 ± 6.89	51.3 ± 8.88	64.5 ± 8.89	55.9 ± 10.81	61.0 ± 8.46	60.9 ± 12.86	58.4 ± 5.01	58.6 ± 10.50	62.8 ± 9.32	-
Sex: Female, Male
Units: participants
Female	2	5	4	5	4	4	2	5	5	33	19	88
Male	3	2	2	2	0	8	3	2	3	20	28	73
Race/Ethnicity, Customized
Units: Subjects
Russian	0	0	0	0	0	0	0	0	0	0	1	1
Mixed Ethnicity	0	0	0	0	0	0	0	0	0	0	1	1
Not reported	0	0	0	0	0	0	0	0	0	0	2	2
Unknown	0	0	0	0	0	0	0	0	0	0	3	3
Hispanic or Latino	0	0	0	0	0	1	0	1	0	0	5	7
Southeast Asian	1	1	0	0	0	0	0	1	1	0	8	12
Other	0	0	0	0	1	2	1	2	0	0	11	17
East Asian	4	6	6	7	3	9	4	3	7	53	16	118

End points

Top of page

Reporting group title

INC280 100 mg Cap QD Phase Ib

Reporting group description

cap=capsule; QD=once daily

Reporting group title

INC280 200 mg Cap QD Phase Ib

Reporting group description

cap=capsule; QD=once daily

Reporting group title

INC280 400 mg Cap QD Phase Ib

Reporting group description

cap=capsule; QD=once daily

Reporting group title

INC280 800 mg Cap QD Phase Ib

Reporting group description

cap=capsule; QD=once daily

Reporting group title

INC280 200 mg Cap BID Phase Ib

Reporting group description

cap=capsule; BID=twice daily

Reporting group title

INC280 400 mg Cap BID Phase Ib

Reporting group description

cap=capsule; BID=twice daily

Reporting group title

INC280 600 mg Cap BID Phase Ib

Reporting group description

cap=capsule; BID=twice daily

Reporting group title

INC280 200 mg Tab BID Phase Ib

Reporting group description

tab=tablet; BID=twice daily

Reporting group title

INC280 400 mg Tab BID Phase Ib

Reporting group description

tab=tablet; BID=twice daily

Reporting group title

INC280 400 mg Cap BID Phase II

Reporting group description

cap=capsule; BID=twice daily

Reporting group title

INC280 400 mg Tab BID Phase II

Reporting group description

tab=tablet; BID=twice daily

Primary: Phase Ib: Frequency of dose limiting toxicities (DLTs)

Top of page

End point title

Phase Ib: Frequency of dose limiting toxicities (DLTs) ^[1] ^[2]

End point description

A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.

End point type

Primary

End point timeframe

Up to 215 weeks

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

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib
Number of subjects analysed	3	7	6	5	4	10	1	7	7
Units: Participants
Cough	0	0	0	0	0	0	1	0	0
Dizziness	0	0	0	1	0	0	0	0	0
Dyspnoea	0	0	0	0	0	0	1	0	0

No statistical analyses for this end point

Primary: Phase II : Overall Response Rate (ORR)

Top of page

End point title

Phase II : Overall Response Rate (ORR) ^[3] ^[4]

End point description

Overall response rate is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 (Overall Response (OR) = CR + PR). Complete Response (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 Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Primary

End point timeframe

Until disease progression, up to 60.8 weeks

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

End point values	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Number of subjects analysed	53	47
Units: Participants	12	17

No statistical analyses for this end point

Secondary: Phase Ib and II: Number of participants with Adverse Events (AEs)

Top of page

End point title

Phase Ib and II: Number of participants with Adverse Events (AEs)

End point description

Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

End point type

Secondary

End point timeframe

Up to 421 weeks

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Number of subjects analysed	5	7	6	7	4	12	5	7	8	53	47
Units: Participants
AEs	5	7	6	7	4	12	5	7	8	51	47
Grade 3/4 AEs	3	4	2	4	2	6	4	6	4	24	35

No statistical analyses for this end point

Secondary: Phase Ib and II: Number of participants with serious adverse events (SAEs)

Top of page

End point title

Phase Ib and II: Number of participants with serious adverse events (SAEs)

End point description

Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

End point type

Secondary

End point timeframe

Up to 421 weeks

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Number of subjects analysed	5	7	6	7	4	12	5	7	8	53	47
Units: Participants	1	2	2	3	0	4	3	5	3	12	19

No statistical analyses for this end point

Secondary: Phase Ib and II: Number of patients with dose reductions of INC280 by dose level

Top of page

End point title

Phase Ib and II: Number of patients with dose reductions of INC280 by dose level

End point description

Number of patients with dose reductions of INC280 by dose level as a measure of tolerability.

End point type

Secondary

End point timeframe

Up to 417 weeks

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Number of subjects analysed	5	7	6	7	4	12	5	7	8	53	47
Units: Participants
Without dose reductions	5	6	5	6	1	8	1	5	5	30	23
Only 1 dose reduction	0	1	0	1	2	2	2	0	1	13	17
2 dose reductions	0	0	1	0	0	1	1	1	1	6	5
3 dose reductions	0	0	0	0	1	0	1	0	0	1	1
>3 dose reductions	0	0	0	0	0	1	0	1	1	3	1

No statistical analyses for this end point

Secondary: Phase Ib and II: Number of patients with dose interruptions of gefitinib by dose level

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End point title

Phase Ib and II: Number of patients with dose interruptions of gefitinib by dose level ^[5]

End point description

Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability

End point type

Secondary

End point timeframe

Up to 417 weeks

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

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase II
Number of subjects analysed	5	7	6	7	4	12	5	7	8	47
Units: Participants
Without dose interruptions	5	5	6	4	4	6	4	4	4	25
With only one dose interruption	0	2	0	2	0	3	0	0	2	16
2 dose interruptions	0	0	0	0	0	1	0	1	0	4
3 dose interruptions	0	0	0	1	0	2	0	0	1	2
>3 dose interruptions	0	0	0	0	0	0	1	2	1	0

No statistical analyses for this end point

Secondary: Phase II: Overall survival (OS)

Top of page

End point title

Phase II: Overall survival (OS) ^[6]

End point description

Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause

End point type

Secondary

End point timeframe

From date of treatment until death due to any cause, up to 70.2 months

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

End point values	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Number of subjects analysed	53	47
Units: Months
median (confidence interval 95%)	12.3 (8.1 to 15.4)	15.2 (11.7 to 20.1)

No statistical analyses for this end point

Secondary: Phase II: Progression free survival (PFS)

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End point title

Phase II: Progression free survival (PFS) ^[7]

End point description

Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.

End point type

Secondary

End point timeframe

Up to 60.8 months

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

End point values	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Number of subjects analysed	53	47
Units: Months
median (confidence interval 95%)	5.1 (3.6 to 5.6)	5.5 (3.8 to 7.3)

No statistical analyses for this end point

Secondary: Phase II: Duration of response (DoR)

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End point title

Phase II: Duration of response (DoR) ^[8]

End point description

Duration of overall response (DOR) is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression or death due to underlying cancer.

End point type

Secondary

End point timeframe

Up to 23.2 months

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

End point values	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Number of subjects analysed	12	17
Units: Months
median (confidence interval 95%)	5.6 (3.7 to 6.2)	5.6 (3.7 to 7.4)

No statistical analyses for this end point

Secondary: Phase I: PK parameters AUCtau of INC280 and gefitinib

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End point title

Phase I: PK parameters AUCtau of INC280 and gefitinib ^[9]

End point description

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Area under the plasma concentration-time curve (AUC) from time zero to the end of dosing interval at steady state (tau), where tau=24 hours for once daily dosing and tau=12 hours for twice daily dosing

End point type

Secondary

End point timeframe

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

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

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib
Number of subjects analysed	4 ^[10]	7 ^[11]	5 ^[12]	3 ^[13]	4 ^[14]	10 ^[15]	2 ^[16]	7 ^[17]	7 ^[18]
Units: hr∙ng/mL
arithmetic mean (standard deviation)
INC280	4510 ± 1960	9140 ± 5550	29200 ± 12700	30300 ± 19800	9660 ± 5780	21400 ± 8420	37300 ± 18800	13900 ± 4470	28700 ± 5460
Gefitinib	7690 ± 1400	8070 ± 2080	7140 ± 1830	12800 ± 999	8440 ± 2360	8500 ± 5330	999 ± 999	7160 ± 2040	7820 ± 1130

Notes
[10] - 4 subjects analyzed for INC280. 3 subjects analyzed for Gefitinib.
[11] - 7 subjects analyzed for INC280. 6 subjects analyzed for Gefitinib.
[12] - 5 subjects analyzed for INC280. 3 subjects analyzed for Gefitinib.
[13] - 3 subjects analyzed for INC280. 1 subjects analyzed for Gefitinib.
[14] - 4 subjects analyzed for INC280. 2 subjects analyzed for Gefitinib.
[15] - 10 subjects analyzed for INC280. 6 subjects analyzed for Gefitinib.
[16] - 2 subjects analyzed for INC280. 0 subjects analyzed for Gefitinib.
[17] - 7 subjects analyzed for INC280. 5 subjects analyzed for Gefitinib.
[18] - 7 subjects analyzed for INC280. 4 subjects analyzed for Gefitinib.

No statistical analyses for this end point

Secondary: Phase I: PK parameters Cmax of INC280 and gefitinib

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End point title

Phase I: PK parameters Cmax of INC280 and gefitinib ^[19]

End point description

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib

End point type

Secondary

End point timeframe

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

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: No statistical analysis was performed

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib
Number of subjects analysed	4	7	6	4	4	10	2	7	7
Units: ng/mL
arithmetic mean (standard deviation)
INC280	826 ± 521	1490 ± 1430	4620 ± 3060	6570 ± 4360	1950 ± 985	4220 ± 2100	4840 ± 1990	2550 ± 676	6760 ± 1740
Gefitinib	417 ± 42.9	378 ± 85.2	405 ± 144	357 ± 225	480 ± 191	464 ± 209	255 ± 158	479 ± 167	355 ± 74.1

No statistical analyses for this end point

Secondary: Phase I: PK parameters Tmax of INC280 and gefitinib

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End point title

Phase I: PK parameters Tmax of INC280 and gefitinib ^[20]

End point description

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib

End point type

Secondary

End point timeframe

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

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: No statistical analysis was performed

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib
Number of subjects analysed	4	7	6	4	4	10	2	7	7
Units: Hours
median (full range (min-max))
INC280	1.96 (1.50 to 3.92)	2.00 (1.00 to 24.0)	2.00 (1.98 to 6.00)	2.05 (1.92 to 5.97)	1.50 (1.00 to 3.98)	2.00 (0.50 to 4.00)	5.00 (4.00 to 6.00)	2.00 (1.00 to 4.00)	1.08 (1.00 to 4.00)
Gefitinib	3.92 (0 to 8.00)	6.00 (3.97 to 24.0)	6.02 (2.00 to 8.0)	5.94 (2.10 to 7.28)	5.00 (4.00 to 8.00)	6.00 (3.97 to 8.00)	11.3 (0 to 22.5)	6.00 (2.00 to 7.50)	6.00 (3.90 to 7.95)

No statistical analyses for this end point

Secondary: Phase I: PK parameters apparent systemic plasma clearance rate of INC280 and gefitinib

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End point title

Phase I: PK parameters apparent systemic plasma clearance rate of INC280 and gefitinib ^[21]

End point description

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib

End point type

Secondary

End point timeframe

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

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: No statistical analysis was performed

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib
Number of subjects analysed	4 ^[22]	7 ^[23]	5 ^[24]	3 ^[25]	4 ^[26]	10 ^[27]	2 ^[28]	7 ^[29]	7 ^[30]
Units: L/hr
arithmetic mean (standard deviation)
INC 280	26.9 ± 15.0	29.4 ± 15.7	16.3 ± 7.61	47.7 ± 49.1	27.0 ± 14.7	24.2 ± 18.3	18.4 ± 9.31	15.4 ± 3.89	14.4 ± 3.10
Gefitinib	33.3 ± 6.78	32.9 ± 9.65	36.5 ± 8.41	19.5 ± 999	30.8 ± 8.61	41.0 ± 24.1	999 ± 999	36.9 ± 8.81	32.5 ± 4.99

Notes
[22] - 4 subjects analyzed for INC280. 3 subjects analyzed for Gefitinib.
[23] - 7 subjects analyzed for INC280. 6 subjects analyzed for Gefitinib.
[24] - 5 subjects analyzed for INC280. 3 subjects analyzed for Gefitinib.
[25] - 3 subjects analyzed for INC280. 1 subjects analyzed for Gefitinib.
[26] - 4 subjects analyzed for INC280. 2 subjects analyzed for Gefitinib.
[27] - 10 subjects analyzed for INC280. 6 subjects analyzed for Gefitinib.
[28] - 2 subjects analyzed for INC280. 0 subjects analyzed for Gefitinib.
[29] - 7 subjects analyzed for INC280. 5 subjects analyzed for Gefitinib.
[30] - 7 subjects analyzed for INC280. 4 subjects analyzed for Gefitinib.

No statistical analyses for this end point

Secondary: Phase I: PK parameters half-life of INC280 and gefitinib

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End point title

Phase I: PK parameters half-life of INC280 and gefitinib ^[31]

End point description

PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. The elimination half-life of INC280 and gefitinib associated with the terminal slope (Lamda_z) of a semi-logarithmic plasma concentration-time curve

End point type

Secondary

End point timeframe

Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(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: No statistical analysis was performed

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib
Number of subjects analysed	4 ^[32]	6 ^[33]	5 ^[34]	3 ^[35]	3 ^[36]	9 ^[37]	0 ^[38]	7 ^[39]	6 ^[40]
Units: hours
arithmetic mean (standard deviation)
INC280	3.86 ± 0.564	5.10 ± 2.01	3.16 ± 0.361	3.67 ± 0.796	3.19 ± 0.942	3.01 ± 1.38	±	3.75 ± 1.94	3.17 ± 0.783
Gefitinib	18.8 ± 999	26.9 ± 4.63	36.3 ± 8.20	37.8 ± 999	16.3 ± 2.16	18.7 ± 7.75	±	17.8 ± 5.08	23.9 ± 999

Notes
[32] - 4 subjects analyzed for INC280. 1 subjects analyzed for Gefitinib.
[33] - 6 subjects analyzed for INC280. 3 subjects analyzed for Gefitinib.
[34] - 5 subjects analyzed for INC280. 2 subjects analyzed for Gefitinib.
[35] - 3 subjects analyzed for INC280. 1 subjects analyzed for Gefitinib.
[36] - 3 subjects analyzed for INC280. 2 subjects analyzed for Gefitinib.
[37] - 9 subjects analyzed for INC280. 3 subjects analyzed for Gefitinib.
[38] - No patients analyzed due to insufficient number of blood samples
[39] - 7 subjects analyzed for INC280. 3 subjects analyzed for Gefitinib.
[40] - 6 subjects analyzed for INC280. 1 subjects analyzed for Gefitinib.

No statistical analyses for this end point

Other pre-specified: Phase I: Percentage of change from baseline in C-MET H score at cycle 1 day 15

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End point title

Phase I: Percentage of change from baseline in C-MET H score at cycle 1 day 15

End point description

Inhibition of c-MET signaling by pre- and post- treatment immunohistochemistry of p-c-MET

End point type

Other pre-specified

End point timeframe

Baseline, Day 15 of cycle 1 (Cycle=28days)

End point values	INC280 100 mg Cap QD Phase Ib	INC280 200 mg Cap QD Phase Ib	INC280 400 mg Cap QD Phase Ib	INC280 800 mg Cap QD Phase Ib	INC280 200 mg Cap BID Phase Ib	INC280 400 mg Cap BID Phase Ib	INC280 600 mg Cap BID Phase Ib	INC280 200 mg Tab BID Phase Ib	INC280 400 mg Tab BID Phase Ib	INC280 400 mg Cap BID Phase II	INC280 400 mg Tab BID Phase II
Number of subjects analysed	1	0 ^[41]	0 ^[42]	0 ^[43]	0 ^[44]	3	0 ^[45]	0 ^[46]	0 ^[47]	1	0 ^[48]
Units: Percentage
median (full range (min-max))	-100 (-100 to -100)	( to )	( to )	( to )	( to )	-100 (-100 to -100)	( to )	( to )	( to )	-31 (-31 to -31)	( to )

Notes
[41] - No tumor samples were available since tumor biopsy was optional for this study.
[42] - No tumor samples were available since tumor biopsy was optional for this study.
[43] - No tumor samples were available since tumor biopsy was optional for this study.
[44] - No tumor samples were available since tumor biopsy was optional for this study.
[45] - No tumor samples were available since tumor biopsy was optional for this study.
[46] - No tumor samples were available since tumor biopsy was optional for this study.
[47] - No tumor samples were available since tumor biopsy was optional for this study.
[48] - No tumor samples were available since tumor biopsy was optional for this study.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 8 years.

Adverse event reporting additional description

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

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

100 mg Cap QD (Ph Ib)

Reporting group description

100 mg Cap QD (Ph Ib)

Reporting group title

200 mg Cap QD (Ph Ib)

Reporting group description

200 mg Cap QD (Ph Ib)

Reporting group title

400 mg Cap QD (Ph Ib)

Reporting group description

400 mg Cap QD (Ph Ib)

Reporting group title

800 mg Cap QD (Ph Ib)

Reporting group description

800 mg Cap QD (Ph Ib)

Reporting group title

200 mg Cap BID (Ph Ib)

Reporting group description

200 mg Cap BID (Ph Ib)

Reporting group title

400 mg Cap BID (Ph Ib)

Reporting group description

400 mg Cap BID (Ph Ib)

Reporting group title

600 mg Cap BID (Ph Ib)

Reporting group description

600 mg Cap BID (Ph Ib)

Reporting group title

200 mg Tab BID (Ph Ib)

Reporting group description

200 mg Tab BID (Ph Ib)

Reporting group title

400 mg Tab BID (Ph Ib)

Reporting group description

400 mg Tab BID (Ph Ib)

Reporting group title

400 mg Cap BID (Ph II)

Reporting group description

400 mg Cap BID (Ph II)

Reporting group title

400 mg Tab BID (Ph II)

Reporting group description

400 mg Tab BID (Ph II)

Serious adverse events	100 mg Cap QD (Ph Ib)	200 mg Cap QD (Ph Ib)	400 mg Cap QD (Ph Ib)	800 mg Cap QD (Ph Ib)	200 mg Cap BID (Ph Ib)	400 mg Cap BID (Ph Ib)	600 mg Cap BID (Ph Ib)	200 mg Tab BID (Ph Ib)	400 mg Tab BID (Ph Ib)	400 mg Cap BID (Ph II)	400 mg Tab BID (Ph II)
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 5 (20.00%)	2 / 7 (28.57%)	2 / 6 (33.33%)	3 / 7 (42.86%)	0 / 4 (0.00%)	4 / 12 (33.33%)	3 / 5 (60.00%)	5 / 7 (71.43%)	3 / 8 (37.50%)	12 / 53 (22.64%)	19 / 47 (40.43%)
number of deaths (all causes)	1	0	0	1	0	1	3	0	1	6	2
number of deaths resulting from adverse events	0	0	0	0	0	0	1	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritumoural oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
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 / 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	0 / 0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	2 / 47 (4.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	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	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	2 / 5 (40.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	1 / 53 (1.89%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Haemoptysis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	2 / 3
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	0 / 0
Respiratory failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
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 / 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	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bilirubin conjugated increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood pressure decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femur fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Fibula fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
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 / 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	0 / 0
Hip fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Cardiac disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	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 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 1
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Gastritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Ileus
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	2 / 47 (4.26%)
occurrences 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	3 / 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	0 / 0
Device related infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Klebsiella infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	4 / 53 (7.55%)	2 / 47 (4.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 3	0 / 0
Pneumonia mycoplasmal
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Septic shock
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences 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	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	0 / 0

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

Non-serious adverse events	100 mg Cap QD (Ph Ib)	200 mg Cap QD (Ph Ib)	400 mg Cap QD (Ph Ib)	800 mg Cap QD (Ph Ib)	200 mg Cap BID (Ph Ib)	400 mg Cap BID (Ph Ib)	600 mg Cap BID (Ph Ib)	200 mg Tab BID (Ph Ib)	400 mg Tab BID (Ph Ib)	400 mg Cap BID (Ph II)	400 mg Tab BID (Ph II)
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	7 / 7 (100.00%)	6 / 6 (100.00%)	7 / 7 (100.00%)	4 / 4 (100.00%)	12 / 12 (100.00%)	4 / 5 (80.00%)	6 / 7 (85.71%)	7 / 8 (87.50%)	49 / 53 (92.45%)	47 / 47 (100.00%)
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Orthostatic hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Peripheral vascular disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Phlebitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	2 / 7 (28.57%)	1 / 8 (12.50%)	3 / 53 (5.66%)	4 / 47 (8.51%)
occurrences all number	0	1	1	0	0	1	1	4	1	3	5
Chest discomfort
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	1 / 47 (2.13%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	1
Face oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	0	0
Fatigue
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	10 / 53 (18.87%)	17 / 47 (36.17%)
occurrences all number	1	1	1	1	0	2	1	1	2	12	22
Generalised oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	2
Influenza like illness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Mucosal inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0	0	0
Non-cardiac chest pain
subjects affected / exposed	1 / 5 (20.00%)	2 / 7 (28.57%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	8 / 53 (15.09%)	4 / 47 (8.51%)
occurrences all number	1	2	2	0	0	1	0	0	1	8	5
Oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	3
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)	1 / 4 (25.00%)	4 / 12 (33.33%)	2 / 5 (40.00%)	3 / 7 (42.86%)	2 / 8 (25.00%)	15 / 53 (28.30%)	21 / 47 (44.68%)
occurrences all number	0	0	2	1	4	4	2	18	2	20	30
Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0
Peripheral swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	4
Pyrexia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	2 / 53 (3.77%)	4 / 47 (8.51%)
occurrences all number	0	0	1	0	2	2	1	1	2	2	6
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)	1 / 4 (25.00%)	3 / 12 (25.00%)	3 / 5 (60.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	14 / 53 (26.42%)	8 / 47 (17.02%)
occurrences all number	0	0	2	1	1	3	3	0	1	16	10
Dysphonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	1	0
Dyspnoea
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 7 (28.57%)	1 / 4 (25.00%)	4 / 12 (33.33%)	1 / 5 (20.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	3 / 53 (5.66%)	9 / 47 (19.15%)
occurrences all number	1	0	1	3	1	4	1	1	2	3	9
Haemoptysis
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	1 / 4 (25.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	8 / 53 (15.09%)	2 / 47 (4.26%)
occurrences all number	2	0	1	1	1	1	0	2	0	12	2
Interstitial lung disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0
Nasal dryness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	4 / 53 (7.55%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	1	0	1	0	4	0
Productive cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	4 / 47 (8.51%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	4
Pulmonary embolism
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Rhinorrhoea
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0
Tachypnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 4 (50.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	2	1	0	0	0	2	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	1	0	1	0	1	0
Depression
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Insomnia
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	3 / 7 (42.86%)	1 / 8 (12.50%)	7 / 53 (13.21%)	2 / 47 (4.26%)
occurrences all number	1	0	1	0	1	0	1	3	1	7	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	1 / 4 (25.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	13 / 53 (24.53%)	5 / 47 (10.64%)
occurrences all number	0	0	1	1	1	2	2	0	0	17	7
Amylase increased
subjects affected / exposed	2 / 5 (40.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	4 / 12 (33.33%)	0 / 5 (0.00%)	2 / 7 (28.57%)	1 / 8 (12.50%)	7 / 53 (13.21%)	11 / 47 (23.40%)
occurrences all number	2	1	0	0	1	6	0	2	1	9	15
Aspartate aminotransferase increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	10 / 53 (18.87%)	7 / 47 (14.89%)
occurrences all number	1	0	1	1	0	1	0	0	0	16	9
Bilirubin conjugated increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	5 / 53 (9.43%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	5	0
Blood albumin decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	2	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	4 / 47 (8.51%)
occurrences all number	0	0	0	1	1	0	0	0	0	2	4
Blood bilirubin increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	5 / 12 (41.67%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	8 / 53 (15.09%)	4 / 47 (8.51%)
occurrences all number	0	0	0	0	0	8	0	0	0	14	6
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	3 / 12 (25.00%)	1 / 5 (20.00%)	2 / 7 (28.57%)	0 / 8 (0.00%)	9 / 53 (16.98%)	8 / 47 (17.02%)
occurrences all number	0	1	0	0	0	3	1	2	0	12	11
Blood glucose increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Blood iron decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	1	0
Blood phosphorus increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Crystal urine present
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	3 / 53 (5.66%)	5 / 47 (10.64%)
occurrences all number	0	0	0	0	0	0	0	0	0	3	6
Haemoglobin decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	3 / 53 (5.66%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	4	0
Lipase increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	5 / 53 (9.43%)	10 / 47 (21.28%)
occurrences all number	1	1	0	0	0	2	3	1	0	6	16
Neutrophil count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	1	0
Protein total increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Protein urine present
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	2 / 5 (40.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	4	0	0	4	0
Urinary sediment present
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0	0	0
Urine analysis abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Urine bilirubin increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Urine ketone body present
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	2	0
Urobilinogen urine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	0 / 53 (0.00%)	4 / 47 (8.51%)
occurrences all number	0	1	0	0	0	1	0	1	3	0	4
Weight increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	4
White blood cell count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1	0	0	0	3	1
White blood cells urine positive
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	1	0
Injury, poisoning and procedural complications
Hand fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Skin abrasion
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Tracheal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Wound complication
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1
Nervous system disorders
Cognitive disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Depressed level of consciousness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 7 (28.57%)	2 / 4 (50.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 8 (25.00%)	6 / 53 (11.32%)	3 / 47 (6.38%)
occurrences all number	0	0	1	2	3	1	0	0	2	8	4
Dyskinesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Facial spasm
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Headache
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	1 / 7 (14.29%)	3 / 8 (37.50%)	3 / 53 (5.66%)	8 / 47 (17.02%)
occurrences all number	0	0	0	1	0	2	1	2	3	4	10
Hypoaesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 53 (1.89%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	1	0	0	1	0	1	1
Nervous system disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	2 / 47 (4.26%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	2
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	1
Taste disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Tremor
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	2 / 53 (3.77%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	2 / 4 (50.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	18 / 53 (33.96%)	4 / 47 (8.51%)
occurrences all number	0	0	0	1	2	1	3	0	0	28	7
Leukopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	5 / 53 (9.43%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	13	0
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	4 / 53 (7.55%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	9	0
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	2 / 47 (4.26%)
occurrences all number	0	0	0	0	2	1	0	0	0	0	2
Tinnitus
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	1
Eye disorders
Dry eye
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	2 / 47 (4.26%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	2
Eye irritation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Lacrimation increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 7 (28.57%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	1	0	0
Photopsia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Vision blurred
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	0
Visual acuity reduced
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	1
Abdominal distension
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	3 / 53 (5.66%)	1 / 47 (2.13%)
occurrences all number	0	1	0	0	0	1	0	0	0	3	2
Abdominal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	1 / 53 (1.89%)	4 / 47 (8.51%)
occurrences all number	0	0	0	0	2	1	1	2	2	1	4
Abdominal pain upper
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	2 / 8 (25.00%)	1 / 53 (1.89%)	4 / 47 (8.51%)
occurrences all number	0	1	0	0	0	1	0	2	3	1	7
Constipation
subjects affected / exposed	3 / 5 (60.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	5 / 53 (9.43%)	11 / 47 (23.40%)
occurrences all number	3	2	0	0	1	1	0	1	0	5	11
Diarrhoea
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 7 (28.57%)	3 / 4 (75.00%)	4 / 12 (33.33%)	1 / 5 (20.00%)	1 / 7 (14.29%)	3 / 8 (37.50%)	7 / 53 (13.21%)	15 / 47 (31.91%)
occurrences all number	1	2	0	2	4	6	2	2	3	10	23
Dry mouth
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	2 / 47 (4.26%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	2
Duodenal ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Dyspepsia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	5
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Gastric ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Gastritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	2 / 47 (4.26%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	2
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0
Gingival bleeding
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	3 / 53 (5.66%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	2	0	0	0	3	1
Mouth ulceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	2 / 53 (3.77%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	2	0
Nausea
subjects affected / exposed	2 / 5 (40.00%)	2 / 7 (28.57%)	3 / 6 (50.00%)	6 / 7 (85.71%)	2 / 4 (50.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	5 / 7 (71.43%)	3 / 8 (37.50%)	7 / 53 (13.21%)	26 / 47 (55.32%)
occurrences all number	3	3	4	7	2	1	1	6	4	11	34
Stomatitis
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences all number	1	1	0	1	0	0	1	1	0	0	3
Vomiting
subjects affected / exposed	2 / 5 (40.00%)	3 / 7 (42.86%)	2 / 6 (33.33%)	7 / 7 (100.00%)	1 / 4 (25.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	2 / 7 (28.57%)	3 / 8 (37.50%)	10 / 53 (18.87%)	10 / 47 (21.28%)
occurrences all number	3	3	3	8	1	1	1	2	5	14	13
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3
Decubitus ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	1 / 5 (20.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	4 / 7 (57.14%)	1 / 8 (12.50%)	0 / 53 (0.00%)	5 / 47 (10.64%)
occurrences all number	1	2	0	1	0	1	0	4	1	0	8
Dermatosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Dry skin
subjects affected / exposed	0 / 5 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 53 (1.89%)	4 / 47 (8.51%)
occurrences all number	0	2	0	0	0	0	0	0	1	1	4
Pruritus
subjects affected / exposed	3 / 5 (60.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 4 (25.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	2 / 53 (3.77%)	5 / 47 (10.64%)
occurrences all number	3	1	0	1	2	1	0	0	1	2	5
Rash
subjects affected / exposed	2 / 5 (40.00%)	3 / 7 (42.86%)	0 / 6 (0.00%)	2 / 7 (28.57%)	2 / 4 (50.00%)	4 / 12 (33.33%)	1 / 5 (20.00%)	2 / 7 (28.57%)	3 / 8 (37.50%)	7 / 53 (13.21%)	15 / 47 (31.91%)
occurrences all number	2	3	0	2	2	4	1	5	4	9	19
Rash macular
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Rash maculo-papular
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0
Rash vesicular
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Skin fissures
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1
Urticaria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1
Renal and urinary disorders
Azotaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	3
Haematuria
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	5 / 53 (9.43%)	2 / 47 (4.26%)
occurrences all number	1	0	1	0	0	1	0	0	0	9	2
Haemoglobinuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0
Pollakiuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	2	0
Proteinuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	5	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	1 / 53 (1.89%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	4
Back pain
subjects affected / exposed	0 / 5 (0.00%)	4 / 7 (57.14%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	4 / 53 (7.55%)	4 / 47 (8.51%)
occurrences all number	0	4	0	1	0	0	0	0	0	4	4
Bone pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	2 / 53 (3.77%)	1 / 47 (2.13%)
occurrences all number	0	1	0	0	0	0	0	1	0	2	1
Flank pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0
Gouty arthritis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Joint swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	2	0
Ligament pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 4 (50.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	1 / 53 (1.89%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	3	0	0	1	1	1	4
Muscle tightness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	2 / 53 (3.77%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	1	2	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	2 / 53 (3.77%)	1 / 47 (2.13%)
occurrences all number	0	0	0	1	0	1	0	1	0	2	1
Musculoskeletal pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	3 / 53 (5.66%)	3 / 47 (6.38%)
occurrences all number	1	0	0	1	0	2	0	1	0	3	4
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	2 / 47 (4.26%)
occurrences all number	0	0	1	0	0	0	1	0	1	0	2
Neck pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	2
Pain in extremity
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	1 / 47 (2.13%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	1
Rhabdomyolysis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4
Conjunctivitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	2 / 47 (4.26%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	3
Cystitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	3 / 7 (42.86%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	5	1	0	0
Ear infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	0	0
Eye infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Folliculitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	1	0	0	0	3	0	0	1
Gastroenteritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Infected dermal cyst
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Influenza
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Localised infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	5 / 53 (9.43%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	2	1	1	0	14	1
Paronychia
subjects affected / exposed	2 / 5 (40.00%)	1 / 7 (14.29%)	2 / 6 (33.33%)	0 / 7 (0.00%)	2 / 4 (50.00%)	4 / 12 (33.33%)	0 / 5 (0.00%)	2 / 7 (28.57%)	3 / 8 (37.50%)	7 / 53 (13.21%)	10 / 47 (21.28%)
occurrences all number	2	1	2	0	2	4	0	6	3	7	11
Periodontitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0
Rhinitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Skin infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 8 (12.50%)	0 / 53 (0.00%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	4 / 47 (8.51%)
occurrences all number	1	0	0	0	0	1	1	0	0	2	4
Urinary tract infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	4 / 47 (8.51%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	5
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 5 (40.00%)	2 / 7 (28.57%)	1 / 6 (16.67%)	4 / 7 (57.14%)	1 / 4 (25.00%)	1 / 12 (8.33%)	3 / 5 (60.00%)	3 / 7 (42.86%)	3 / 8 (37.50%)	13 / 53 (24.53%)	19 / 47 (40.43%)
occurrences all number	2	2	1	4	1	1	3	4	5	19	21
Hyperamylasaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	8 / 53 (15.09%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	14	0
Hyperglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	4 / 47 (8.51%)
occurrences all number	0	0	0	0	0	1	2	0	0	4	5
Hyperkalaemia
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	0 / 53 (0.00%)	1 / 47 (2.13%)
occurrences all number	1	2	0	0	0	0	0	0	0	0	2
Hypoalbuminaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 7 (28.57%)	3 / 4 (75.00%)	7 / 12 (58.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	23 / 53 (43.40%)	12 / 47 (25.53%)
occurrences all number	0	0	0	2	4	7	4	0	0	28	20
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	8 / 53 (15.09%)	3 / 47 (6.38%)
occurrences all number	0	0	0	0	0	1	2	1	0	13	4
Hypochloraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	2 / 53 (3.77%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	3	0
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 4 (25.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	7 / 53 (13.21%)	4 / 47 (8.51%)
occurrences all number	0	0	1	0	1	2	6	0	0	8	4
Hypomagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	1 / 53 (1.89%)	2 / 47 (4.26%)
occurrences all number	0	0	0	0	0	1	1	0	0	1	2
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	2 / 7 (28.57%)	0 / 8 (0.00%)	6 / 53 (11.32%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	1	3	2	0	11	3
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 8 (0.00%)	3 / 53 (5.66%)	1 / 47 (2.13%)
occurrences all number	0	0	0	0	0	0	0	1	0	5	2
Hypoproteinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 12 (0.00%)	2 / 5 (40.00%)	0 / 7 (0.00%)	0 / 8 (0.00%)	5 / 53 (9.43%)	0 / 47 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	5	0

More information

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Were there any global substantial amendments to the protocol? Yes

03 Jul 2012

The main purpose of Amendment 1 was to further clarify the patient population with EGFR mutation, cMET amplified NSCLC who progressed on prior EGFR TKIs (e.g. gefitinib or erlotinib). Also a bid administration of capmatinib was to be investigated, based on emerging safety, PK, PD and efficacy results.

20 Dec 2013

The main purpose of Amendment 2 was to introduce the use of capmatinib tablets.

15 Jul 2014

The main purpose of Amendment 3 was to include additional NSCLC patients (200 in total) in Phase II. These additional NSCLC patients were to be selected based on high cMET dysregulation defined as ≥ 50% of tumor cells with an IHC score of =3+; or an IHC score of =2+ and ≥ 5 gene copies detected by FISH.

24 Jul 2015

The main purpose of Amendment 4 was to provide a safety update, revised inclusion and exclusion criteria including the molecular pre-screening criteria, and reassess the sample size.

Were there any global interruptions to the trial? No

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

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

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The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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