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Clinical Trial Results:
A Phase I/II study of safety and efficacy of ribociclib (LEE011) in combination with trametinib (TMT212) in patients with metastatic or advanced solid tumors

Summary
EudraCT number	2015-005019-34
Trial protocol	NL BE ES
Global end of trial date	24 Sep 2019

Results information
Results version number	v1(current)
This version publication date	23 Sep 2020
First version publication date	23 Sep 2020
Other versions

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

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Trial information

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Sponsor protocol code

CTMT212X2106

ISRCTN number

US NCT number

NCT02703571

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

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

Scientific contact

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

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

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

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

Analysis stage

Final

Date of interim/final analysis

24 Sep 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Sep 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of Phase Ib was to define the maximum tolerated dose (MTD) and/or the recommended Phase II regimen (RP2R) of ribociclib and trametinib in patients with solid tumors. The Phase II part was not pursued, and the study was closed after completion of the Phase Ib part of the study.

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

29 Jun 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 13

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

Germany: 5

Country: Number of subjects enrolled

Netherlands: 10

Country: Number of subjects enrolled

Spain: 4

Country: Number of subjects enrolled

United States: 46

Country: Number of subjects enrolled

Australia: 7

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in 15 investigative sites in 7 countries from 29-Jun-2016 to 14-Mar-2019

Screening details

Subjects with advanced or metastatic solid tumors independently of the RAS mutation status were screened for eligibility during the 28 days prior to starting study treatment on Cycle 1 Day 1. The eligibility assessments were performed and ensured that all inclusion and exclusion were satisfied.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

TMT212+LEE011

Arm description

Phase Ib part: Patients with advanced or metastatic solid tumors participating in the Phase I part received combination treatment with ribociclib (projected dose levels: 0.5 mg, 1 mg, 1.5 mg and 2 mg) and trametinib (projected dose levels: 200 mg, 300 mg, 400 mg, 500 mg and 600 mg) at different dosing regimens. Phase II part: Patients with advanced or metastatic pancreatic adenocarcinoma who have failed at least one prior systemic treatment and patients with advanced or metastatic KRAS mutant colorectal carcinoma who have failed at least two prior lines of treatment.

Arm type

Experimental

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Tablet, Capsule

Routes of administration

Oral use

Dosage and administration details

During the Phase I part, ribociclib was administered orally and escalated from 200 to 600mg at different dosing schedules: 1) once daily on days 1 to 21 of a 28 days cycle; 2) once daily on days 8 to 21 of a 21-day cycle (Schedule 1); and 3) once daily on days 1 to 14 of a 21-day cycle (Schedule 2).

Investigational medicinal product name

Trametinib

Investigational medicinal product code

TMT212

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

During the Phase I part, trametinib 0.5, 1, 1.5 or 2 mg was administered orally at different dosing schedules: 1) once daily on days 1 to 21 of a 28-day cycle; 2) once daily on days 1 to 14 of a 21-day cycle (Schedule 1 and Schedule 2)

Number of subjects in period 1	TMT212+LEE011
Started	95
Full analysis set	95
Safety set	95
Dose determining set	79
Completed	0
Not completed	95
Adverse event, serious fatal	1
Physician decision	8
Disease progression	55
Adverse event, non-fatal	14
Lost to follow-up	1
Sponsor decision	1
Subject/guardian decision	15

Baseline characteristics

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Reporting group title

Overall study

Reporting group description

Patients with advanced or metastatic solid tumors participating in the Phase I part received combination treatment with ribociclib (projected dose levels: 0.5 mg, 1 mg, 1.5 mg and 2 mg) and trametinib (projected dose levels: 200 mg, 300 mg, 400 mg, 500 mg and 600 mg) at different dosing regimens. Phase II part of the study was not conducted

Reporting group values	Overall study	Total
Number of subjects	95	95
Age categorical
Units: Subjects
In utero	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0
Newborns (0-27 days)	0	0
Infants and toddlers (28 days-23 months)	0	0
Children (2-11 years)	0	0
Adolescents (12-17 years)	0	0
Adults (18-64 years)	66	66
From 65-84 years	29	29
85 years and over	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	58.0 ± 9.89	-
Sex: Female, Male
Units: Participants
Female	46	46
Male	49	49
Race/Ethnicity, Customized
Units: Subjects
Asian	5	5
Black	2	2
Caucasian	84	84
Pacific islander	1	1
Unknown	3	3

End points

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Reporting group title

TMT212+LEE011

Reporting group description

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

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End point title

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

End point description

Phase Ib part: Incidence of DLTs during the first 21 days of therapy. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle of treatment with ribociclib and trametinib and meets any of the criteria described in the protocol.

End point type

Primary

End point timeframe

21-day cycle one of treatment

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned for this endpoint

End point values	TMT212+LEE011
Number of subjects analysed	79
Units: Participants	12

No statistical analyses for this end point

Primary: Phase II: Objective Response Rate (ORR)

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End point title

Phase II: Objective Response Rate (ORR) ^[2]

End point description

Phase II part: ORR is defined as the proportion of patients with a best overall confirmed complete response (CR) or partial response (PR), as assessed per RECIST 1.1 by investigator assessment.

End point type

Primary

End point timeframe

Until progression of disease up to 1 year

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned for this endpoint

End point values	TMT212+LEE011
Number of subjects analysed	0 ^[3]
Units: Percentage of participants
number (confidence interval 95%)	( to )

Notes
[3] - Phase 2 was not initiated; no data was collected.

No statistical analyses for this end point

Secondary: Phase Ib: Progression disease rate

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End point title

Phase Ib: Progression disease rate

End point description

Phase Ib part: Progression disease rate defined as the proportion of patients with a progression disease as assessed per RECIST 1.1 by investigator assessment.

End point type

Secondary

End point timeframe

Until progression of disease, up to approximately 2 years

End point values	TMT212+LEE011
Number of subjects analysed	95
Units: Percentage of Participants
number (confidence interval 95%)	44.2 (34.0 to 54.8)

No statistical analyses for this end point

Secondary: Phase Ib: Progression free survival (PFS)

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End point title

Phase Ib: Progression free survival (PFS)

End point description

Phase Ib part: PFS is defined as the time from the date of the first dose of study drug to the date of first documented disease progression per RECIST 1.1 and investigator assessment or death due to any cause.

End point type

Secondary

End point timeframe

Until progression of disease or death, up to approximately 2 years

End point values	TMT212+LEE011
Number of subjects analysed	95
Units: Months
median (confidence interval 95%)	2.6 (1.8 to 3.2)

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)

End point description

Phase II part: Among patients with a confirmed response (PR or CR) per RECIST 1.1, DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause.

End point type

Secondary

End point timeframe

From first documented response until progression of disease or death, up to 1 year

End point values	TMT212+LEE011
Number of subjects analysed	0 ^[4]
Units: Months
arithmetic mean (confidence interval 95%)	( to )

Notes
[4] - Phase 2 was not initiated; no data was collected.

No statistical analyses for this end point

Secondary: Phase II: Time to response

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End point title

Phase II: Time to response

End point description

Phase II part:Time to overall response of CR or PR (TTR) is defined as the time from start of study drug to first documented response (CR or PR, which must be confirmed subsequently) for patients with a confirmed CR or PR. Phase 2 was not initiated; no data was collected.

End point type

Secondary

End point timeframe

From start of study drug to first documented response, up to 1 year

End point values	TMT212+LEE011
Number of subjects analysed	0 ^[5]
Units: Months
arithmetic mean (confidence interval 95%)	( to )

Notes
[5] - Phase 2 was not initiated; no data was collected.

No statistical analyses for this end point

Secondary: Phase II: Disease Control Rate (DCR)

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End point title

Phase II: Disease Control Rate (DCR)

End point description

Phase II part: DCR is defined as the proportion of patients with best overall response of CR, PR, or SD per RECIST 1.1. Phase 2 was not initiated; no data was collected.

End point type

Secondary

End point timeframe

Until progression of disease up to 1 year

End point values	TMT212+LEE011
Number of subjects analysed	0 ^[6]
Units: Percentage of Participants
number (confidence interval 95%)	( to )

Notes
[6] - Phase 2 was not initiated; no data was collected.

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)

End point description

Phase II part: PFS is defined as the time from the date of the first dose of study drug to the date of first documented disease progression per RECIST 1.1 and investigator assessment or death due to any cause. Phase 2 was not initiated; no data was collected.

End point type

Secondary

End point timeframe

Until progression of disease or death, up to 1 year

End point values	TMT212+LEE011
Number of subjects analysed	0 ^[7]
Units: Months
median (confidence interval 95%)	( to )

Notes
[7] - Phase 2 was not initiated; no data was collected.

No statistical analyses for this end point

Secondary: Phase II: Overall Survival (OS)

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End point title

Phase II: Overall Survival (OS)

End point description

Phase II part: OS is defined as the time from the date of first dose of study drug to the date of death due to any cause. Phase 2 was not initiated; no data was collected.

End point type

Secondary

End point timeframe

Up to 1 year

End point values	TMT212+LEE011
Number of subjects analysed	0 ^[8]
Units: Months
median (confidence interval 95%)	( to )

Notes
[8] - Phase 2 was not initiated; no data was collected.

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 25.53 months.

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

21.1

Reporting group title

Cohort 0: LEE011 200mg 21 on/7 off + TMT212 2 mg QD

Reporting group description

2 mg TMT212 administered once daily on Days 1-28 and 200 mg LEE011 administered once daily on Days 1-21 followed by a 7-day break of a 28-day cycle

Reporting group title

Cohort 1: TMT212 1.5 mg QD + LEE011 200 mg QD - Schedule 1

Reporting group description

1.5 mg TMT212 administered once daily on Days 1-14 and 200 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle.

Reporting group title

Cohort 2a: TMT212 2 mg QD + LEE011 200 mg QD- Schedule 1

Reporting group description

2 mg TMT212 administered once daily on Days 1-14 and 200 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle

Reporting group title

Cohort 2b: TMT212 1.5 mg QD + LEE011 300 mg QD- Schedule 1

Reporting group description

1.5 mg TMT212 administered once daily on Days 1-14 and 300 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle

Reporting group title

Cohort 3a: TMT212 2 mg QD + LEE011 300 mg QD- Schedule 1

Reporting group description

2 mg TMT212 administered once daily on Days 1-14 and 300 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle

Reporting group title

Cohort 3b: TMT212 1.5 mg QD + LEE011 400 mg QD - Schedule 1

Reporting group description

1.5 mg TMT212 administered once daily on Days 1-14 and 400 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle

Reporting group title

Cohort 4a: TMT212 2 mg QD + LEE011 400 mg QD - Schedule 1

Reporting group description

2 mg TMT212 administered once daily on Days 1-14 and 400 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle

Reporting group title

Cohort 4a*: TMT212 2 mg QD + LEE011 400 mg QD- Schedule 2

Reporting group description

2 mg TMT212 administered once daily on Days 1-14 and LEE011 administered once daily on Days 1-14 of a 21-day cycle

Reporting group title

Cohort 5a: TMT212 2 mg QD + LEE011 500 mg QD- Schedule 1

Reporting group description

2 mg TMT212 administered once daily on Days 1-14 and 500 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle

Reporting group title

Cohort Xa: TMT212 1 mg QD + LEE011 300 mg QD- Schedule 1

Reporting group description

1 mg TMT212 administered once daily on Days 1-14 and 300 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle

Reporting group title

Cohort Xb: TMT212 1 mg QD + LEE011 400 mg QD- Schedule 1

Reporting group description

1 mg TMT212 administered once daily on Days 1-14 and 400 mg LEE011 administered once daily on Days 8-21 of a 21-day cycle

Reporting group title

All Subjects

Reporting group description

All subjects who received at least one dose of either study drug in the Phase I part of the study

Cohort 0: LEE011 200mg 21 on/7 off + TMT212 2 mg QD

Cohort 1: TMT212 1.5 mg QD + LEE011 200 mg QD - Schedule 1

Cohort 2a: TMT212 2 mg QD + LEE011 200 mg QD- Schedule 1

Cohort 2b: TMT212 1.5 mg QD + LEE011 300 mg QD- Schedule 1

Cohort 3a: TMT212 2 mg QD + LEE011 300 mg QD- Schedule 1

Cohort 3b: TMT212 1.5 mg QD + LEE011 400 mg QD - Schedule 1

Cohort 4a: TMT212 2 mg QD + LEE011 400 mg QD - Schedule 1

Cohort 4a*: TMT212 2 mg QD + LEE011 400 mg QD- Schedule 2

Cohort 5a: TMT212 2 mg QD + LEE011 500 mg QD- Schedule 1

Cohort Xa: TMT212 1 mg QD + LEE011 300 mg QD- Schedule 1

Cohort Xb: TMT212 1 mg QD + LEE011 400 mg QD- Schedule 1

All Subjects

Total subjects affected by serious adverse events

subjects affected / exposed

2 / 5 (40.00%)

1 / 7 (14.29%)

1 / 6 (16.67%)

2 / 5 (40.00%)

5 / 12 (41.67%)

4 / 12 (33.33%)

6 / 10 (60.00%)

6 / 9 (66.67%)

5 / 10 (50.00%)

2 / 10 (20.00%)

6 / 9 (66.67%)

40 / 95 (42.11%)

number of deaths (all causes)

number of deaths resulting from adverse events

General disorders and administration site conditions

Administration site extravasation

subjects affected / exposed

0 / 5 (0.00%)

1 / 7 (14.29%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

General physical health deterioration

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Malaise

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

2 / 10 (20.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

2 / 95 (2.11%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

1 / 2

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pharyngeal inflammation

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Pulmonary arterial hypertension

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

1 / 5 (20.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Investigations

Blood creatine phosphokinase increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Blood creatinine increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 12 (8.33%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Ejection fraction decreased

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Occult blood positive

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 12 (8.33%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Overdose

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 12 (8.33%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Cerebral ischaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

Haemorrhage intracranial

subjects affected / exposed

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 1

0 / 0

0 / 1

Presyncope

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 12 (8.33%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Eye disorders

Retinal vein occlusion

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

1 / 9 (11.11%)

3 / 95 (3.16%)

occurrences causally related to treatment / all

1 / 1

0 / 0

0 / 1

0 / 0

0 / 1

1 / 3

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 6 (16.67%)

1 / 5 (20.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

2 / 95 (2.11%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Dysphagia

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 6 (16.67%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

2 / 95 (2.11%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

deaths causally related to treatment / all

0 / 0

0 / 1

Gastrointestinal perforation

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Intestinal obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 12 (8.33%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

2 / 95 (2.11%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 3

deaths causally related to treatment / all

0 / 0

Intestinal perforation

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 12 (8.33%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Large intestinal obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 6 (16.67%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 12 (8.33%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

2 / 9 (22.22%)

3 / 95 (3.16%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 3

1 / 4

deaths causally related to treatment / all

0 / 0

Obstruction gastric

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Oesophagitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Pancreatitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Small intestinal obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 6 (16.67%)

1 / 5 (20.00%)

1 / 12 (8.33%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

6 / 95 (6.32%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 6

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 2

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Bile duct obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Cholangitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hepatotoxicity

subjects affected / exposed

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Rash

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 12 (8.33%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

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 / 5 (0.00%)

1 / 12 (8.33%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

2 / 95 (2.11%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

deaths causally related to treatment / all

0 / 0

Groin pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Musculoskeletal pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Infections and infestations

Abdominal sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 12 (8.33%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

Biliary tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 12 (8.33%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Clostridium difficile infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Rash pustular

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

1 / 10 (10.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

1 / 12 (8.33%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Urinary tract infection bacterial

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 6 (0.00%)

0 / 5 (0.00%)

0 / 12 (0.00%)

0 / 10 (0.00%)

1 / 9 (11.11%)

0 / 10 (0.00%)

0 / 9 (0.00%)

1 / 95 (1.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Cohort 0: LEE011 200mg 21 on/7 off + TMT212 2 mg QD	Cohort 1: TMT212 1.5 mg QD + LEE011 200 mg QD - Schedule 1	Cohort 2a: TMT212 2 mg QD + LEE011 200 mg QD- Schedule 1	Cohort 2b: TMT212 1.5 mg QD + LEE011 300 mg QD- Schedule 1	Cohort 3a: TMT212 2 mg QD + LEE011 300 mg QD- Schedule 1	Cohort 3b: TMT212 1.5 mg QD + LEE011 400 mg QD - Schedule 1	Cohort 4a: TMT212 2 mg QD + LEE011 400 mg QD - Schedule 1	Cohort 4a*: TMT212 2 mg QD + LEE011 400 mg QD- Schedule 2	Cohort 5a: TMT212 2 mg QD + LEE011 500 mg QD- Schedule 1	Cohort Xa: TMT212 1 mg QD + LEE011 300 mg QD- Schedule 1	Cohort Xb: TMT212 1 mg QD + LEE011 400 mg QD- Schedule 1	All Subjects
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	7 / 7 (100.00%)	6 / 6 (100.00%)	5 / 5 (100.00%)	12 / 12 (100.00%)	12 / 12 (100.00%)	10 / 10 (100.00%)	8 / 9 (88.89%)	10 / 10 (100.00%)	10 / 10 (100.00%)	9 / 9 (100.00%)	94 / 95 (98.95%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pyogenic granuloma
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Tumour pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 12 (0.00%)	2 / 12 (16.67%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 95 (4.21%)
occurrences all number	0	0	1	1	0	2	0	0	0	0	0	4
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Embolism
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1
Hypertension
subjects affected / exposed	1 / 5 (20.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	3 / 10 (30.00%)	0 / 9 (0.00%)	2 / 10 (20.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	11 / 95 (11.58%)
occurrences all number	1	2	0	0	2	0	3	0	2	1	1	12
Hypotension
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	1	0	0	0	0	0	0	1	1	0	0	3
Lymphoedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	2
Vascular rupture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 5 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	1 / 10 (10.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	8 / 95 (8.42%)
occurrences all number	0	2	0	0	1	1	1	3	1	1	0	10
Device related thrombosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Face oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Fatigue
subjects affected / exposed	3 / 5 (60.00%)	5 / 7 (71.43%)	3 / 6 (50.00%)	4 / 5 (80.00%)	8 / 12 (66.67%)	7 / 12 (58.33%)	6 / 10 (60.00%)	4 / 9 (44.44%)	5 / 10 (50.00%)	5 / 10 (50.00%)	4 / 9 (44.44%)	54 / 95 (56.84%)
occurrences all number	3	5	3	4	9	7	7	5	6	5	4	58
Gait disturbance
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Influenza like illness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Malaise
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	3	0	0	3
Oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	2 / 6 (33.33%)	1 / 5 (20.00%)	5 / 12 (41.67%)	5 / 12 (41.67%)	5 / 10 (50.00%)	3 / 9 (33.33%)	1 / 10 (10.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	26 / 95 (27.37%)
occurrences all number	0	1	4	1	7	6	6	3	1	1	2	32
Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Peripheral swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	0	1	1	0	0	2
Pyrexia
subjects affected / exposed	1 / 5 (20.00%)	3 / 7 (42.86%)	1 / 6 (16.67%)	1 / 5 (20.00%)	4 / 12 (33.33%)	3 / 12 (25.00%)	2 / 10 (20.00%)	3 / 9 (33.33%)	3 / 10 (30.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	22 / 95 (23.16%)
occurrences all number	1	5	1	1	4	3	2	3	3	1	0	24
Secretion discharge
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Suprapubic pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Swelling face
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Temperature intolerance
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Xerosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	2
Immune system disorders
Contrast media reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	2
Immune system disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Seasonal allergy
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1
Breast pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Pelvic pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Scrotal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Uterine pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Vulvovaginal pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Respiratory, thoracic and mediastinal disorders
Aphonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Cough
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)	8 / 95 (8.42%)
occurrences all number	1	1	1	0	1	1	0	2	0	0	2	9
Dysphonia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 95 (4.21%)
occurrences all number	0	1	0	0	1	0	1	1	0	0	0	4
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	2 / 6 (33.33%)	1 / 5 (20.00%)	3 / 12 (25.00%)	1 / 12 (8.33%)	2 / 10 (20.00%)	2 / 9 (22.22%)	1 / 10 (10.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	16 / 95 (16.84%)
occurrences all number	0	1	2	1	3	1	2	2	1	1	2	16
Dyspnoea at rest
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Dyspnoea exertional
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Epistaxis
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 95 (4.21%)
occurrences all number	1	1	0	0	1	0	0	0	1	0	0	4
Haemoptysis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	2
Increased upper airway secretion
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	2
Oropharyngeal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 12 (16.67%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	0	0	0	0	2	0	0	1	0	0	0	3
Pharyngeal inflammation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Pleural effusion
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	0	2
Pleuritic pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Pneumonitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Productive cough
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	1	0	0	0	0	0	1	0	0	1	0	3
Rhinorrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	2
Sleep apnoea syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	1	0	1	0	0	0	2
Bruxism
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Confusional state
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	2
Depression
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	0	1	0	0	0	0	0	1	1	0	0	3
Insomnia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	2
Mental status changes
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Sleep disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	2
Alanine aminotransferase increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	2 / 5 (40.00%)	2 / 12 (16.67%)	2 / 12 (16.67%)	2 / 10 (20.00%)	4 / 9 (44.44%)	2 / 10 (20.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)	19 / 95 (20.00%)
occurrences all number	2	0	3	3	2	3	2	12	3	0	2	32
Amylase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	7 / 95 (7.37%)
occurrences all number	0	0	2	0	0	1	0	3	2	1	4	13
Aspartate aminotransferase increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	4 / 6 (66.67%)	4 / 5 (80.00%)	5 / 12 (41.67%)	4 / 12 (33.33%)	7 / 10 (70.00%)	5 / 9 (55.56%)	4 / 10 (40.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	38 / 95 (40.00%)
occurrences all number	2	2	5	5	6	4	8	8	6	1	2	49
Bilirubin conjugated increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 5 (0.00%)	3 / 7 (42.86%)	2 / 6 (33.33%)	2 / 5 (40.00%)	2 / 12 (16.67%)	1 / 12 (8.33%)	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)	15 / 95 (15.79%)
occurrences all number	0	3	2	2	4	1	1	0	3	0	4	20
Blood bilirubin increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	2 / 10 (20.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	6 / 95 (6.32%)
occurrences all number	1	0	1	0	0	1	3	0	0	1	0	7
Blood creatine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	1	0	0	1	0	0	2
Blood creatine phosphokinase increased
subjects affected / exposed	2 / 5 (40.00%)	3 / 7 (42.86%)	3 / 6 (50.00%)	1 / 5 (20.00%)	6 / 12 (50.00%)	6 / 12 (50.00%)	4 / 10 (40.00%)	4 / 9 (44.44%)	5 / 10 (50.00%)	0 / 10 (0.00%)	3 / 9 (33.33%)	37 / 95 (38.95%)
occurrences all number	2	3	4	1	10	6	6	8	7	0	3	50
Blood creatinine decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	3 / 6 (50.00%)	0 / 5 (0.00%)	2 / 12 (16.67%)	2 / 12 (16.67%)	0 / 10 (0.00%)	2 / 9 (22.22%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	11 / 95 (11.58%)
occurrences all number	0	0	3	0	2	3	0	3	3	2	0	16
Blood urea increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
C-reactive protein increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Ejection fraction decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	4 / 95 (4.21%)
occurrences all number	1	0	1	0	0	0	0	0	1	1	0	4
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 5 (20.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	8 / 95 (8.42%)
occurrences all number	1	1	2	1	1	1	0	1	0	0	1	9
International normalised ratio increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Lipase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	1 / 10 (10.00%)	1 / 9 (11.11%)	2 / 10 (20.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)	9 / 95 (9.47%)
occurrences all number	0	0	1	0	1	1	1	6	3	0	4	17
Liver function test increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Lymphocyte count decreased
subjects affected / exposed	0 / 5 (0.00%)	2 / 7 (28.57%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 95 (4.21%)
occurrences all number	0	2	1	0	0	0	0	0	1	0	0	4
Monocyte count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	4 / 12 (33.33%)	0 / 12 (0.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	10 / 95 (10.53%)
occurrences all number	0	0	2	0	6	0	3	1	1	0	2	15
Neutrophil count increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Platelet count decreased
subjects affected / exposed	2 / 5 (40.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	2 / 12 (16.67%)	1 / 10 (10.00%)	1 / 9 (11.11%)	2 / 10 (20.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	10 / 95 (10.53%)
occurrences all number	2	0	0	0	2	2	1	1	2	1	0	11
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	7 / 95 (7.37%)
occurrences all number	0	1	0	0	1	0	1	1	0	1	2	7
Weight increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
White blood cell count decreased
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	3 / 12 (25.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	3 / 10 (30.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	9 / 95 (9.47%)
occurrences all number	0	2	0	0	0	4	0	2	4	0	1	13
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Avulsion fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Thermal burn
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Wrist fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Cardiac disorders
Atrioventricular block first degree
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1
Mitral valve thickening
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Sinus bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	2	0	1	0	0	3
Ventricular arrhythmia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Balance disorder
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Dizziness
subjects affected / exposed	1 / 5 (20.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	2 / 5 (40.00%)	1 / 12 (8.33%)	2 / 12 (16.67%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	11 / 95 (11.58%)
occurrences all number	1	3	0	2	1	2	0	2	1	1	0	13
Dysgeusia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	2 / 10 (20.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	7 / 95 (7.37%)
occurrences all number	0	0	2	1	1	0	2	0	2	0	1	9
Headache
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	2 / 12 (16.67%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	5 / 95 (5.26%)
occurrences all number	0	0	0	2	2	1	0	0	0	1	0	6
Hyperaesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	2
Hypoaesthesia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	2	0	0	0	0	0	0	2	0	0	4
Neuropathy peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	3 / 12 (25.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 95 (4.21%)
occurrences all number	0	0	0	0	3	3	0	0	0	0	0	6
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	1	0	0	0	0	1	0	0	0	0	2
Peripheral sensory neuropathy
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	0	1	2	0	0	0	1	0	0	0	0	4
Seizure
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	2
Somnolence
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Syncope
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	0	2
Taste disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	2
Tongue paralysis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Transient ischaemic attack
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 5 (60.00%)	2 / 7 (28.57%)	3 / 6 (50.00%)	2 / 5 (40.00%)	8 / 12 (66.67%)	7 / 12 (58.33%)	3 / 10 (30.00%)	5 / 9 (55.56%)	3 / 10 (30.00%)	2 / 10 (20.00%)	2 / 9 (22.22%)	40 / 95 (42.11%)
occurrences all number	4	3	3	3	9	9	3	8	3	4	3	52
Leukopenia
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	5 / 95 (5.26%)
occurrences all number	1	0	0	0	0	0	1	1	1	3	0	7
Lymphopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	2
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	3 / 12 (25.00%)	1 / 12 (8.33%)	1 / 10 (10.00%)	2 / 9 (22.22%)	3 / 10 (30.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)	14 / 95 (14.74%)
occurrences all number	0	1	0	0	5	2	1	3	6	2	1	21
Thrombocytopenia
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 12 (16.67%)	0 / 12 (0.00%)	2 / 10 (20.00%)	3 / 9 (33.33%)	4 / 10 (40.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	15 / 95 (15.79%)
occurrences all number	2	0	0	0	2	0	2	4	7	1	2	20
Ear and labyrinth disorders
Ear congestion
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Tinnitus
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Vertigo
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Eye disorders
Chorioretinopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Dry eye
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	0	1	0	0	1	0	0	1	0	0	0	3
Eye irritation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Eye pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1
Eye swelling
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Periorbital oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Retinal detachment
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Retinal disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	0	2
Retinal exudates
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Subretinal fluid
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Vision blurred
subjects affected / exposed	0 / 5 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	0	2	0	0	0	0	1	0	0	0	0	3
Visual impairment
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	2
Vitreous floaters
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0	2
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	0	0	0	1	0	0	1	2	0	0	0	4
Abdominal distension
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	2
Abdominal pain
subjects affected / exposed	1 / 5 (20.00%)	3 / 7 (42.86%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	1 / 10 (10.00%)	3 / 9 (33.33%)	0 / 10 (0.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	13 / 95 (13.68%)
occurrences all number	1	3	0	1	0	1	1	4	0	2	2	15
Abdominal pain lower
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Abdominal pain upper
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	1	1	0	0	0	0	0	1	0	0	0	3
Anal incontinence
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Aphthous ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Ascites
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Constipation
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	2 / 6 (33.33%)	2 / 5 (40.00%)	1 / 12 (8.33%)	2 / 12 (16.67%)	3 / 10 (30.00%)	2 / 9 (22.22%)	0 / 10 (0.00%)	2 / 10 (20.00%)	2 / 9 (22.22%)	17 / 95 (17.89%)
occurrences all number	0	2	2	2	1	2	3	2	0	2	2	18
Diarrhoea
subjects affected / exposed	3 / 5 (60.00%)	5 / 7 (71.43%)	2 / 6 (33.33%)	3 / 5 (60.00%)	6 / 12 (50.00%)	7 / 12 (58.33%)	4 / 10 (40.00%)	5 / 9 (55.56%)	9 / 10 (90.00%)	1 / 10 (10.00%)	5 / 9 (55.56%)	50 / 95 (52.63%)
occurrences all number	3	12	6	3	6	10	6	6	13	1	6	72
Dry mouth
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	2 / 12 (16.67%)	0 / 12 (0.00%)	3 / 10 (30.00%)	2 / 9 (22.22%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	10 / 95 (10.53%)
occurrences all number	1	0	1	0	2	0	3	3	1	0	0	11
Duodenal ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Dyspepsia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	4 / 95 (4.21%)
occurrences all number	0	0	0	0	0	1	0	1	0	1	2	5
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Flatulence
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	2
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	4 / 95 (4.21%)
occurrences all number	0	0	1	0	0	0	1	1	0	0	1	4
Haemorrhoids
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1
Intra-abdominal haematoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Lip dry
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Lip pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Lip swelling
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0	2
Mouth ulceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Nausea
subjects affected / exposed	0 / 5 (0.00%)	3 / 7 (42.86%)	4 / 6 (66.67%)	3 / 5 (60.00%)	7 / 12 (58.33%)	7 / 12 (58.33%)	3 / 10 (30.00%)	3 / 9 (33.33%)	5 / 10 (50.00%)	4 / 10 (40.00%)	5 / 9 (55.56%)	44 / 95 (46.32%)
occurrences all number	0	6	5	3	10	8	4	5	6	5	6	58
Oesophageal discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Oesophagitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	2
Oral discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Proctalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Rectal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	0	2
Retching
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	2 / 7 (28.57%)	3 / 6 (50.00%)	2 / 5 (40.00%)	8 / 12 (66.67%)	3 / 12 (25.00%)	3 / 10 (30.00%)	5 / 9 (55.56%)	6 / 10 (60.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	33 / 95 (34.74%)
occurrences all number	0	2	6	2	12	3	3	7	6	1	0	42
Tongue discolouration
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1
Tooth loss
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Toothache
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Vomiting
subjects affected / exposed	2 / 5 (40.00%)	5 / 7 (71.43%)	3 / 6 (50.00%)	1 / 5 (20.00%)	3 / 12 (25.00%)	5 / 12 (41.67%)	3 / 10 (30.00%)	5 / 9 (55.56%)	2 / 10 (20.00%)	3 / 10 (30.00%)	6 / 9 (66.67%)	38 / 95 (40.00%)
occurrences all number	2	6	7	1	10	5	3	8	2	3	8	55
Hepatobiliary disorders
Gallbladder obstruction
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Hepatosplenomegaly
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)	2 / 12 (16.67%)	0 / 12 (0.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	6 / 95 (6.32%)
occurrences all number	0	1	1	0	3	0	0	2	0	0	0	7
Dermatitis acneiform
subjects affected / exposed	2 / 5 (40.00%)	3 / 7 (42.86%)	3 / 6 (50.00%)	1 / 5 (20.00%)	4 / 12 (33.33%)	2 / 12 (16.67%)	3 / 10 (30.00%)	1 / 9 (11.11%)	2 / 10 (20.00%)	2 / 10 (20.00%)	5 / 9 (55.56%)	28 / 95 (29.47%)
occurrences all number	2	13	4	1	4	2	4	1	2	2	5	40
Dry skin
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	2 / 6 (33.33%)	0 / 5 (0.00%)	2 / 12 (16.67%)	4 / 12 (33.33%)	3 / 10 (30.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	16 / 95 (16.84%)
occurrences all number	1	1	2	0	2	4	3	1	0	1	1	16
Eczema asteatotic
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Erythema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	4 / 95 (4.21%)
occurrences all number	0	0	0	1	1	0	0	1	0	0	1	4
Hyperhidrosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	0	1	0	0	0	1	0	0	0	1	0	3
Ingrowing nail
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Night sweats
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	2
Pain of skin
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Photosensitivity reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	3 / 95 (3.16%)
occurrences all number	0	0	1	1	0	0	0	0	0	1	0	3
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 12 (16.67%)	1 / 12 (8.33%)	4 / 10 (40.00%)	2 / 9 (22.22%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	11 / 95 (11.58%)
occurrences all number	0	0	0	0	4	1	4	2	2	0	0	13
Rash
subjects affected / exposed	0 / 5 (0.00%)	3 / 7 (42.86%)	3 / 6 (50.00%)	1 / 5 (20.00%)	8 / 12 (66.67%)	8 / 12 (66.67%)	4 / 10 (40.00%)	5 / 9 (55.56%)	7 / 10 (70.00%)	5 / 10 (50.00%)	1 / 9 (11.11%)	45 / 95 (47.37%)
occurrences all number	0	3	7	2	16	10	6	13	8	5	1	71
Rash macular
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	2	1	0	0	0	3
Rash maculo-papular
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	2 / 10 (20.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	6 / 95 (6.32%)
occurrences all number	0	1	0	0	0	1	2	0	1	1	0	6
Rash pruritic
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Skin burning sensation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	2
Skin fissures
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 95 (4.21%)
occurrences all number	0	1	0	0	1	1	0	0	1	0	0	4
Skin necrosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Urticaria
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0	2
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	1	0	1	0	0	0	2
Chronic kidney disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	0	2
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1	2
Haematuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	4 / 95 (4.21%)
occurrences all number	0	0	0	1	0	1	0	0	1	0	1	4
Hydronephrosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Micturition urgency
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Proteinuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	4 / 12 (33.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	7 / 95 (7.37%)
occurrences all number	0	0	0	0	1	4	0	0	2	1	0	8
Renal failure
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Urinary incontinence
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Urinary retention
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Arthritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Back pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	6 / 95 (6.32%)
occurrences all number	0	0	1	0	1	0	1	0	0	1	3	7
Flank pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Groin pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1
Muscle spasms
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	0	2
Muscle swelling
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Muscle tightness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Musculoskeletal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0	2
Musculoskeletal stiffness
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	4 / 95 (4.21%)
occurrences all number	0	1	1	0	0	0	1	1	0	0	0	4
Myositis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Neck pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0	2
Pain in extremity
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	2
Infections and infestations
Arthritis infective
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Bronchitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Catheter site cellulitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Cellulitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	0	2
Erysipelas
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	2
Eye infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Fungal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	1	0	1	0	0	0	2
Herpes simplex
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Localised infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	2
Paronychia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Postoperative wound infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1
Pustule
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Rash pustular
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	2
Rhinitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Skin infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Staphylococcal skin infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Tinea cruris
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1
Tooth infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	0	3	1	0	0	4
Urinary tract infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)	0 / 12 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	8 / 95 (8.42%)
occurrences all number	1	0	0	1	1	0	1	1	1	1	1	8
Viral infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1
Metabolism and nutrition disorders
Appetite disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1
Decreased appetite
subjects affected / exposed	0 / 5 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	2 / 5 (40.00%)	3 / 12 (25.00%)	3 / 12 (25.00%)	1 / 10 (10.00%)	2 / 9 (22.22%)	1 / 10 (10.00%)	3 / 10 (30.00%)	4 / 9 (44.44%)	21 / 95 (22.11%)
occurrences all number	0	2	0	2	4	3	1	2	1	3	4	22
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	1 / 12 (8.33%)	2 / 12 (16.67%)	0 / 10 (0.00%)	2 / 9 (22.22%)	2 / 10 (20.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	9 / 95 (9.47%)
occurrences all number	0	0	1	0	1	2	0	2	3	0	2	11
Hypercalcaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1
Hyperglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	1 / 12 (8.33%)	2 / 10 (20.00%)	0 / 9 (0.00%)	2 / 10 (20.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)	6 / 95 (6.32%)
occurrences all number	0	0	0	0	0	1	3	0	2	1	0	7
Hyperkalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1
Hypernatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 95 (2.11%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	1	3
Hyperphosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Hypoalbuminaemia
subjects affected / exposed	1 / 5 (20.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	1 / 5 (20.00%)	3 / 12 (25.00%)	4 / 12 (33.33%)	2 / 10 (20.00%)	4 / 9 (44.44%)	4 / 10 (40.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)	23 / 95 (24.21%)
occurrences all number	1	2	0	1	4	4	2	5	4	1	1	25
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)	1 / 12 (8.33%)	0 / 10 (0.00%)	1 / 9 (11.11%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	5 / 95 (5.26%)
occurrences all number	0	0	0	0	1	1	0	1	2	0	0	5
Hypoglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 5 (0.00%)	2 / 12 (16.67%)	2 / 12 (16.67%)	2 / 10 (20.00%)	2 / 9 (22.22%)	1 / 10 (10.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)	12 / 95 (12.63%)
occurrences all number	0	0	1	0	2	2	2	2	1	0	3	13
Hypomagnesaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 5 (20.00%)	4 / 12 (33.33%)	2 / 12 (16.67%)	0 / 10 (0.00%)	1 / 9 (11.11%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	11 / 95 (11.58%)
occurrences all number	0	0	1	1	6	3	0	2	1	0	2	16
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 5 (0.00%)	2 / 12 (16.67%)	1 / 12 (8.33%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)	5 / 95 (5.26%)
occurrences all number	0	0	0	0	4	1	0	0	1	0	1	7
Hypophosphataemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)	0 / 12 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)	1 / 95 (1.05%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1

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Were there any global substantial amendments to the protocol? Yes

15 Apr 2016

The purpose of this amendment was to instruct female subjects to use highly effective methods of contraception for 4 months after their last dose of the drug. The original protocol erroneously indicated that only 30 days of post-drug contraception was necessary. The 4-month period was based on a washout period (5 half-lives) calculated using the longest individual half-life (523 hours) observed with trametinib.

03 Jan 2017

The purpose of this amendment was to revise the treatment schedule in order to improve the safety of trametinib and ribociclib given in combination. DLTs were observed in the first 5 subjects of this study, along with other adverse events, which were already reported in prior single agent studies with either trametinib or ribociclib. The original 28-day cycle of continuous trametinib 2 mg and 3 weeks on/1 week off of ribociclib 200 mg was then modified to an intermittent schedule for safety reasons. A 21-day schedule of 2 weeks on/1 week-off of trametinib and ribociclib was explored with two different dosing schedules: Schedule 1 (trametinib administered once daily from Day 1 to Day 14, and ribociclib administered once daily from Day 8 to Day 21 of a 21-day cycle. This schedule was assessed in successive cohorts of subjects receiving trametinib 1.5 to 2 mg and increasing doses of ribociclib (150 to 600 mg)); and Schedule 2: (trametinib administered once daily from Day 1 to Day 14, and ribociclib administered once daily from Day 1 to Day 14 of a 21-day cycle. This schedule was assessed with the MTD obtained with Schedule 1).

12 Jul 2018

This amendment was implemented in order to explore additional cohorts to achieve the target plasma concentrations for trametinib and establish MTD/RP2R. The following cohorts were explored in parallel: Cohort Xa (1.0 mg trametinib daily in combination with 300 mg ribociclib daily (using Schedule 1)); and Cohort Xb (1.0 mg trametinib daily in combination with 400 mg ribociclib daily (using Schedule 1)). Based on the analyses of above 2 cohorts, there was an option to assess additional cohorts (Ya and Yb) with 0.5 mg trametinib in combination with ribociclib, if 1 mg trametinib was not tolerated. The decision to test either Ya or Yb, or both cohorts in parallel was to be made based on BLRM, safety and PK data.

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.

Upon careful review of all available efficacy and safety data from the study phase Ib part, Novartis decided to not start the study phase II part. This decision was in no means triggered by an unfavorable safety profile of the combination.

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Clinical trials

Clinical Trial Results:
A Phase I/II study of safety and efficacy of ribociclib (LEE011) in combination with trametinib (TMT212) in patients with metastatic or advanced solid tumors

Trial information

Trial information

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Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Primary: Phase II: Objective Response Rate (ORR)

Primary: Phase II: Objective Response Rate (ORR)

Secondary: Phase Ib: Progression disease rate

Secondary: Phase Ib: Progression disease rate

Secondary: Phase Ib: Progression free survival (PFS)

Secondary: Phase Ib: Progression free survival (PFS)

Secondary: Phase II: Duration of response (DOR)

Secondary: Phase II: Duration of response (DOR)

Secondary: Phase II: Time to response

Secondary: Phase II: Time to response

Secondary: Phase II: Disease Control Rate (DCR)

Secondary: Phase II: Disease Control Rate (DCR)

Secondary: Phase II: Progression Free Survival (PFS)

Secondary: Phase II: Progression Free Survival (PFS)

Secondary: Phase II: Overall Survival (OS)

Secondary: Phase II: Overall Survival (OS)

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: A Phase I/II study of safety and efficacy of ribociclib (LEE011) in combination with trametinib (TMT212) in patients with metastatic or advanced solid tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Primary: Phase II: Objective Response Rate (ORR)

Primary: Phase II: Objective Response Rate (ORR)

Secondary: Phase Ib: Progression disease rate

Secondary: Phase Ib: Progression disease rate

Secondary: Phase Ib: Progression free survival (PFS)

Secondary: Phase Ib: Progression free survival (PFS)

Secondary: Phase II: Duration of response (DOR)

Secondary: Phase II: Duration of response (DOR)

Secondary: Phase II: Time to response

Secondary: Phase II: Time to response

Secondary: Phase II: Disease Control Rate (DCR)

Secondary: Phase II: Disease Control Rate (DCR)

Secondary: Phase II: Progression Free Survival (PFS)

Secondary: Phase II: Progression Free Survival (PFS)

Secondary: Phase II: Overall Survival (OS)

Secondary: Phase II: Overall Survival (OS)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase I/II study of safety and efficacy of ribociclib (LEE011) in combination with trametinib (TMT212) in patients with metastatic or advanced solid tumors