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Clinical Trial Results:
A Phase Ib/II, open-label, multicenter study of oral HDM201 in combination with oral LEE011 in adult patients with liposarcoma

Summary
EudraCT number	2014-003604-75
Trial protocol	ES DE FR
Global end of trial date	16 Oct 2019

Results information
Results version number	v1(current)
This version publication date	02 Oct 2020
First version publication date	02 Oct 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

CHDM201X2103C

ISRCTN number

US NCT number

NCT02343172

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 614231111, 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

16 Oct 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 Oct 2019

Was the trial ended prematurely?

Main objective of the trial

The main objective for this trial was to determine the maximum tolerated dose (MTD) and/or the recommended phase two dose (RP2D) of HDM201 in combination with LEE011 in one or more of the pre-defined regimens

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Mar 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 14

Country: Number of subjects enrolled

France: 21

Country: Number of subjects enrolled

Germany: 18

Country: Number of subjects enrolled

Singapore: 6

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

Taiwan: 6

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

The study did not enter the initially planned phase 2 part.

Screening details

Three different dosing regimen were tested : regimen 1, 4 and 5 (see detailed description for the definitions of these 3 different dosing regimen)

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Regimen 1: 2.5mg HDM201+400mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

HDM201

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

HDM201 was supplied as capsules of dosage strengths of 2.5, 10 and 100 mg. This information applies for all dosing cohorts

Investigational medicinal product name

LEE011

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

LEE011 was supplied as capsules of dosage strengths of 50 and 200 mg This information applies for all dosing cohorts

Regimen 1: 5mg HDM201+400mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 1: 10mg HDM201+400mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 1: 15mg HDM201+400mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 4: 50mg HDM201+400mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 4: 150mg HDM201+400mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 4: 200mg HDM201+400mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 4: 150mg HDM201+300mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 4: 120mg HDM201+200mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 5: 100mg HDM201+300mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 5: 120mg HDM201+300mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 5: 150mg HDM201+300mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 5: 200mg HDM201+300mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Regimen 5: 120mg HDM201+400mg LEE011

Arm description

escalation

Arm type

escalation cohort

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 1	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011	Regimen 5: 100mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 200mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011
Started	4	10	5	7	4	11	4	4	6	4	6	4	1	4
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	4	10	5	7	4	11	4	4	6	4	6	4	1	4
Adverse event, serious fatal	-	-	-	-	1	-	-	-	-	-	-	1	-	-
Physician decision	-	-	-	1	-	-	-	1	-	-	1	-	-	-
Adverse event, non-fatal	-	1	-	2	-	4	2	1	-	-	1	-	1	2
progressive disease	4	9	4	4	2	6	2	2	6	4	4	3	-	2
Subject/guardian decision	-	-	1	-	1	1	-	-	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

Regimen 1: 2.5mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 1: 5mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 1: 10mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 1: 15mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 50mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 150mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 200mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 150mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 120mg HDM201+200mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 100mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 120mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 150mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 200mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 120mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011	Regimen 5: 100mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 200mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011	Total
Number of subjects	4	10	5	7	4	11	4	4	6	4	6	4	1	4	74
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	4	6	3	4	2	6	1	2	3	2	3	2	0	3	41
From 65-84 years	0	4	2	3	2	5	3	2	3	2	3	2	1	1	33
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	50.3 ( 10.24 )	61.1 ( 13.50 )	61.4 ( 13.35 )	61.9 ( 6.84 )	61.5 ( 9.33 )	61.4 ( 11.51 )	67.8 ( 11.44 )	67.5 ( 10.02 )	67.5 ( 10.02 )	65.5 ( 4.80 )	62.0 ( 16.46 )	67.0 ( 10.10 )	67.0 ( 0 )	53.0 ( 10.95 )	-
Sex: Female, Male
Units: participants
Female	1	3	4	3	2	2	4	1	2	1	3	3	1	2	32
Male	3	7	1	4	2	9	0	3	4	3	3	1	0	2	42
Race/Ethnicity, Customized
Units: Subjects
Asian	1	2	1	2	1	3	1	1	1	1	1	1	0	1	17
Caucasian	3	8	4	4	3	8	3	2	5	3	5	3	1	3	55
Unknown	0	0	0	1	0	0	0	1	0	0	0	0	0	0	2

Subject analysis set title

2.5mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

5mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

10mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

15mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

50mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

100mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

120mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

150mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

200mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis sets values	2.5mg HDM201	5mg HDM201	10mg HDM201	15mg HDM201	50mg HDM201	100mg HDM201	120mg HDM201	150mg HDM201	200mg HDM201
Number of subjects	4	9	5	7	4	4	15	18	5
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Units: years
arithmetic mean (standard deviation)	1.5 ( )	3.1 ( )	4.1 ( )	6.1 ( )	7.8 ( )	11 ( )	12 ( )	13 ( )	10 ( )
Sex: Female, Male
Units: participants
Female
Male
Race/Ethnicity, Customized
Units: Subjects
Asian
Caucasian
Unknown

End points

Top of page

Reporting group title

Regimen 1: 2.5mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 1: 5mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 1: 10mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 1: 15mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 50mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 150mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 200mg HDM201+400mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 150mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 4: 120mg HDM201+200mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 100mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 120mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 150mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 200mg HDM201+300mg LEE011

Reporting group description

escalation

Reporting group title

Regimen 5: 120mg HDM201+400mg LEE011

Reporting group description

escalation

Subject analysis set title

2.5mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

5mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

10mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

15mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

50mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

100mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

120mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

150mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Subject analysis set title

200mg HDM201

Subject analysis set type

Sub-group analysis

Subject analysis set description

escalation

Primary: Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment.

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End point title

Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment. ^[1]

End point description

DLTs in the first cycle of treatment.

End point type

Primary

End point timeframe

5 years

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

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011	Regimen 5: 100mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 200mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011
Number of subjects analysed	4	8	4	7	3	11	4	4	6	4	6	3	1	4
Units: participants
Total	0	0	0	2	0	4	3	1	1	0	0	2	1	2
neutropenia	0	0	0	0	0	2	1	0	0	0	0	1	0	1
thrombocytopenia	0	0	0	0	0	1	2	0	0	0	0	0	0	1
anemia	0	0	0	0	0	0	1	0	1	0	0	0	0	0
platelet count decreased	0	0	0	2	0	2	1	1	1	0	0	1	1	1
neutrophil count decreased	0	0	0	1	0	1	1	0	0	0	0	0	1	0
white blood cell count decreased	0	0	0	0	0	1	1	0	0	0	0	0	1	0
Febrile neutropenia	0	0	0	0	0	0	0	0	0	0	0	0	0	1

No statistical analyses for this end point

Primary: Exposure to HDM201 and LEE011 as measured by AUC 0-24h

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End point title

Exposure to HDM201 and LEE011 as measured by AUC 0-24h ^[2] ^[3]

End point description

as measured by AUC0-24h

End point type

Primary

End point timeframe

5 years

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

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011	Regimen 5: 100mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011
Number of subjects analysed	3	4	4	6	3	9	3	2	6	4	4	4	4
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
HDM201	267.2 ( 66.2 )	587.6 ( 127.0 )	1339.3 ( 14.8 )	1458.2 ( 13.6 )	6547.9 ( 47.2 )	26066.2 ( 37.7 )	45670.5 ( 20.4 )	28307.2 ( 11.2 )	26294.4 ( 45.5 )	22069.8 ( 31.9 )	15473.7 ( 67.4 )	36102.4 ( 96.6 )	25249.2 ( 37.1 )
LEE011	11290.0 ( 85.6 )	5537.4 ( 138.1 )	6314.2 ( 38.8 )	3675.0 ( 21.8 )	8669.1 ( 80.5 )	8152.8 ( 64.6 )	9006.9 ( 18.7 )	5264.5 ( 17.7 )	3859.2 ( 70.7 )	5958.0 ( 71.6 )	3387.1 ( 88.8 )	7259.2 ( 106.0 )	11185.4 ( 67.0 )

No statistical analyses for this end point

Secondary: Number of patients with dose interruptions and reduction

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End point title

Number of patients with dose interruptions and reduction

End point description

To assess tolerability of HDM201 in combination with LEE011

End point type

Secondary

End point timeframe

5 years

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011	Regimen 5: 100mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 200mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011
Number of subjects analysed	4	10	5	7	4	11	4	4	6	4	6	4	1	4
Units: participants
HDM201 at least 1 dose reduction	0	0	1	2	0	7	2	3	3	0	3	0	1	1
LEE011 at least 1 dose interruption	1	0	1	0	0	2	1	2	0	0	0	0	0	2
HDM201 at least 1 dose delay	3	5	3	5	2	10	3	3	5	1	4	1	1	3
LEE011 at least 1 dose delay	3	5	3	5	2	11	4	3	5	1	5	3	1	3

No statistical analyses for this end point

Secondary: Dose intensity

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End point title

Dose intensity

End point description

To assess tolerability of HDM201 in combination with LEE011 SD of 999999 means not evaluable (only 1 participant in the subgroup)

End point type

Secondary

End point timeframe

5 years

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011	Regimen 5: 100mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 200mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011
Number of subjects analysed	4	10	5	7	4	11	4	4	6	4	6	4	1	4
Units: mg
arithmetic mean (standard deviation)
LEE011	411.5 ( 22.92 )	384.0 ( 25.36 )	368.0 ( 57.01 )	374.5 ( 39.09 )	392.8 ( 13.14 )	318.9 ( 60.72 )	293.1 ( 141.34 )	257.6 ( 29.31 )	189.6 ( 14.15 )	300.0 ( 0.00 )	256.6 ( 46.62 )	289.0 ( 21.95 )	300.0 ( 999999 )	338.4 ( 72.34 )
HDM201	2.6 ( 0.16 )	4.8 ( 0.31 )	8.5 ( 2.41 )	13.5 ( 2.28 )	67.9 ( 27.82 )	116.3 ( 42.92 )	159.8 ( 88.84 )	113.1 ( 65.96 )	117.7 ( 7.71 )	181.3 ( 37.50 )	131.8 ( 41.58 )	275.0 ( 43.30 )	128.6 ( 999999 )	205.3 ( 60.04 )

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 1

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End point title

Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 1 ^[4]

End point description

to evaluate PK parameters of HDM201 and LEE011

End point type

Secondary

End point timeframe

day 1, day 14

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

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011
Number of subjects analysed	4	8	5	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
HDM201 day 1	21.0 ( 48.5 )	41.0 ( 61.3 )	92.4 ( 5.0 )	107.3 ( 18.8 )
LEE011 day 1	1117.2 ( 66.4 )	664.2 ( 114.5 )	609.6 ( 53.2 )	459.5 ( 35.0 )
HDM201 day 14	52.3 ( 88.7 )	54.5 ( 62.5 )	131.7 ( 52.4 )	167.9 ( 36.0 )
LEE011 Day 14	1581.6 ( 61.3 )	635.8 ( 55.1 )	609.9 ( 92.9 )	447.0 ( 46.2 )

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 4

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End point title

Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 4 ^[5]

End point description

to evaluate PK parameters of HDM201 and LEE011

End point type

Secondary

End point timeframe

day 1, day 21

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

End point values	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011
Number of subjects analysed	4	10	3	2	6
Units: ng/mL
geometric mean (geometric coefficient of variation)
HDM201 day 1	275.9 ( 30.6 )	1277.6 ( 43.7 )	1982.7 ( 34.4 )	1475.9 ( 10.6 )	1284.4 ( 33.7 )
LEE011 day 1	685.7 ( 80.9 )	652.8 ( 88.5 )	932.9 ( 25.9 )	477.8 ( 24.8 )	491.0 ( 84.3 )
HDM201 day 21	201.2 ( 13.1 )	991.9 ( 77.5 )	2180.0 ( 0 )	1320.0 ( 0 )	1412.5 ( 24.8 )
LEE011 Day 21	516.0 ( 0 )	0 ( 0 )	2630.0 ( 0 )	0 ( 0 )	338.1 ( 36.4 )

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 5

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End point title

Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 5 ^[6]

End point description

to evaluate PK parameters of HDM201 and LEE011

End point type

Secondary

End point timeframe

day 1, day 28

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

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011
Number of subjects analysed	4	6	3	4
Units: ng/mL
geometric mean (geometric coefficient of variation)
HDM201 day 1	1043.3 ( 62.1 )	1103.1 ( 43.3 )	1544.7 ( 70.2 )	1180.4 ( 10.2 )
LEE011 day 1	614.6 ( 63.4 )	494.6 ( 88.5 )	805.2 ( 72.5 )	967.9 ( 89.0 )
HDM201 day 28	1023.1 ( 33.5 )	1010.7 ( 50.6 )	1170.9 ( 50.5 )	1170.1 ( 40.4 )
LEE011 Day 28	533.9 ( 54.0 )	465.6 ( 56.9 )	613.0 ( 30.3 )	547.1 ( 8.3 )

No statistical analyses for this end point

Secondary: Best overall response (BOR), Overall response rate (ORR) as per RECIST v1.1, assessed by investigator

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End point title

Best overall response (BOR), Overall response rate (ORR) as per RECIST v1.1, assessed by investigator

End point description

to assess the preliminary anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma: BOR (complete response, partial response, stable disease), ORR (complete response + partial response) , assessed by investigator

End point type

Secondary

End point timeframe

5 years

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011	Regimen 5: 100mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 200mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011
Number of subjects analysed	4	10	5	7	4	11	4	4	6	4	6	4	1	4
Units: participants
confirmed complete response	0	0	0	0	0	0	0	0	0	0	0	0	0	0
confirmed partial response	0	0	0	0	0	1	1	0	0	0	1	0	0	0
stable disease	1	5	2	3	2	7	2	4	2	2	4	1	1	2
overall response rate	0	0	0	0	0	1	1	0	0	0	1	0	0	0

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 1

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End point title

Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 1 ^[7]

End point description

to evaluate PK parameters of HDM201 and LEE011

End point type

Secondary

End point timeframe

day 1, day 14

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

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 1: 5mg HDM201+400mg LEE011	Regimen 1: 10mg HDM201+400mg LEE011	Regimen 1: 15mg HDM201+400mg LEE011
Number of subjects analysed	4	8	5	6
Units: ng*h/mL
geometric mean (geometric coefficient of variation)
HDM201 day 1	372.8 ( 59.8 )	547.6 ( 73.4 )	1289.7 ( 12.1 )	1495.1 ( 13.7 )
LEE011 day 1	11929.6 ( 67.8 )	5456.9 ( 103.8 )	5804.6 ( 38.5 )	3668.9 ( 21.7 )
HDM201 day 14	989.7 ( 106.8 )	857.3 ( 64.5 )	1854.5 ( 64.5 )	2088.9 ( 31.5 )
LEE011 Day 14	22807.5 ( 90.8 )	9247.0 ( 54.2 )	7589.5 ( 88.7 )	4833.7 ( 35.7 )

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 4

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End point title

Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 4 ^[8]

End point description

to evaluate PK parameters of HDM201 and LEE011

End point type

Secondary

End point timeframe

day 1, day 21

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

End point values	Regimen 4: 50mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+400mg LEE011	Regimen 4: 200mg HDM201+400mg LEE011	Regimen 4: 150mg HDM201+300mg LEE011	Regimen 4: 120mg HDM201+200mg LEE011
Number of subjects analysed	4	10	3	2	6
Units: ng*h/mL
geometric mean (geometric coefficient of variation)
HDM201 day 1	8316.9 ( 47.2 )	26039.0 ( 38.3 )	45554.1 ( 19.4 )	28048.9 ( 11.3 )	25570.9 ( 40.6 )
LEE011 day 1	7728.8 ( 68.4 )	6427.9 ( 78.6 )	8735.9 ( 18.7 )	5116.5 ( 17.3 )	3815.3 ( 69.8 )
HDM201 day 21	3652.1 ( 15.1 )	14617.1 ( 65.6 )	34451.4 ( 0 )	13209.5 ( 0 )	19065.0 ( 30.9 )
LEE011 Day 21	4249.0 ( 0 )	0 ( 0 )	19212.3 ( 0 )	0 ( 0 )	3389.4 ( 34.4 )

No statistical analyses for this end point

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 5

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End point title

Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 5 ^[9]

End point description

to evaluate PK parameters of HDM201 and LEE011

End point type

Secondary

End point timeframe

day 1, day 28

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

End point values	Regimen 1: 2.5mg HDM201+400mg LEE011	Regimen 5: 120mg HDM201+300mg LEE011	Regimen 5: 150mg HDM201+300mg LEE011	Regimen 5: 120mg HDM201+400mg LEE011
Number of subjects analysed	4	6	3	4
Units: ng*h/mL
geometric mean (geometric coefficient of variation)
HDM201 day 1	22014.2 ( 74.0 )	21593.8 ( 80.6 )	36044.8 ( 97.1 )	25086.4 ( 30.2 )
LEE011 day 1	5947.3 ( 71.9 )	4175.7 ( 109.3 )	7214.2 ( 108.1 )	11048.0 ( 68.3 )
HDM201 day 28	16136.7 ( 37.2 )	14516.4 ( 51.2 )	18343.0 ( 52.6 )	14214.2 ( 9.6 )
LEE011 Day 28	5803.3 ( 63.0 )	4622.2 ( 42.5 )	5381.0 ( 41.4 )	6149.6 ( 1.6 )

No statistical analyses for this end point

Secondary: Changes from baseline of Pharmacodynamics (PD) markers in blood (GDF-15)

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End point title

Changes from baseline of Pharmacodynamics (PD) markers in blood (GDF-15)

End point description

measure of GDF-15 fold-change in protein levels (PD direct targets of p53)

End point type

Secondary

End point timeframe

5 years

End point values	2.5mg HDM201	5mg HDM201	10mg HDM201	15mg HDM201	50mg HDM201	100mg HDM201	120mg HDM201	150mg HDM201	200mg HDM201
Number of subjects analysed	4	9	5	7	4	4	15	18	5
Units: mg
arithmetic mean (full range (min-max))	1.5 (1.2 to 1.7)	3.1 (1.4 to 8.8)	4.1 (1.4 to 6.4)	6.1 (3.9 to 9.2)	7.8 (2.1 to 13)	11 (9.1 to 13)	12 (5.7 to 21)	13 (4.9 to 25)	10 (7.6 to 13)

No statistical analyses for this end point

Secondary: Changes from baseline of Pharmacodynamics (PD) markers in tumor tissue (p21, MDM2)

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End point title

Changes from baseline of Pharmacodynamics (PD) markers in tumor tissue (p21, MDM2)

End point description

measure of MDM2 H-score versus HDM201 dose - all regimen. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors. The score is obtained by the formula: 3 x percentage of strongly staining nuclei + 2 x percentage of moderately staining nuclei + percentage of weakly staining nuclei, giving a range of 0 to 300.

End point type

Secondary

End point timeframe

5 years

End point values	2.5mg HDM201	5mg HDM201	10mg HDM201	15mg HDM201	50mg HDM201	100mg HDM201	120mg HDM201	150mg HDM201	200mg HDM201
Number of subjects analysed	4	9	5	7	4	4	15	18	5
Units: H-score
arithmetic mean (full range (min-max))
MDM2	98 (60 to 115)	55 (0.0 to 250)	38 (0.0 to 70)	83 (30 to 150)	155 (90 to 220)	157 (70 to 220)	92 (0.0 to 215)	134 (20 to 170)	275 (270 to 280)
p21	123 (30 to 195)	73 (0.0 to 250)	50 (0.0 to 140)	60 (0.0 to 190)	110 (0.0 to 220)	202 (130 to 240)	70 (0.0 to 163)	147 (0.0 to 240)	243 (130 to 255)

No statistical analyses for this end point

Secondary: Progression free survival (PFS) as per RECIST v1.1, assessed by investigator

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End point title

Progression free survival (PFS) as per RECIST v1.1, assessed by investigator

End point description

to assess the preliminary anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma: PFS as per RECIST v1.1, assessed by investigator. PFS rate is the estimated probability that a patient will remain progression-free up to the specified time point. PFS rates are obtained from the Kaplan-Meier survival estimates for all treatment groups; Greenwood formula is used for CIs of KM estimates. 999999 value for the CI means not evaluable

End point type

Secondary

End point timeframe

5 years

Regimen 1: 2.5mg HDM201+400mg LEE011

Regimen 1: 5mg HDM201+400mg LEE011

Regimen 1: 10mg HDM201+400mg LEE011

Regimen 1: 15mg HDM201+400mg LEE011

Regimen 4: 50mg HDM201+400mg LEE011

Regimen 4: 150mg HDM201+400mg LEE011

Regimen 4: 200mg HDM201+400mg LEE011

Regimen 4: 150mg HDM201+300mg LEE011

Regimen 4: 120mg HDM201+200mg LEE011

Regimen 5: 100mg HDM201+300mg LEE011

Regimen 5: 120mg HDM201+300mg LEE011

Regimen 5: 150mg HDM201+300mg LEE011

Regimen 5: 200mg HDM201+300mg LEE011

Regimen 5: 120mg HDM201+400mg LEE011

Number of subjects analysed

Units: months

median (confidence interval 95%)

2.5 (1.2 to 999999)

5.5 (2.7 to 8.2)

1.9 (1.4 to 19.1)

2.8 (1.4 to 999999)

5.5 (0.3 to 9.8)

4.8 (4.2 to 35.9)

4.2 (1.5 to 999999)

0 (0 to 0)

2.7 (1.6 to 4.0)

1.8 (1.3 to 4.2)

6.1 (4.0 to 14.1)

1.4 (1.0 to 999999)

9.2 (0 to 999999)

5.8 (1.4 to 5.8)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events were collected from the first patient first visit until the last patient last visit, plus a 30 day safety follow up period. The total duration for the collection of adverse events for this trials was approximately 4.5 years.

Adverse event reporting additional description

AE additional description

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Regimen 1@2.5 mg HDM201+ @400 mg LEE011

Reporting group description

Regimen 1@2.5 mg HDM201+ @400 mg LEE011

Reporting group title

Regimen 1@5 mg HDM201+ @400 mg LEE011

Reporting group description

Regimen 1@5 mg HDM201+ @400 mg LEE011

Reporting group title

Regimen 1@10 mg HDM201+ @400 mg LEE011

Reporting group description

Regimen 1@10 mg HDM201+ @400 mg LEE011

Reporting group title

Regimen 1@15 mg HDM201+ @400 mg LEE011

Reporting group description

Regimen 1@15 mg HDM201+ @400 mg LEE011

Reporting group title

Regimen 4@50 mg HDM201+ @400 mg LEE011

Reporting group description

Regimen 4@50 mg HDM201+ @400 mg LEE011

Reporting group title

Regimen 4@150 mg HDM201+ @400 mg LEE011

Reporting group description

Regimen 4@150 mg HDM201+ @400 mg LEE011

Reporting group title

Regimen 4@200 mg HDM201+ @400 mg LEE011

Reporting group description

Regimen 4@200 mg HDM201+ @400 mg LEE011

Reporting group title

Regimen 4@150 mg HDM201+ @300 mg LEE011

Reporting group description

Regimen 4@150 mg HDM201+ @300 mg LEE011

Reporting group title

Regimen 4@120 mg HDM201+ @200 mg LEE011

Reporting group description

Regimen 4@120 mg HDM201+ @200 mg LEE011

Reporting group title

Regimen 5@100 mg HDM201+ @300 mg LEE011

Reporting group description

Regimen 5@100 mg HDM201+ @300 mg LEE011

Reporting group title

Regimen 5@120 mg HDM201+ @300 mg LEE011

Reporting group description

Regimen 5@120 mg HDM201+ @300 mg LEE011

Reporting group title

Regimen 5@150 mg HDM201+ @300 mg LEE011

Reporting group description

Regimen 5@150 mg HDM201+ @300 mg LEE011

Reporting group title

Regimen 5@200 mg HDM201+ @300 mg LEE011

Reporting group description

Regimen 5@200 mg HDM201+ @300 mg LEE011

Reporting group title

Regimen 5@120 mg HDM201+ @400 mg LEE011

Reporting group description

Regimen 5@120 mg HDM201+ @400 mg LEE011

Reporting group title

Total

Reporting group description

Total

Regimen 1@2.5 mg HDM201+ @400 mg LEE011

Regimen 1@5 mg HDM201+ @400 mg LEE011

Regimen 1@10 mg HDM201+ @400 mg LEE011

Regimen 1@15 mg HDM201+ @400 mg LEE011

Regimen 4@50 mg HDM201+ @400 mg LEE011

Regimen 4@150 mg HDM201+ @400 mg LEE011

Regimen 4@200 mg HDM201+ @400 mg LEE011

Regimen 4@150 mg HDM201+ @300 mg LEE011

Regimen 4@120 mg HDM201+ @200 mg LEE011

Regimen 5@100 mg HDM201+ @300 mg LEE011

Regimen 5@120 mg HDM201+ @300 mg LEE011

Regimen 5@150 mg HDM201+ @300 mg LEE011

Regimen 5@200 mg HDM201+ @300 mg LEE011

Regimen 5@120 mg HDM201+ @400 mg LEE011

Total

Total subjects affected by serious adverse events

subjects affected / exposed

3 / 4 (75.00%)

2 / 10 (20.00%)

3 / 5 (60.00%)

2 / 7 (28.57%)

2 / 4 (50.00%)

4 / 11 (36.36%)

3 / 4 (75.00%)

0 / 4 (0.00%)

2 / 6 (33.33%)

1 / 4 (25.00%)

3 / 6 (50.00%)

1 / 4 (25.00%)

1 / 1 (100.00%)

2 / 4 (50.00%)

29 / 74 (39.19%)

number of deaths (all causes)

number of deaths resulting from adverse events

Investigations

Neutrophil count decreased

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

1 / 7 (14.29%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Platelet count decreased

subjects affected / exposed

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 5 (0.00%)

2 / 7 (28.57%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

4 / 74 (5.41%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

1 / 1

0 / 0

4 / 4

deaths causally related to treatment / all

0 / 0

White blood cell count decreased

subjects affected / exposed

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Vascular disorders

Hypotension

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Peripheral arterial occlusive disease

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Pericarditis

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 4 (25.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Aphasia

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 1 (100.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Disturbance in attention

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 1 (100.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Dizziness

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

1 / 11 (9.09%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Memory impairment

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 1 (100.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

2 / 4 (50.00%)

1 / 10 (10.00%)

0 / 5 (0.00%)

1 / 7 (14.29%)

0 / 4 (0.00%)

0 / 11 (0.00%)

1 / 4 (25.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

5 / 74 (6.76%)

occurrences causally related to treatment / all

1 / 2

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

4 / 5

deaths causally related to treatment / all

0 / 0

Febrile neutropenia

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 4 (25.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

2 / 74 (2.70%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

2 / 2

deaths causally related to treatment / all

0 / 0

Leukopenia

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Neutropenia

subjects affected / exposed

0 / 4 (0.00%)

1 / 10 (10.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

1 / 4 (25.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

3 / 74 (4.05%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

3 / 3

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

1 / 4 (25.00%)

0 / 10 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

2 / 4 (50.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

5 / 74 (6.76%)

occurrences causally related to treatment / all

1 / 1

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

1 / 1

5 / 5

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Asthenia

subjects affected / exposed

1 / 4 (25.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Chest pain

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

1 / 11 (9.09%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

2 / 4 (50.00%)

1 / 10 (10.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

5 / 74 (6.76%)

occurrences causally related to treatment / all

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

0 / 5

deaths causally related to treatment / all

0 / 0

Ascites

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal haemorrhage

subjects affected / exposed

1 / 4 (25.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Intestinal perforation

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

1 / 11 (9.09%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Subileus

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

1 / 5 (20.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Renal failure

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

1 / 4 (25.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

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

Fistula

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 4 (25.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

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

Infections and infestations

Abdominal infection

subjects affected / exposed

1 / 4 (25.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Aspergillus infection

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

1 / 11 (9.09%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Creutzfeldt-Jakob disease

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 1 (100.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Pneumonia

subjects affected / exposed

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 4 (25.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

2 / 74 (2.70%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

2 / 2

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

Sepsis

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

1 / 4 (25.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 4 (25.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

2 / 74 (2.70%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

1 / 2

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

1 / 2

Septic shock

subjects affected / exposed

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Tracheobronchitis

subjects affected / exposed

0 / 4 (0.00%)

0 / 10 (0.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

1 / 11 (9.09%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 74 (1.35%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 4 (0.00%)

1 / 10 (10.00%)

0 / 5 (0.00%)

0 / 7 (0.00%)

0 / 4 (0.00%)

0 / 11 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 4 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

2 / 74 (2.70%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

1 / 2

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Regimen 1@2.5 mg HDM201+ @400 mg LEE011	Regimen 1@5 mg HDM201+ @400 mg LEE011	Regimen 1@10 mg HDM201+ @400 mg LEE011	Regimen 1@15 mg HDM201+ @400 mg LEE011	Regimen 4@50 mg HDM201+ @400 mg LEE011	Regimen 4@150 mg HDM201+ @400 mg LEE011	Regimen 4@200 mg HDM201+ @400 mg LEE011	Regimen 4@150 mg HDM201+ @300 mg LEE011	Regimen 4@120 mg HDM201+ @200 mg LEE011	Regimen 5@100 mg HDM201+ @300 mg LEE011	Regimen 5@120 mg HDM201+ @300 mg LEE011	Regimen 5@150 mg HDM201+ @300 mg LEE011	Regimen 5@200 mg HDM201+ @300 mg LEE011	Regimen 5@120 mg HDM201+ @400 mg LEE011	Total
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 4 (100.00%)	10 / 10 (100.00%)	5 / 5 (100.00%)	7 / 7 (100.00%)	4 / 4 (100.00%)	11 / 11 (100.00%)	4 / 4 (100.00%)	4 / 4 (100.00%)	6 / 6 (100.00%)	4 / 4 (100.00%)	6 / 6 (100.00%)	4 / 4 (100.00%)	1 / 1 (100.00%)	4 / 4 (100.00%)	74 / 74 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lipoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Tumour pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	3 / 6 (50.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	6 / 74 (8.11%)
occurrences all number	0	3	0	0	0	0	1	0	1	0	3	0	0	0	8
Vascular disorders
Haematoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Hot flush
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Hypertension
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	2	0	0	0	4
Pallor
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 4 (50.00%)	2 / 10 (20.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	2 / 4 (50.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	10 / 74 (13.51%)
occurrences all number	2	4	1	1	5	1	0	0	2	0	0	0	0	0	16
Chills
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	0	0	1	0	0	0	1	1	0	0	2	0	0	0	5
Face oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Fatigue
subjects affected / exposed	2 / 4 (50.00%)	4 / 10 (40.00%)	2 / 5 (40.00%)	5 / 7 (71.43%)	2 / 4 (50.00%)	8 / 11 (72.73%)	1 / 4 (25.00%)	4 / 4 (100.00%)	2 / 6 (33.33%)	4 / 4 (100.00%)	4 / 6 (66.67%)	2 / 4 (50.00%)	0 / 1 (0.00%)	2 / 4 (50.00%)	42 / 74 (56.76%)
occurrences all number	2	4	3	5	4	11	1	10	2	4	6	5	0	6	63
Feeling cold
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Gait disturbance
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Influenza like illness
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	0	1	0	0	0	1	0	0	1	0	0	0	1	0	4
Malaise
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	5	0	0	0	0	0	0	0	0	5
Mucosal inflammation
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0	0	0	2
Non-cardiac chest pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Oedema peripheral
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	2 / 5 (40.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 11 (9.09%)	1 / 4 (25.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	8 / 74 (10.81%)
occurrences all number	1	0	2	1	0	1	1	2	0	0	0	0	0	0	8
Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	2	3
Pyrexia
subjects affected / exposed	3 / 4 (75.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	2 / 4 (50.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	10 / 74 (13.51%)
occurrences all number	3	1	0	0	0	3	3	0	2	0	0	1	0	0	13
Swelling
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Thirst
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0	0	2
Immune system disorders
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 4 (25.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	8 / 74 (10.81%)
occurrences all number	2	2	1	1	0	3	0	2	0	0	2	0	0	0	13
Dyspnoea
subjects affected / exposed	1 / 4 (25.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	2 / 7 (28.57%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	8 / 74 (10.81%)
occurrences all number	1	2	0	2	0	3	0	1	0	0	0	0	0	0	9
Epistaxis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Hiccups
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Interstitial lung disease
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Lung disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Nasal congestion
subjects affected / exposed	1 / 4 (25.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	4 / 74 (5.41%)
occurrences all number	1	1	0	0	0	2	0	0	0	0	0	0	0	1	5
Oropharyngeal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	1	0	0	0	3
Pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Productive cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	0	0	0	0	2
Pulmonary embolism
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Pulmonary infarction
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Rhinitis allergic
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Rhinorrhoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Confusional state
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Depression
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Insomnia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	5 / 74 (6.76%)
occurrences all number	0	2	0	0	0	2	0	0	1	0	1	0	0	0	6
Psychomotor retardation
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Sleep disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	1	0	0	0	0	2	0	0	0	0	0	0	3
Amylase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	0	0	0	0	0	2	0	0	6	0	1	0	1	0	10
Aspartate aminotransferase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	0	1	0	0	0	0	2	0	0	1	0	0	0	4
Basophil count increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Blood albumin increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Blood alkaline phosphatase decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	4 / 74 (5.41%)
occurrences all number	0	1	0	0	0	0	0	6	0	0	1	0	0	2	10
Blood bilirubin increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1
Blood cholesterol increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 4 (0.00%)	7 / 10 (70.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	1 / 4 (25.00%)	5 / 11 (45.45%)	1 / 4 (25.00%)	0 / 4 (0.00%)	3 / 6 (50.00%)	1 / 4 (25.00%)	3 / 6 (50.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	24 / 74 (32.43%)
occurrences all number	0	10	1	2	1	8	2	0	3	2	4	1	0	0	34
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	0	0	0	0	0	0	3	2	0	0	1	0	0	6
Blood potassium increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	1	2
Blood urea increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	1	0	0	3
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Haemoglobin decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Lipase increased
subjects affected / exposed	2 / 4 (50.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	5 / 74 (6.76%)
occurrences all number	7	0	0	0	0	4	0	0	11	0	0	0	1	0	23
Lymphocyte count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	3 / 7 (42.86%)	1 / 4 (25.00%)	3 / 11 (27.27%)	1 / 4 (25.00%)	2 / 4 (50.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 1 (100.00%)	1 / 4 (25.00%)	15 / 74 (20.27%)
occurrences all number	0	0	0	6	3	8	1	15	2	1	6	0	1	1	44
Lymphocyte count increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Neutrophil count decreased
subjects affected / exposed	1 / 4 (25.00%)	2 / 10 (20.00%)	2 / 5 (40.00%)	2 / 7 (28.57%)	0 / 4 (0.00%)	3 / 11 (27.27%)	1 / 4 (25.00%)	3 / 4 (75.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	1 / 1 (100.00%)	2 / 4 (50.00%)	22 / 74 (29.73%)
occurrences all number	5	4	2	4	0	24	2	10	2	2	3	2	1	2	63
Platelet count decreased
subjects affected / exposed	1 / 4 (25.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	5 / 7 (71.43%)	0 / 4 (0.00%)	4 / 11 (36.36%)	1 / 4 (25.00%)	3 / 4 (75.00%)	3 / 6 (50.00%)	1 / 4 (25.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	1 / 1 (100.00%)	1 / 4 (25.00%)	25 / 74 (33.78%)
occurrences all number	2	3	1	8	0	10	1	5	4	1	5	1	1	1	43
Vitamin B12 decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Weight decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0	0	0	0	2
Weight increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0	0	2
White blood cell count decreased
subjects affected / exposed	0 / 4 (0.00%)	2 / 10 (20.00%)	2 / 5 (40.00%)	3 / 7 (42.86%)	2 / 4 (50.00%)	5 / 11 (45.45%)	1 / 4 (25.00%)	2 / 4 (50.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	1 / 1 (100.00%)	2 / 4 (50.00%)	26 / 74 (35.14%)
occurrences all number	0	5	2	6	2	16	2	6	3	1	3	2	3	3	54
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Fall
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Procedural pain
subjects affected / exposed	1 / 4 (25.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	0	0	0	2
Product use complaint
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Road traffic accident
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Wound
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0	0	2
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1
Cardiovascular disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0	0	2
Nervous system disorders
Ageusia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Anosmia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Balance disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Dizziness
subjects affected / exposed	0 / 4 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	9 / 74 (12.16%)
occurrences all number	0	2	0	1	0	7	0	2	1	0	5	0	1	0	19
Dysaesthesia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Dysgeusia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	4 / 74 (5.41%)
occurrences all number	0	2	0	1	0	3	0	0	0	0	0	0	0	2	8
Haemorrhage intracranial
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Head discomfort
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0	0	2
Headache
subjects affected / exposed	1 / 4 (25.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	2 / 4 (50.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	10 / 74 (13.51%)
occurrences all number	1	2	0	0	4	1	0	2	1	1	0	1	0	3	16
Hypoaesthesia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Neuropathy peripheral
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Parosmia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Sciatica
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Somnolence
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	0	0	0	0	3	0	0	0	0	2	0	0	0	5
Syncope
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0	0	2
Taste disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Tremor
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 4 (75.00%)	3 / 10 (30.00%)	2 / 5 (40.00%)	3 / 7 (42.86%)	0 / 4 (0.00%)	7 / 11 (63.64%)	2 / 4 (50.00%)	3 / 4 (75.00%)	4 / 6 (66.67%)	1 / 4 (25.00%)	3 / 6 (50.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)	3 / 4 (75.00%)	35 / 74 (47.30%)
occurrences all number	5	4	2	3	0	11	2	5	8	1	6	0	2	4	53
Leukopenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	8 / 74 (10.81%)
occurrences all number	0	1	1	3	0	3	0	0	1	1	0	0	0	1	11
Lymphopenia
subjects affected / exposed	2 / 4 (50.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	6 / 74 (8.11%)
occurrences all number	3	1	1	0	0	0	0	0	0	0	6	0	0	0	11
Neutropenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	5 / 7 (71.43%)	0 / 4 (0.00%)	6 / 11 (54.55%)	2 / 4 (50.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	0 / 6 (0.00%)	2 / 4 (50.00%)	0 / 1 (0.00%)	2 / 4 (50.00%)	22 / 74 (29.73%)
occurrences all number	0	2	1	8	0	10	2	0	5	1	0	2	0	4	35
Thrombocytopenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	2 / 5 (40.00%)	2 / 7 (28.57%)	0 / 4 (0.00%)	3 / 11 (27.27%)	2 / 4 (50.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	2 / 6 (33.33%)	0 / 4 (0.00%)	0 / 1 (0.00%)	2 / 4 (50.00%)	17 / 74 (22.97%)
occurrences all number	0	1	3	2	0	4	2	0	4	1	2	0	0	5	24
Thrombocytosis
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	2	0	0	0	3
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Eye disorders
Cataract
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Dry eye
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Eye pain
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Periorbital oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Vision blurred
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Vitreous floaters
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0	1
Gastrointestinal disorders
Abdominal adhesions
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Abdominal discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	1	0	2	0	0	0	0	0	0	0	0	3
Abdominal distension
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	0	1	0	0	0	2	0	0	0	0	0	1	0	0	4
Abdominal pain
subjects affected / exposed	2 / 4 (50.00%)	2 / 10 (20.00%)	2 / 5 (40.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	3 / 11 (27.27%)	0 / 4 (0.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	3 / 4 (75.00%)	0 / 6 (0.00%)	2 / 4 (50.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	18 / 74 (24.32%)
occurrences all number	4	2	2	0	1	5	0	8	0	3	0	2	0	1	28
Abdominal pain lower
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Abdominal pain upper
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	1 / 4 (25.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	6 / 74 (8.11%)
occurrences all number	0	1	1	0	0	1	1	4	1	0	0	0	0	0	9
Breath odour
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Constipation
subjects affected / exposed	2 / 4 (50.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	3 / 6 (50.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	11 / 74 (14.86%)
occurrences all number	3	2	1	0	0	2	0	0	3	1	0	0	0	1	13
Dental caries
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Diarrhoea
subjects affected / exposed	1 / 4 (25.00%)	2 / 10 (20.00%)	1 / 5 (20.00%)	2 / 7 (28.57%)	2 / 4 (50.00%)	7 / 11 (63.64%)	2 / 4 (50.00%)	2 / 4 (50.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	2 / 6 (33.33%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	23 / 74 (31.08%)
occurrences all number	1	2	1	2	2	12	2	4	0	4	3	1	0	0	34
Dry mouth
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	2 / 5 (40.00%)	2 / 7 (28.57%)	0 / 4 (0.00%)	2 / 11 (18.18%)	1 / 4 (25.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	10 / 74 (13.51%)
occurrences all number	0	1	2	3	0	2	1	1	0	0	1	0	0	0	11
Dyspepsia
subjects affected / exposed	1 / 4 (25.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	5 / 74 (6.76%)
occurrences all number	1	2	0	1	0	1	0	0	0	0	0	0	0	0	5
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0	0	2
Epigastric discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Gingival bleeding
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Gingival discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Loose tooth
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1
Nausea
subjects affected / exposed	2 / 4 (50.00%)	7 / 10 (70.00%)	5 / 5 (100.00%)	7 / 7 (100.00%)	4 / 4 (100.00%)	8 / 11 (72.73%)	4 / 4 (100.00%)	2 / 4 (50.00%)	4 / 6 (66.67%)	4 / 4 (100.00%)	3 / 6 (50.00%)	1 / 4 (25.00%)	1 / 1 (100.00%)	4 / 4 (100.00%)	56 / 74 (75.68%)
occurrences all number	3	11	6	12	11	52	4	28	10	6	7	2	1	8	161
Odynophagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1
Stomatitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	4 / 74 (5.41%)
occurrences all number	0	0	1	0	0	1	1	0	0	0	0	0	0	1	4
Subileus
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Tongue ulceration
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Tooth discolouration
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Toothache
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0	0	2
Vomiting
subjects affected / exposed	1 / 4 (25.00%)	3 / 10 (30.00%)	2 / 5 (40.00%)	4 / 7 (57.14%)	2 / 4 (50.00%)	7 / 11 (63.64%)	2 / 4 (50.00%)	2 / 4 (50.00%)	4 / 6 (66.67%)	2 / 4 (50.00%)	3 / 6 (50.00%)	3 / 4 (75.00%)	1 / 1 (100.00%)	2 / 4 (50.00%)	38 / 74 (51.35%)
occurrences all number	2	4	3	8	4	26	3	13	13	2	33	5	1	6	123
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	0	0	0	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	2	0	0	0	4
Cold sweat
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Dermatitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Dry skin
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	2 / 5 (40.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	0	0	2	2	0	1	0	0	0	0	0	0	0	0	5
Hyperhidrosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Onychoclasis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Onycholysis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Pain of skin
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Penile ulceration
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Pruritus
subjects affected / exposed	1 / 4 (25.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	5 / 74 (6.76%)
occurrences all number	1	2	0	0	0	1	0	1	0	0	0	0	0	0	5
Psoriasis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Purpura
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Rash
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Rash maculo-papular
subjects affected / exposed	0 / 4 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	0	2	0	0	0	1	0	1	0	0	0	0	0	0	4
Skin discolouration
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Xeroderma
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	1 / 4 (25.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Dysuria
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	1	0	0	0	3
Haematuria
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Leukocyturia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Micturition urgency
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Nocturia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Pollakiuria
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Renal failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	0	0	0	2
Back pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	1	0	0	3
Flank pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Joint swelling
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	1	0	0	0	0	1	0	0	0	0	0	0	2
Limb discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Muscle spasms
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0	0	2
Muscular weakness
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 4 (0.00%)	2 / 10 (20.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0	0	2
Musculoskeletal pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Musculoskeletal stiffness
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Myalgia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	1	1	0	0	0	0	1	0	0	0	0	0	0	3
Pain in extremity
subjects affected / exposed	0 / 4 (0.00%)	4 / 10 (40.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	6 / 74 (8.11%)
occurrences all number	0	5	0	0	0	0	0	1	0	0	0	0	0	1	7
Infections and infestations
Device related infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Ear infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Gastroenteritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Gastroenteritis norovirus
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Gastrointestinal viral infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	1
Gingivitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1
Influenza
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	0	0	0	0	2
Laryngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	0	0	2
Oral herpes
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	2 / 11 (18.18%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0	0	2
Rhinitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Sinusitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1
Skin infection
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Soft tissue infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1
Staphylococcal infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Tracheitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0	0	0	2
Urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Vaginal infection
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Viral upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Vulvitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1
Decreased appetite
subjects affected / exposed	3 / 4 (75.00%)	3 / 10 (30.00%)	1 / 5 (20.00%)	3 / 7 (42.86%)	0 / 4 (0.00%)	3 / 11 (27.27%)	1 / 4 (25.00%)	3 / 4 (75.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	3 / 6 (50.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	23 / 74 (31.08%)
occurrences all number	3	4	1	3	0	3	1	3	0	1	10	1	0	5	35
Dehydration
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0	0	2
Dyslipidaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Hyperglycaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	1	0	0	0	0	2	0	0	0	0	0	3
Hyperkalaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 4 (25.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 74 (2.70%)
occurrences all number	0	2	0	0	1	0	0	0	0	0	0	0	0	0	3
Hypertriglyceridaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	5	0	0	0	0	0	5
Hypoalbuminaemia
subjects affected / exposed	1 / 4 (25.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	1	1	0	0	0	2	0	1	0	0	0	0	0	0	5
Hypocalcaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	2 / 74 (2.70%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	1	2
Hypokalaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	3 / 74 (4.05%)
occurrences all number	0	2	0	1	0	0	0	1	0	0	0	0	0	0	4
Hypomagnesaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 10 (10.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	1 / 11 (9.09%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	0	2	0	0	0	1	0	0	0	0	1	1	0	0	5
Hyponatraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2	0	2
Hypophosphataemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	1 / 4 (25.00%)	1 / 6 (16.67%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	4 / 74 (5.41%)
occurrences all number	0	0	0	0	0	0	0	1	1	1	2	0	0	0	5
Iron overload
subjects affected / exposed	0 / 4 (0.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1
Lack of satiety
subjects affected / exposed	1 / 4 (25.00%)	0 / 10 (0.00%)	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 4 (0.00%)	0 / 11 (0.00%)	0 / 4 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 4 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 74 (1.35%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	1

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Were there any global substantial amendments to the protocol? Yes

16 Feb 2015

• To add a new regimen which investigates intermittent dosing of HDM201. This new regimen combines HDM201 administered once every 3 weeks (q3w) and LEE011 administered daily for two weeks followed by one week off treatment • Clarification of inclusion criteria, to specify that patients who have received more than one prior line of treatment, are eligible to enroll in the study • Introduce an HDM201 new drug product variant using a drug substance of smaller particle size with improved in vitro dissolution rate characteristics. • Include analysis of PK/safety relationships as an exploratory endpoint, to highlight its importance in guiding the selection of the appropriate dose and regimen in terms of efficacy and safety • Incorporate, in GDF-15 sampling, a 24 hr profile at Cycle 1 Day 1 for a more robust assessment of GDF-15 kinetics in exploratory PK/PD and PK/safety modeling, and reduce pre-dose samples at Days 8 and 14

01 Oct 2015

• To update and reinforce safety measures. This amendment aligns the cardiac and liver safety measures with guidance implemented in the LEE011 program. Moreover, in order to prevent the bleeding risk associated with HDM201–related thrombocytopenia, the exclusion criteria and concomitant medications were updated.

07 Jul 2016

• to implement additional safety measures for the monitoring of tumor lysis syndrome (TLS)

08 Mar 2019

• to add language to allow the transfer of on-treatment patient to a Novartis rollover clinical study that continues to provide study treatment (CLEE011X2X01B), considering that there no new patients will be enrolled into the study. In addition, the timing requirements for the primary and final CSR were updated to remove reference to the phase II part of the study

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.

After evaluation of the data collected in the phase Ib part of the study, Novartis decided to not open the Phase II part. This decision was not based on safety concerns and patients who benefit from the treatment were allowed to remain on study.

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Clinical trials

Clinical Trial Results: A Phase Ib/II, open-label, multicenter study of oral HDM201 in combination with oral LEE011 in adult patients with liposarcoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment.

Primary: Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment.

Primary: Exposure to HDM201 and LEE011 as measured by AUC 0-24h

Primary: Exposure to HDM201 and LEE011 as measured by AUC 0-24h

Secondary: Number of patients with dose interruptions and reduction

Secondary: Number of patients with dose interruptions and reduction

Secondary: Dose intensity

Secondary: Dose intensity

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 1

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 1

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 4

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 4

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 5

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax Regimen 5

Secondary: Best overall response (BOR), Overall response rate (ORR) as per RECIST v1.1, assessed by investigator

Secondary: Best overall response (BOR), Overall response rate (ORR) as per RECIST v1.1, assessed by investigator

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 1

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 1

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 4

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 4

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 5

Secondary: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast Regimen 5

Secondary: Changes from baseline of Pharmacodynamics (PD) markers in blood (GDF-15)

Secondary: Changes from baseline of Pharmacodynamics (PD) markers in blood (GDF-15)

Secondary: Changes from baseline of Pharmacodynamics (PD) markers in tumor tissue (p21, MDM2)

Secondary: Changes from baseline of Pharmacodynamics (PD) markers in tumor tissue (p21, MDM2)

Secondary: Progression free survival (PFS) as per RECIST v1.1, assessed by investigator

Secondary: Progression free survival (PFS) as per RECIST v1.1, assessed by investigator

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase Ib/II, open-label, multicenter study of oral HDM201 in combination with oral LEE011 in adult patients with liposarcoma