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Clinical Trial Results:
An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescents Subjects with Cancer or Plexiform Neurofibromas and Trametinib in Combination with Dabrafenib in Children and Adolescents with Cancers Harboring V600 mutation

Summary
EudraCT number	2013-003596-35
Trial protocol	GB FR
Global end of trial date	29 Dec 2020

Results information
Results version number	v1(current)
This version publication date	07 Jul 2021
First version publication date	07 Jul 2021
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

MEK116540

ISRCTN number

US NCT number

NCT02124772

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

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

Scientific contact

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

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001177-PIP01-11

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?

Yes

Analysis stage

Final

Date of interim/final analysis

29 Dec 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Dec 2020

Was the trial ended prematurely?

Main objective of the trial

The overall objective of the study was to establish a safe and tolerable dose of trametinib in infants, children, and adolescents and determine preliminary activity of trametinib monotherapy in selected recurrent, refractory or unresectable childhood tumors. In addition, this study also aimed to establish the safety, tolerability and activity of trametinib in combination with dabrafenib in children and adolescents with recurrent, refractory or unresectable BRAF V600 mutated tumors.

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

15 Jan 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 58

Country: Number of subjects enrolled

Canada: 36

Country: Number of subjects enrolled

France: 23

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

United Kingdom: 15

Worldwide total number of subjects

139

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in 16 investigative sites in 5 countries.

Screening details

The participants were screened within 14 days prior to enrollment. After screening, the treatment period started on Cycle 1 Day 1.

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

Part A – TMT 0.0125 mg/kg/day

Arm description

Participants treated with trametinib 0.0125 mg/kg/day

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose). The administered dose was 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Arm description

Participants treated with trametinib 0.025 mg/kg/day

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Part A – TMT 0.032 mg/kg/day

Arm description

Participants under 6 years of age treated with trametinib 0.032 mg/kg/day

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Part A – TMT 0.04 mg/kg/day

Arm description

Participants treated with trametinib 0.04 mg/kg/day

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Part B – Neuroblastoma

Arm description

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Part B – LGG fusion

Arm description

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Part B – NF-1 with PN

Arm description

Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Part B – BRAF V600 mutant solid tumor

Arm description

Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Arm description

Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects)

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Capsule, Oral suspension, Dispersible tablet

Routes of administration

Oral use

Dosage and administration details

Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose). The administered dose was 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy: 2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Arm description

Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet, Capsule, Oral suspension

Routes of administration

Oral use

Dosage and administration details

Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose). The administered dose was 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy: 5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Arm description

Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet, Capsule, Oral suspension

Routes of administration

Oral use

Dosage and administration details

Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose). The administered dose was 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy for <12 years old subjects as all participants in this arm were under 6 years of age: 5.25 mg/kg/day.

Part D – LGG

Arm description

Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet, Capsule, Oral suspension

Routes of administration

Oral use

Dosage and administration details

Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose). The administered dose was 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy: 5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects

Part D – LCH

Arm description

Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Oral solution

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Dabrafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet, Capsule, Oral suspension

Routes of administration

Oral use

Dosage and administration details

Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose). The administered dose was 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy: 5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects

Number of subjects in period 1	Part A – TMT 0.0125 mg/kg/day	Part A – TMT 0.025 mg/kg/day	Part A – TMT 0.032 mg/kg/day	Part A – TMT 0.04 mg/kg/day	Part B – Neuroblastoma	Part B – LGG fusion	Part B – NF-1 with PN	Part B – BRAF V600 mutant solid tumor	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH
Started	3	19	12	16	11	10	10	10	3	9	6	20	10
Completed	0	5	6	3	2	2	2	1	2	2	4	14	8
Not completed	3	14	6	13	9	8	8	9	1	7	2	6	2
Adverse event, non-fatal	1	4	1	5	2	1	1	5	-	3	1	3	1
Withdrawal consent	-	1	1	1	-	1	1	-	-	1	-	1	-
Not specified	-	7	2	5	4	3	4	1	1	1	1	1	-
Investigator discretion	-	2	2	1	1	-	1	-	-	1	-	1	-
Progressive disease	-	-	-	-	-	-	1	1	-	-	-	-	-
Lack of efficacy	2	-	-	1	2	3	-	2	-	1	-	-	1

Baseline characteristics

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Reporting group title

Part A – TMT 0.0125 mg/kg/day

Reporting group description

Participants treated with trametinib 0.0125 mg/kg/day

Reporting group title

Part A – TMT 0.025 mg/kg/day

Reporting group description

Participants treated with trametinib 0.025 mg/kg/day

Reporting group title

Part A – TMT 0.032 mg/kg/day

Reporting group description

Participants under 6 years of age treated with trametinib 0.032 mg/kg/day

Reporting group title

Part A – TMT 0.04 mg/kg/day

Reporting group description

Participants treated with trametinib 0.04 mg/kg/day

Reporting group title

Part B – Neuroblastoma

Reporting group description

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – LGG fusion

Reporting group description

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – NF-1 with PN

Reporting group description

Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – BRAF V600 mutant solid tumor

Reporting group description

Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day

Reporting group title

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Reporting group description

Reporting group title

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Reporting group description

Reporting group title

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Reporting group description

Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)

Reporting group title

Part D – LGG

Reporting group description

Reporting group title

Part D – LCH

Reporting group description

Reporting group values	Part A – TMT 0.0125 mg/kg/day	Part A – TMT 0.025 mg/kg/day	Part A – TMT 0.032 mg/kg/day	Part A – TMT 0.04 mg/kg/day	Part B – Neuroblastoma	Part B – LGG fusion	Part B – NF-1 with PN	Part B – BRAF V600 mutant solid tumor	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Total
Number of subjects	3	19	12	16	11	10	10	10	3	9	6	20	10	139
Age Categorical
Units: participants
< 2 years	0	4	1	2	1	0	1	0	0	0	1	0	0	10
2 - <6 years	1	5	11	0	3	4	4	5	0	2	5	2	6	48
6 - <12 years	1	4	0	9	5	5	3	1	1	2	0	9	3	43
≥ 12 years	1	6	0	5	2	1	2	4	2	5	0	9	1	38
Age continuous
Units: years
arithmetic mean (standard deviation)	9.7 ± 6.43	7.2 ± 5.16	3.3 ± 1.18	9.7 ± 4.99	8.2 ± 5.18	7.0 ± 3.56	6.6 ± 4.86	7.9 ± 5.20	12.7 ± 3.06	10.6 ± 5.15	2.7 ± 1.28	10.5 ± 3.79	5.6 ± 3.63	-
Sex: Female, Male
Units: participants
Female	1	7	6	7	6	5	5	5	0	6	4	10	2	64
Male	2	12	6	9	5	5	5	5	3	3	2	10	8	75
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0	0	0	1	1
Asian	0	1	0	1	0	0	0	2	1	2	0	0	1	8
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Black or African American	0	2	0	1	2	2	1	0	0	1	0	0	0	9
White	3	16	7	14	9	6	7	5	2	6	4	16	3	98
More than one race	0	0	0	0	0	0	1	0	0	0	0	0	1	2
Unknown or Not Reported	0	0	5	0	0	2	1	3	0	0	2	4	4	21

End points

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Reporting group title

Part A – TMT 0.0125 mg/kg/day

Reporting group description

Participants treated with trametinib 0.0125 mg/kg/day

Reporting group title

Part A – TMT 0.025 mg/kg/day

Reporting group description

Participants treated with trametinib 0.025 mg/kg/day

Reporting group title

Part A – TMT 0.032 mg/kg/day

Reporting group description

Participants under 6 years of age treated with trametinib 0.032 mg/kg/day

Reporting group title

Part A – TMT 0.04 mg/kg/day

Reporting group description

Participants treated with trametinib 0.04 mg/kg/day

Reporting group title

Part B – Neuroblastoma

Reporting group description

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – LGG fusion

Reporting group description

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – NF-1 with PN

Reporting group description

Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – BRAF V600 mutant solid tumor

Reporting group description

Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day

Reporting group title

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Reporting group description

Reporting group title

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Reporting group description

Reporting group title

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Reporting group description

Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)

Reporting group title

Part D – LGG

Reporting group description

Reporting group title

Part D – LCH

Reporting group description

Subject analysis set title

Part B – All tumor types TMT 0.025 mg/kg/day

Subject analysis set type

Full analysis

Subject analysis set description

Participants (all tumor types in Part B) treated with trametinib 0.025 mg/kg/day

Subject analysis set title

Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D

Subject analysis set type

Full analysis

Subject analysis set description

Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)

Subject analysis set title

Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D

Subject analysis set type

Full analysis

Subject analysis set description

Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Subject analysis set title

Part A, B, C and D – All participants with PK data

Subject analysis set type

Full analysis

Subject analysis set description

Participants in the study (all doses and all tumor types) with available pharmacokinetic data

Subject analysis set title

Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

TMT 0.0125 mg/kg/day

Subject analysis set type

Full analysis

Subject analysis set description

Participants treated with trametinib oral solution at a dose level of 0.0125 mg/kg/day

Subject analysis set title

TMT 0.025 mg/kg/day

Subject analysis set type

Full analysis

Subject analysis set description

Participants treated with trametinib oral solution at a dose level of 0.025 mg/kg/day

Subject analysis set title

TMT 0.032 mg/kg/day

Subject analysis set type

Full analysis

Subject analysis set description

Participants treated with trametinib oral solution at a dose level of 0.032 mg/kg/day

Subject analysis set title

TMT 0.04 mg/kg/day

Subject analysis set type

Full analysis

Subject analysis set description

Participants treated with trametinib oral solution at a dose level of 0.04 mg/kg/day

Subject analysis set title

TMT 0.025 mg/kg/day + 50% DRB RP2D

Subject analysis set type

Full analysis

Subject analysis set description

Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the RP2D of dabrafenib monotherapy (oral suspension formulation)

Subject analysis set title

TMT 0.025 mg/kg/day + 100% DRB RP2D

Subject analysis set type

Full analysis

Subject analysis set description

Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the RP2D of dabrafenib monotherapy (oral suspension formulation)

Subject analysis set title

TMT 0.032 mg/kg/day + 100% DRB RP2D

Subject analysis set type

Full analysis

Subject analysis set description

Participants treated with a combination therapy of trametinib (0.032 mg/kg/day) plus 100% of the RP2D of dabrafenib monotherapy (oral suspension formulation)

Primary: Incidence of treatment emergent adverse events in subjects treated with trametinib monotherapy

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End point title

Incidence of treatment emergent adverse events in subjects treated with trametinib monotherapy ^[1] ^[2]

End point description

Incidence of treatment emergent adverse events is defined as number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. The number of participants in each category is reported in the table.

End point type

Primary

End point timeframe

From the day of the first dose of trametinib up to 30 days after the last dose, up to maximum duration of 64 months

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

End point values	Part A – TMT 0.0125 mg/kg/day	Part A – TMT 0.025 mg/kg/day	Part A – TMT 0.032 mg/kg/day	Part A – TMT 0.04 mg/kg/day	Part B – Neuroblastoma	Part B – LGG fusion	Part B – NF-1 with PN	Part B – BRAF V600 mutant solid tumor
Number of subjects analysed	3	19	12	16	11	10	10	10
Units: participants
AEs	3	19	12	16	11	10	10	10
Treatment-related AEs	3	19	12	16	10	10	10	10
SAEs	1	8	3	11	6	6	6	5
Treatment-related SAEs	0	5	1	6	1	2	2	3
Fatal SAEs	0	0	0	0	0	0	0	0
AEs leading to discontinuation	1	4	1	6	4	1	1	5
AEs requiring dose interruptions	0	12	6	14	3	8	5	8
AEs requiring dose reductions	0	9	5	9	2	4	3	7
AEs requiring dose reductions or interruptions	0	13	7	14	3	8	6	9

No statistical analyses for this end point

Primary: Average steady state plasma concentration (Cavg) of trametinib when administered alone (monotherapy)

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End point title

Average steady state plasma concentration (Cavg) of trametinib when administered alone (monotherapy) ^[3] ^[4]

End point description

End point type

Primary

End point timeframe

pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

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

End point values	Part A – TMT 0.0125 mg/kg/day	Part A – TMT 0.025 mg/kg/day	Part A – TMT 0.032 mg/kg/day	Part A – TMT 0.04 mg/kg/day	Part B – Neuroblastoma	Part B – LGG fusion	Part B – NF-1 with PN	Part B – BRAF V600 mutant solid tumor	Part B – All tumor types TMT 0.025 mg/kg/day
Number of subjects analysed	3	18	9	15	9	10	10	9	38
Units: ng/mL
geometric mean (geometric coefficient of variation)	5.76 ± 24.8	13.9 ± 27.1	15.2 ± 16.9	21.3 ± 20.7	15.1 ± 36.0	13.2 ± 40.4	13.5 ± 25.1	15.8 ± 42.8	14.3 ± 35.8

No statistical analyses for this end point

Secondary: Trough concentration (Ctrough) of trametinib when administered alone and in combination with dabrafenib

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End point title

Trough concentration (Ctrough) of trametinib when administered alone and in combination with dabrafenib

End point description

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (coefficient of variation when n=1) are indicated as ‘999’.

End point type

Secondary

End point timeframe

pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Part B – All tumor types TMT 0.025 mg/kg/day

Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D

Number of subjects analysed

Units: ng/mL

geometric mean (geometric coefficient of variation)

4.37 ± 30.6

11.1 ± 44.0

10.2 ± 19.4

15.6 ± 30.1

10.7 ± 43.3

9.45 ± 53.6

9.25 ± 29.0

11.3 ± 50.3

8.31 ± 999

10.2 ± 999

3.86 ± 34.9

8.60 ± 42.2

3.74 ± 66.3

10.1 ± 43.6

3.05 ± 50.7

8.68 ± 38.6

No statistical analyses for this end point

Secondary: Maximum observed plasma concentration (Cmax) of trametinib when administered alone and in combination with dabrafenib

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End point title

Maximum observed plasma concentration (Cmax) of trametinib when administered alone and in combination with dabrafenib

End point description

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (coefficient of variation when n=1) are indicated as ‘999’.

End point type

Secondary

End point timeframe

pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Part B – All tumor types TMT 0.025 mg/kg/day

Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D

Number of subjects analysed

Units: ng/mL

geometric mean (geometric coefficient of variation)

9.61 ± 32.9

21.1 ± 33.3

26.1 ± 16.8

32.6 ± 28.9

26.6 ± 39.6

22.1 ± 41.9

21.6 ± 26.1

27.5 ± 31.6

26.0 ± 999

24.5 ± 999

23.7 ± 36.3

22.9 ± 29.2

15.6 ± 52.5

24.2 ± 35.6

25.9 ± 35.8

20.0 ± 38.1

No statistical analyses for this end point

Secondary: Time to reach maximum plasma concentration (Tmax) of trametinib when administered alone and in combination with dabrafenib

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End point title

Time to reach maximum plasma concentration (Tmax) of trametinib when administered alone and in combination with dabrafenib

End point description

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.

End point type

Secondary

End point timeframe

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Part B – All tumor types TMT 0.025 mg/kg/day

Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D

Number of subjects analysed

Units: hours

median (full range (min-max))

1.00 (1.00 to 2.00)

2.00 (1.00 to 4.00)

1.00 (1.00 to 2.00)

2.00 (1.00 to 24.0)

1.00 (1.00 to 4.00)

1.50 (1.00 to 2.00)

1.00 (1.00 to 2.00)

1.00 (1.00 to 1.00)

1.50 (1.00 to 2.00)

2.00 (1.00 to 3.00)

1.00 (1.00 to 4.00)

1.00 (1.00 to 1.00)

2.00 (1.00 to 4.00)

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of trametinib when administered alone and in combination with dabrafenib

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End point title

Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of trametinib when administered alone and in combination with dabrafenib

End point description

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (coefficient of variation when n=1) are indicated as ‘999’.

End point type

Secondary

End point timeframe

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Part B – All tumor types TMT 0.025 mg/kg/day

Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D

Number of subjects analysed

Units: hours*ng/mL

geometric mean (geometric coefficient of variation)

138 ± 24.8

341 ± 28.3

364 ± 16.9

413 ± 76.2

362 ± 36.0

316 ± 40.4

304 ± 36.9

379 ± 42.8

290 ± 999

331 ± 999

122 ± 29.0

270 ± 35.8

118 ± 53.4

337 ± 38.6

126 ± 30.7

255 ± 49.2

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state (AUCtau) of trametinib when administered alone and in combination with dabrafenib

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End point title

Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state (AUCtau) of trametinib when administered alone and in combination with dabrafenib

End point description

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation. The duration of the dosing interval (tau) was 24 hours for trametinib. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (coefficient of variation when n=1) are indicated as ‘999’.

End point type

Secondary

End point timeframe

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Part B – All tumor types TMT 0.025 mg/kg/day

Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D

Number of subjects analysed

Units: hours*ng/mL

geometric mean (geometric coefficient of variation)

138 ± 24.8

334 ± 27.1

364 ± 16.9

511 ± 20.7

362 ± 36.0

316 ± 40.4

323 ± 25.1

379 ± 42.8

290 ± 999

331 ± 999

236 ± 28.4

308 ± 20.0

186 ± 23.7

343 ± 35.8

228 ± 33.1

286 ± 28.4

No statistical analyses for this end point

Secondary: Apparent plasma clearance (CL/F) of trametinib when administered alone and in combination with dabrafenib

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End point title

Apparent plasma clearance (CL/F) of trametinib when administered alone and in combination with dabrafenib

End point description

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (coefficient of variation when n=1) are indicated as ‘999’.

End point type

Secondary

End point timeframe

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Part B – All tumor types TMT 0.025 mg/kg/day

Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D

Number of subjects analysed

Units: mL/hour

geometric mean (geometric coefficient of variation)

2750 ± 69.4

1530 ± 64.5

1240 ± 25.5

2040 ± 71.5

1710 ± 55.6

1910 ± 47.8

1590 ± 65.3

1820 ± 42.6

2590 ± 999

3770 ± 999

2010 ± 38.5

3540 ± 54.0

3060 ± 44.9

1750 ± 51.5

2180 ± 23.9

3810 ± 49.6

No statistical analyses for this end point

Secondary: Average steady state plasma concentration (Cavg) of trametinib when administered in combination with dabrafenib

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End point title

Average steady state plasma concentration (Cavg) of trametinib when administered in combination with dabrafenib ^[5]

End point description

Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of trametinib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 24 h for trametinib. Due to EudraCT system limitations, data fields cannot be blank if the number of subjects analyzed in the corresponding column is greater than 0. Therefore, not applicable values (coefficient of variation when n=1) are indicated as ‘999’.

End point type

Secondary

End point timeframe

pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	1	1	6	20	6	5	21
Units: ng/mL
geometric mean (geometric coefficient of variation)	12.1 ± 999	13.8 ± 999	9.83 ± 28.4	12.8 ± 20.0	7.76 ± 23.7	9.50 ± 33.1	11.9 ± 28.4

No statistical analyses for this end point

Secondary: Incidence of treatment emergent adverse events in subjects treated with trametinib in combination with dabrafenib

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End point title

Incidence of treatment emergent adverse events in subjects treated with trametinib in combination with dabrafenib ^[6]

End point description

End point type

Secondary

End point timeframe

From the day of the first dose of the combination up to 30 days after the last dose, up to maximum duration of 53 months

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH
Number of subjects analysed	3	9	6	20	10
Units: participants
AEs	3	9	6	20	10
Treatment-related AEs	3	9	6	20	10
SAEs	1	5	2	8	6
Treatment-related SAEs	0	2	1	5	3
Fatal SAEs	0	0	0	0	0
AEs leading to discontinuation	0	3	1	5	1
AEs requiring dose interruptions	1	6	4	16	8
AEs requiring dose reductions	1	3	1	6	1
AEs requiring dose reductions or interruptions	1	7	4	16	8

No statistical analyses for this end point

Secondary: Best Overall Response (BOR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

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End point title

Best Overall Response (BOR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

End point description

Response evaluations were assessed using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for subjects with solid tumors except neuroblastomas, primary central nervous system tumors (gliomas) or plexiform neurofibromas (PNs). Response evaluations for subjects with neuroblastomas could have included: measureable disease (by CT/MRI alone) assessed according to RECIST v1.1, evaluable disease assessed for meta-iodobenzylguanidine (MIBG) response, and biochemical (urine HVA/VMA) with bone marrow involvement assessed by Hematoxylin and Eosin staining of bilateral bone marrow biopsies and aspirates. Response evaluations for glioma subjects was assessed using Response Assessment in Neuro Oncology (RANO) criteria with solid tumors through MRI scans. Response evaluations of PNs were assessed using volumetric determination and Dombi criteria through MRI scans. The number of participants in each response category is reported in the table.

End point type

Secondary

End point timeframe

From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

End point values	Part A – TMT 0.0125 mg/kg/day	Part A – TMT 0.025 mg/kg/day	Part A – TMT 0.032 mg/kg/day	Part A – TMT 0.04 mg/kg/day	Part B – Neuroblastoma	Part B – LGG fusion	Part B – NF-1 with PN	Part B – BRAF V600 mutant solid tumor	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH
Number of subjects analysed	3	19	12	16	11	10	10	10	3	9	6	20	10
Units: participants
Complete response (CR)	0	0	0	0	0	0	0	0	0	0	2	2	3
Partial response (PR)	0	1	1	0	1	3	0	5	2	3	2	9	3
Stable disease (SD)	1	2	3	4	1	7	8	4	1	5	1	8	3
Progressive disease (PD)	0	0	2	0	5	0	0	1	0	1	0	0	0
Non-CR/Non-PD	0	0	0	0	0	0	0	0	0	0	0	0	0
Unknown	0	0	0	2	1	0	0	0	0	0	0	1	0
Missing	2	16	6	10	3	0	2	0	0	0	1	0	1

No statistical analyses for this end point

Secondary: Objective response rate (ORR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

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End point title

Objective response rate (ORR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

End point description

Objective response rate (ORR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR) or partial response (PR) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.

End point type

Secondary

End point timeframe

From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Number of subjects analysed

Units: percentage of participants

number (confidence interval 95%)

0 (0.0 to 70.8)

5.3 (0.1 to 26.0)

8.3 (0.2 to 38.5)

0 (0.0 to 20.6)

9.1 (0.2 to 41.3)

30.0 (6.7 to 65.2)

0 (0.0 to 30.8)

50.0 (18.7 to 81.3)

66.7 (9.4 to 99.2)

33.3 (7.5 to 70.1)

66.7 (22.3 to 95.7)

55.0 (31.5 to 76.9)

60.0 (26.2 to 87.8)

No statistical analyses for this end point

Secondary: Clinical Benefit Rate (CBR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

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End point title

Clinical Benefit Rate (CBR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

End point description

Clinical Benefit Rate (CBR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR), partial response (PR) or stable disease (SD) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.

End point type

Secondary

End point timeframe

From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Number of subjects analysed

Units: percentage of participants

number (confidence interval 95%)

33.3 (0.8 to 90.6)

15.8 (3.4 to 39.6)

33.3 (9.9 to 65.1)

25.0 (7.3 to 52.4)

18.2 (2.3 to 51.8)

100 (69.2 to 100)

80.0 (44.4 to 97.5)

90.0 (55.5 to 99.7)

100 (29.2 to 100)

88.9 (51.8 to 99.7)

83.3 (35.9 to 99.6)

95.0 (75.1 to 99.9)

90.0 (55.5 to 99.7)

No statistical analyses for this end point

Secondary: Apparent clearance (CL/F) of trametinib estimated with a PopPK model

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End point title

Apparent clearance (CL/F) of trametinib estimated with a PopPK model

End point description

End point type

Secondary

End point timeframe

End point values	Part A, B, C and D – All participants with PK data
Number of subjects analysed	133
Units: liters/hour
number (not applicable)	5.07

No statistical analyses for this end point

Secondary: Apparent central volume (Vc/F) of trametinib estimated with a PopPK model

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End point title

Apparent central volume (Vc/F) of trametinib estimated with a PopPK model

End point description

End point type

Secondary

End point timeframe

End point values	Part A, B, C and D – All participants with PK data
Number of subjects analysed	133
Units: liters	184

No statistical analyses for this end point

Secondary: Absorption rate constants (Ka1 and Ka2) of trametinib estimated with a PopPK model

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End point title

Absorption rate constants (Ka1 and Ka2) of trametinib estimated with a PopPK model

End point description

End point type

Secondary

End point timeframe

End point values	Part A, B, C and D – All participants with PK data
Number of subjects analysed	133
Units: 1/hours
number (not applicable)
Ka1	0.134
Ka2	1.55

No statistical analyses for this end point

Secondary: Significant covariates estimated with a PopPK model

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End point title

Significant covariates estimated with a PopPK model

End point description

The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Sex and weight are significant covariates on apparent clearance (CL/F), and weight is also a significant covariate on apparent intercompartmental clearance (Q/F). Use of dabrafenib, yes or no, is a covariate on the relative bioavailability of trametinib, reflecting the effect of dabrafenib on the PK of trametinib. The estimates of these covariates (effect of weight on CL/F, effect of sex on CL/F, effect of weight on Q/F, effect of combination with dabrafenib on relative bioavailability F1) calculated with the PopPK model are summarized in this record.

End point type

Secondary

End point timeframe

End point values	Part A, B, C and D – All participants with PK data
Number of subjects analysed	133
Units: no units
number (not applicable)
Effect of weight on CL/F	0.788
Effect of sex on CL/F	1.24
Effect of weight on Q/F	0.679
Effect of combination with dabrafenib on F1	0.876

No statistical analyses for this end point

Secondary: Trough concentration (Ctrough) of dabrafenib when administered in combination with trametinib

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End point title

Trough concentration (Ctrough) of dabrafenib when administered in combination with trametinib ^[7]

End point description

Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.

End point type

Secondary

End point timeframe

pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D	Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	3	7	6	19	8	21	6
Units: ng/mL
geometric mean (geometric coefficient of variation)	88.9 ± 99.6	28.6 ± 203.5	8.10 ± 159.6	38.2 ± 130.9	11.8 ± 869.4	42.7 ± 137.4	5.36 ± 429.6

No statistical analyses for this end point

Secondary: Maximum observed plasma concentration (Cmax) of dabrafenib when administered in combination with trametinib

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End point title

Maximum observed plasma concentration (Cmax) of dabrafenib when administered in combination with trametinib ^[8]

End point description

Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.

End point type

Secondary

End point timeframe

pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D	Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	3	7	6	19	8	21	6
Units: ng/mL
geometric mean (geometric coefficient of variation)	630 ± 235.2	1560 ± 35.3	1440 ± 43.3	1360 ± 55.6	1490 ± 88.1	1290 ± 68.7	1840 ± 35.2

No statistical analyses for this end point

Secondary: Time to reach maximum plasma concentration (Tmax) of dabrafenib when administered in combination with trametinib

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End point title

Time to reach maximum plasma concentration (Tmax) of dabrafenib when administered in combination with trametinib ^[9]

End point description

Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.

End point type

Secondary

End point timeframe

pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D	Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	3	7	6	19	8	21	6
Units: hours
median (full range (min-max))	2.00 (2.00 to 4.00)	1.00 (1.00 to 2.00)	2.00 (1.00 to 2.00)	2.00 (1.00 to 3.00)	1.00 (1.00 to 3.00)	2.00 (1.00 to 3.00)	1.00 (1.00 to 3.00)

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of dabrafenib when administered in combination with trametinib

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End point title

Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of dabrafenib when administered in combination with trametinib ^[10]

End point description

Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation.

End point type

Secondary

End point timeframe

pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D	Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	3	7	6	19	8	21	6
Units: hours*ng/mL
geometric mean (geometric coefficient of variation)	2560 ± 157.1	4160 ± 24.6	3910 ± 48.8	4030 ± 46.4	3800 ± 35.4	3950 ± 46.9	3990 ± 28.3

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state (AUCtau) of dabrafenib when administered in combination with trametinib

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End point title

Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state (AUCtau) of dabrafenib when administered in combination with trametinib ^[11]

End point description

End point type

Secondary

End point timeframe

pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D	Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	3	7	6	19	8	21	6
Units: hours*ng/mL
geometric mean (geometric coefficient of variation)	2870 ± 116.6	4160 ± 24.6	4040 ± 47.9	4070 ± 46.7	3910 ± 37.4	3990 ± 47.3	4150 ± 30.2

No statistical analyses for this end point

Secondary: Apparent plasma clearance (CL/F) of dabrafenib when administered in combination with trametinib

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End point title

Apparent plasma clearance (CL/F) of dabrafenib when administered in combination with trametinib ^[12]

End point description

Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau.

End point type

Secondary

End point timeframe

pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D	Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	3	7	6	19	8	21	6
Units: mL/hour
geometric mean (geometric coefficient of variation)	22900 ± 191.2	20400 ± 45.4	10100 ± 67.0	25400 ± 70.5	12500 ± 63.0	25100 ± 69.3	10200 ± 41.6

No statistical analyses for this end point

Secondary: Average steady state plasma concentration (Cavg) of dabrafenib when administered in combination with trametinib

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End point title

Average steady state plasma concentration (Cavg) of dabrafenib when administered in combination with trametinib ^[13]

End point description

Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of dabrafenib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 12 h for dabrafenib.

End point type

Secondary

End point timeframe

pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to subjects treated with trametinib in combination with dabrafenib.

End point values	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH	Part D – All tumor types TMT 0.025 mg/kg/day + 100% DRB RP2D	Part D – All tumor types TMT 0.032 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	3	7	6	19	8	21	6
Units: ng/mL
geometric mean (geometric coefficient of variation)	239 ± 116.6	347 ± 24.6	337 ± 47.9	339 ± 46.7	326 ± 37.4	332 ± 47.3	346 ± 30.2

No statistical analyses for this end point

Secondary: Palatability of trametinib oral solution in pediatric subjects assessed by palatability questionnaire

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End point title

Palatability of trametinib oral solution in pediatric subjects assessed by palatability questionnaire

End point description

For subjects ≥ 12 years of age who received the trametinib oral solution, the subject completed a form to evaluate the various properties of the solution (e.g., bitterness, sweetness, appearance, texture and overall taste). For subjects < 12 years of age who received the solution, their caregiver (e.g. parent or guardian) evaluated the solution with the child based on verbal and non-verbal feedback. The questionnaire was completed after the first dose of study drug and no later than Day 8 (±3 days). Subjects completed a form for each drug separately if enrolled in Parts C and D.

End point type

Secondary

End point timeframe

After the first dose of trametinib oral solution and no later than Day 8 (±3 days)

End point values	TMT 0.0125 mg/kg/day	TMT 0.025 mg/kg/day	TMT 0.032 mg/kg/day	TMT 0.04 mg/kg/day
Number of subjects analysed	2	29	21	4
Units: participants
Was the medicine difficult to mix?\|Yes	0	1	1	0
Was the medicine difficult to mix?\|No	2	26	19	4
Was the medicine difficult to mix?\|Missing	0	2	1	0
Was the medicine difficult to measure?\|Yes	0	0	2	0
Was the medicine difficult to measure?\|No	2	29	18	4
Was the medicine difficult to measure?\|Missing	0	0	1	0
Was the medicine difficult to administer?\|Yes	0	5	5	1
Was the medicine difficult to administer?\|No	2	24	15	3
Was the medicine difficult to administer?\|Missing	0	0	1	0
Did the subject like the taste?\|Yes	2	8	6	2
Did the subject like the taste?\|No	0	16	13	1
Did the subject like the taste?\|Missing	0	5	2	1
Did subject have difficulty in taking it?\|Yes	0	6	7	1
Did subject have difficulty in taking it?\|No	2	19	13	3
Did subject have difficulty in taking it?\|Missing	0	4	1	0
Did subject resist taking the medicine?\|Yes	0	7	6	1
Did subject resist taking the medicine?\|No	2	18	14	3
Did subject resist taking the medicine?\|Missing	0	4	1	0
Was the medicine bitter?\|Yes	0	3	0	0
Was the medicine bitter?\|No	0	2	1	0
Was the medicine bitter?\|Missing	2	24	20	4
Was the medicine sweet?\|Yes	0	2	1	0
Was the medicine sweet?\|No	0	3	0	0
Was the medicine sweet?\|Missing	2	24	20	4
Was the medicine sour?\|Yes	0	2	0	0
Was the medicine sour?\|No	0	3	1	0
Was the medicine sour?\|Missing	2	24	20	4
Was the medicine gritty?\|Yes	0	1	0	0
Was the medicine gritty?\|No	0	4	1	0
Was the medicine gritty?\|Missing	2	24	20	4
Was the medicine difficult to swallow?\|Yes	0	1	0	0
Was the medicine difficult to swallow?\|No	0	5	1	0
Was the medicine difficult to swallow?\|Missing	2	23	20	4

No statistical analyses for this end point

Secondary: Palatability of dabrafenib oral suspension in pediatric subjects assessed by palatability questionnaire

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End point title

Palatability of dabrafenib oral suspension in pediatric subjects assessed by palatability questionnaire

End point description

For subjects ≥ 12 years of age who received the dabrafenib suspension, the subject completed a form to evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, texture and overall taste). For subjects < 12 years of age who received the suspension, their caregiver (e.g. parent or guardian) evaluated the suspension with the child based on verbal and non-verbal feedback. The questionnaire was completed after the first dose of study drug and no later than Day 8 (±3 days). Subjects completed a form for each drug separately if enrolled in Parts C and D.

End point type

Secondary

End point timeframe

After the first dose of dabrafenib oral suspension and no later than Day 8 (±3 days)

End point values	TMT 0.025 mg/kg/day + 50% DRB RP2D	TMT 0.025 mg/kg/day + 100% DRB RP2D	TMT 0.032 mg/kg/day + 100% DRB RP2D
Number of subjects analysed	0 ^[14]	4	6
Units: participants
Was the medicine difficult to mix?\|Yes		0	1
Was the medicine difficult to mix?\|No		4	5
Was the medicine difficult to mix?\|Missing		0	0
Was the medicine difficult to measure?\|Yes		0	1
Was the medicine difficult to measure?\|No		4	5
Was the medicine difficult to measure?\|Missing		0	0
Was the medicine difficult to administer?\|Yes		0	1
Was the medicine difficult to administer?\|No		4	5
Was the medicine difficult to administer?\|Missing		0	0
Did the subject like the taste?\|Yes		0	4
Did the subject like the taste?\|No		1	2
Did the subject like the taste?\|Missing		3	0
Did subject have difficulty in taking it?\|Yes		0	2
Did subject have difficulty in taking it?\|No		1	4
Did subject have difficulty in taking it?\|Missing		3	0
Did subject resist taking the medicine?\|Yes		0	4
Did subject resist taking the medicine?\|No		1	2
Did subject resist taking the medicine?\|Missing		3	0
Was the medicine bitter?\|Yes		1	0
Was the medicine bitter?\|No		2	0
Was the medicine bitter?\|Missing		1	6
Was the medicine sweet?\|Yes		0	0
Was the medicine sweet?\|No		3	0
Was the medicine sweet?\|Missing		1	6
Was the medicine sour?\|Yes		2	0
Was the medicine sour?\|No		1	0
Was the medicine sour?\|Missing		1	6
Was the medicine gritty?\|Yes		1	0
Was the medicine gritty?\|No		2	0
Was the medicine gritty?\|Missing		1	6
Was the medicine difficult to swallow?\|Yes		0	0
Was the medicine difficult to swallow?\|No		3	0
Was the medicine difficult to swallow?\|Missing		1	6

Notes
[14] - 0 participants filled in the palatability form

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the day of the first dose of any study drug up to 30 days after the last dose, up to maximum duration of 64 months.

Adverse event reporting additional description

Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Part A – TMT 0.0125 mg/kg/day

Reporting group description

Participants treated with trametinib 0.0125 mg/kg/day

Reporting group title

Part A – TMT 0.025 mg/kg/day

Reporting group description

Participants treated with trametinib 0.025 mg/kg/day

Reporting group title

Part A – TMT 0.032 mg/kg/day

Reporting group description

Participants under 6 years of age treated with trametinib 0.032 mg/kg/day

Reporting group title

Part A – TMT 0.04 mg/kg/day

Reporting group description

Participants treated with trametinib 0.04 mg/kg/day

Reporting group title

Part B – Neuroblastoma

Reporting group description

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – LGG fusion

Reporting group description

Participants with recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – NF-1 with PN

Reporting group description

Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day

Reporting group title

Part B – BRAF V600 mutant solid tumor

Reporting group description

Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day

Reporting group title

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Reporting group description

Reporting group title

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Reporting group description

Reporting group title

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Reporting group description

Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)

Reporting group title

Part D – LGG

Reporting group description

Reporting group title

Part D – LCH

Reporting group description

Part A – TMT 0.0125 mg/kg/day

Part A – TMT 0.025 mg/kg/day

Part A – TMT 0.032 mg/kg/day

Part A – TMT 0.04 mg/kg/day

Part B – Neuroblastoma

Part B – LGG fusion

Part B – NF-1 with PN

Part B – BRAF V600 mutant solid tumor

Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D

Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D

Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D

Part D – LGG

Part D – LCH

Total subjects affected by serious adverse events

subjects affected / exposed

1 / 3 (33.33%)

8 / 19 (42.11%)

3 / 12 (25.00%)

11 / 16 (68.75%)

6 / 11 (54.55%)

6 / 10 (60.00%)

5 / 10 (50.00%)

1 / 3 (33.33%)

5 / 9 (55.56%)

2 / 6 (33.33%)

8 / 20 (40.00%)

6 / 10 (60.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

Vascular disorders

Hypertension

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypotension

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

1 / 10 (10.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

0 / 1

1 / 1

deaths causally related to treatment / all

0 / 0

Surgical and medical procedures

Gastrointestinal tube insertion

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

1 / 12 (8.33%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Fatigue

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypothermia

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Influenza like illness

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mucosal inflammation

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Oedema peripheral

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 3 (0.00%)

2 / 19 (10.53%)

1 / 12 (8.33%)

1 / 16 (6.25%)

2 / 11 (18.18%)

0 / 10 (0.00%)

2 / 10 (20.00%)

0 / 3 (0.00%)

3 / 9 (33.33%)

1 / 6 (16.67%)

4 / 20 (20.00%)

4 / 10 (40.00%)

occurrences causally related to treatment / all

0 / 0

1 / 4

1 / 1

0 / 1

0 / 2

0 / 0

0 / 3

0 / 0

1 / 3

0 / 4

4 / 4

7 / 12

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Aspiration

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cough

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

1 / 6 (16.67%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypoxia

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lung disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory distress

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tonsillar hypertrophy

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Restlessness

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Alanine aminotransferase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

1 / 10 (10.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

1 / 10 (10.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Blood alkaline phosphatase increased

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood bilirubin increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood culture positive

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

C-reactive protein increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

1 / 9 (11.11%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ejection fraction decreased

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

2 / 9 (22.22%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

4 / 4

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Weight decreased

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

White blood cell count decreased

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Accidental overdose

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Femur fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Foot fracture

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hip fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper limb fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

1 / 9 (11.11%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular access complication

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Wound secretion

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Bradycardia

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tachycardia

subjects affected / exposed

1 / 3 (33.33%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

1 / 10 (10.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Ataxia

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

1 / 9 (11.11%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Balance disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

1 / 9 (11.11%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Brain oedema

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 3 (33.33%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Depressed level of consciousness

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysarthria

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

1 / 9 (11.11%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Encephalopathy

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Epilepsy

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Headache

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hydrocephalus

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 6

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intracranial pressure increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Posterior reversible encephalopathy syndrome

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyramidal tract syndrome

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

3 / 16 (18.75%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 5

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Neutropenia

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Anal haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

1 / 9 (11.11%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pancreatitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

1 / 12 (8.33%)

1 / 16 (6.25%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

2 / 9 (22.22%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

4 / 5

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Rash

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Haematuria

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Endocrine disorders

Adrenal insufficiency

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Kyphosis

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Muscular weakness

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain in extremity

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Spinal instability

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Adenovirus infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

1 / 10 (10.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Arthritis infective

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchiolitis

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Device related infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

2 / 10 (20.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

1 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Enterobacter infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Enterococcal bacteraemia

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Escherichia infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis

subjects affected / exposed

0 / 3 (0.00%)

2 / 19 (10.53%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Influenza

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lymphangitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Medical device site infection

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Osteomyelitis

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Paronychia

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Parotitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

1 / 10 (10.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

deaths causally related to treatment / all

0 / 0

Pelvic abscess

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pharyngitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pharyngitis streptococcal

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

1 / 10 (10.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 3 (0.00%)

2 / 19 (10.53%)

1 / 12 (8.33%)

0 / 16 (0.00%)

1 / 11 (9.09%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rotavirus infection

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin infection

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tonsillitis

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

1 / 6 (16.67%)

0 / 20 (0.00%)

1 / 10 (10.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Varicella

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

1 / 6 (16.67%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular device infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

1 / 10 (10.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Viral infection

subjects affected / exposed

0 / 3 (0.00%)

2 / 19 (10.53%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Decreased appetite

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

1 / 11 (9.09%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dehydration

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

1 / 9 (11.11%)

1 / 6 (16.67%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 4

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperglycaemia

subjects affected / exposed

0 / 3 (0.00%)

0 / 19 (0.00%)

0 / 12 (0.00%)

0 / 16 (0.00%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypernatraemia

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 4

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 3 (0.00%)

1 / 19 (5.26%)

0 / 12 (0.00%)

1 / 16 (6.25%)

0 / 11 (0.00%)

0 / 10 (0.00%)

1 / 10 (10.00%)

0 / 3 (0.00%)

0 / 9 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Part A – TMT 0.0125 mg/kg/day	Part A – TMT 0.025 mg/kg/day	Part A – TMT 0.032 mg/kg/day	Part A – TMT 0.04 mg/kg/day	Part B – Neuroblastoma	Part B – LGG fusion	Part B – NF-1 with PN	Part B – BRAF V600 mutant solid tumor	Part C – TMT 0.025 mg/kg/day + 50% DRB RP2D	Part C – TMT 0.025 mg/kg/day + 100% DRB RP2D	Part C – TMT 0.032 mg/kg/day + 100% DRB RP2D	Part D – LGG	Part D – LCH
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	19 / 19 (100.00%)	12 / 12 (100.00%)	16 / 16 (100.00%)	11 / 11 (100.00%)	10 / 10 (100.00%)	10 / 10 (100.00%)	10 / 10 (100.00%)	3 / 3 (100.00%)	9 / 9 (100.00%)	6 / 6 (100.00%)	20 / 20 (100.00%)	10 / 10 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0	0	0	1	0	1	0
Neoplasm progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Skin papilloma
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	2	1
Tumour pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	1	0	2	2
Haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	0	0	1	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	3	0	0	1	0	0	0	0	0
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	3 / 12 (25.00%)	3 / 16 (18.75%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	4	3	3	0	2	1	3	0	5	0	0	1
Lymphoedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	0	0
Pallor
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	1	0	0	0	1	0	0	0
Surgical and medical procedures
Central venous catheter removal
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Tonsillectomy
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	0 / 12 (0.00%)	4 / 16 (25.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	4	0	5	0	1	1	1	0	1	0	1	0
Catheter site hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Catheter site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Catheter site rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Chest discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0
Chills
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 6 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	0	0	1	0	1	0	8	0	10	0
Cyst
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Face oedema
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	1	0	0	0	0	0	0	0	0	0
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	10 / 19 (52.63%)	9 / 12 (75.00%)	4 / 16 (25.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	6 / 10 (60.00%)	2 / 3 (66.67%)	4 / 9 (44.44%)	1 / 6 (16.67%)	9 / 20 (45.00%)	4 / 10 (40.00%)
occurrences all number	1	14	11	5	2	1	0	10	3	9	2	10	4
Feeling cold
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	1	0	0	0	0
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	1	0	1	0	1	0	0	0	1	0
Granuloma
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Hypothermia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1	0
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	2 / 12 (16.67%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	2 / 6 (33.33%)	2 / 20 (10.00%)	3 / 10 (30.00%)
occurrences all number	0	1	4	1	0	1	0	1	1	1	4	3	6
Localised oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	2	0
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	3 / 10 (30.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	8	1	2	0	4	2	4	1	0	0	2	0
Non-cardiac chest pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	1	0	0	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 20 (15.00%)	1 / 10 (10.00%)
occurrences all number	0	9	0	2	0	0	0	4	0	0	0	3	1
Pain
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	5	1	0	0	0	2	0	0	1	0	0	0
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	0	0	0	0	0	0	0	0	0	0
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	11 / 19 (57.89%)	8 / 12 (66.67%)	10 / 16 (62.50%)	5 / 11 (45.45%)	5 / 10 (50.00%)	6 / 10 (60.00%)	4 / 10 (40.00%)	0 / 3 (0.00%)	7 / 9 (77.78%)	4 / 6 (66.67%)	15 / 20 (75.00%)	8 / 10 (80.00%)
occurrences all number	2	33	18	19	13	8	14	9	0	23	10	45	26
Swelling face
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Xerosis
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	2 / 12 (16.67%)	2 / 16 (12.50%)	1 / 11 (9.09%)	2 / 10 (20.00%)	1 / 10 (10.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	6	2	3	1	2	1	3	0	0	0	0	0
Immune system disorders
Allergy to arthropod sting
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	2	0
Reproductive system and breast disorders
Menstruation irregular
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Perineal rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Vulvovaginal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Vulvovaginal pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Apnoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0	1	0	0	0	1	0
Aspiration
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Cough
subjects affected / exposed	1 / 3 (33.33%)	7 / 19 (36.84%)	6 / 12 (50.00%)	4 / 16 (25.00%)	2 / 11 (18.18%)	4 / 10 (40.00%)	5 / 10 (50.00%)	4 / 10 (40.00%)	1 / 3 (33.33%)	4 / 9 (44.44%)	1 / 6 (16.67%)	8 / 20 (40.00%)	6 / 10 (60.00%)
occurrences all number	1	18	12	6	4	7	7	5	1	6	1	14	6
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	0	0	0	0	3	0	1	0	1	1
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Epistaxis
subjects affected / exposed	1 / 3 (33.33%)	9 / 19 (47.37%)	4 / 12 (33.33%)	8 / 16 (50.00%)	2 / 11 (18.18%)	2 / 10 (20.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	1 / 3 (33.33%)	2 / 9 (22.22%)	0 / 6 (0.00%)	2 / 20 (10.00%)	3 / 10 (30.00%)
occurrences all number	1	9	5	12	5	3	1	3	1	2	0	3	8
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	2	0	0	0	0	0
Laryngeal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1	0
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	3 / 10 (30.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	1 / 6 (16.67%)	5 / 20 (25.00%)	3 / 10 (30.00%)
occurrences all number	0	2	1	1	1	0	3	1	0	3	1	6	3
Nasal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Nasal odour
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	1 / 12 (8.33%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	3 / 10 (30.00%)	1 / 3 (33.33%)	3 / 9 (33.33%)	0 / 6 (0.00%)	3 / 20 (15.00%)	2 / 10 (20.00%)
occurrences all number	0	9	3	2	0	4	1	4	1	3	0	4	2
Pharyngeal swelling
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	0	0	2	0	0	0	0	0
Respiratory disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0	0	0
Respiratory tract congestion
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	1	0	0	0	0	0	2	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	0	1	1	0	0	0	2	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	4 / 12 (33.33%)	1 / 16 (6.25%)	1 / 11 (9.09%)	2 / 10 (20.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2	9	1	1	2	1	1	0	3	0	0	1
Sinus congestion
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	1	1	1	0	0	0	1	0
Sneezing
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	1	0	0	0
Snoring
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1	0
Tachypnoea
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	1 / 12 (8.33%)	2 / 16 (12.50%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	8	1	4	1	2	0	3	0	7	0	0	1
Throat irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Tonsillar hypertrophy
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	0	0
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0	1	0	0	0	0	0
Psychiatric disorders
Abnormal behaviour
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Agitation
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	1	1	1	0	0	0	0	0	1	0
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	1	0	1	1	1	0	0	0	2	0
Attention deficit hyperactivity disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	0	1	0	0	0	0	0	0	0	1
Delirium
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	0	0	1	1	0	0	0	0	1	0
Dyssomnia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Enuresis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Initial insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	4	1	0	0	0	2	0	0	1	0	0	2
Irritability
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	1	1	0	0	1	0	0	0	0	0
Mood altered
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1	0
Obsessive-compulsive disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Restlessness
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	1 / 12 (8.33%)	5 / 16 (31.25%)	2 / 11 (18.18%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	1 / 6 (16.67%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	3	1	6	6	3	0	0	1	1	1	4	0
Albumin urine present
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Anion gap decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	8 / 19 (42.11%)	4 / 12 (33.33%)	7 / 16 (43.75%)	3 / 11 (27.27%)	1 / 10 (10.00%)	1 / 10 (10.00%)	6 / 10 (60.00%)	1 / 3 (33.33%)	3 / 9 (33.33%)	3 / 6 (50.00%)	5 / 20 (25.00%)	1 / 10 (10.00%)
occurrences all number	1	9	7	11	4	4	1	8	1	4	3	9	1
Bacterial test positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	4	0	0	0	0	1	0	0	0	0	0
Blood albumin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	5 / 19 (26.32%)	0 / 12 (0.00%)	2 / 16 (12.50%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	2 / 6 (33.33%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	8	0	3	5	0	0	1	0	3	2	5	1
Blood bicarbonate decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Blood bicarbonate increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Blood chloride increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	1 / 12 (8.33%)	2 / 16 (12.50%)	5 / 11 (45.45%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	2 / 6 (33.33%)	0 / 20 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	3	1	3	7	1	0	1	0	8	2	0	2
Blood glucose increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Blood urea decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Blood urea increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	1	0
Body temperature fluctuation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Ejection fraction decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	1	0	3	0	0	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	3	0	0	0
Electrocardiogram ST-T segment abnormal
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Electrocardiogram T wave amplitude decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
End-tidal CO2 decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	2 / 16 (12.50%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	1 / 3 (33.33%)	2 / 9 (22.22%)	2 / 6 (33.33%)	3 / 20 (15.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	2	1	0	0	6	2	2	3	4	1
Grip strength decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Haematocrit increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Haemoglobin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	3	0
Lung diffusion test decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Lymphocyte count decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	2 / 12 (16.67%)	1 / 16 (6.25%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	2	3	1	2	0	0	5	0	2	0	2	1
Lymphocyte count increased
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	0	0	0	0	0	0	0	0	0	0
Lymphocyte percentage decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	2 / 16 (12.50%)	2 / 11 (18.18%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 6 (0.00%)	3 / 20 (15.00%)	5 / 10 (50.00%)
occurrences all number	0	0	1	5	3	1	0	0	0	8	0	5	8
Neutrophil percentage increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Nitrite urine present
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	2 / 16 (12.50%)	2 / 11 (18.18%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	2	3	3	0	1	0	1	0	1	1
Protein total decreased
subjects affected / exposed	1 / 3 (33.33%)	1 / 19 (5.26%)	2 / 12 (16.67%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	2	0	0	0	0	0	0	0	0	0	0
Protein urine
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Red blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	0
Red blood cells urine
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Red blood cells urine positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Specific gravity urine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1	0	0
Staphylococcus test positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0	0
Urine ketone body present
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	0	1	0	0
Urine leukocyte esterase positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0	0	0	1	0	0
Urine output decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	1	1	1	0	0	1	0	0	0	0
Weight increased
subjects affected / exposed	0 / 3 (0.00%)	5 / 19 (26.32%)	3 / 12 (25.00%)	0 / 16 (0.00%)	2 / 11 (18.18%)	3 / 10 (30.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	2 / 6 (33.33%)	5 / 20 (25.00%)	1 / 10 (10.00%)
occurrences all number	0	8	3	0	3	3	0	1	1	1	2	7	1
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	3 / 12 (25.00%)	4 / 16 (25.00%)	3 / 11 (27.27%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	3 / 20 (15.00%)	1 / 10 (10.00%)
occurrences all number	0	2	7	6	5	1	0	0	0	4	0	6	1
White blood cell count increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	2	0
White blood cells urine positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	3	0	0	0	0	1	0	0	0	0	0
pH urine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	1	0	0	1	0
Contusion
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	2	0	0	1	0	1	1	0	0
Fall
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	2	1	1	0	1	0	1	0
Fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	1
Gastrostomy tube site complication
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0
Hand fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	2	0	0	0	0	0	0	0
Head injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0	0	0
Incision site pruritus
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Limb injury
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	2	0	3	0	0	0	0	0	0	0
Muscle strain
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Nasal injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Overdose
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Procedural pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Procedural vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Radius fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Scar
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Scratch
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Skin abrasion
subjects affected / exposed	1 / 3 (33.33%)	2 / 19 (10.53%)	3 / 12 (25.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	1	3	6	0	1	0	0	2	0	0	0	1	0
Skin laceration
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0	0	1	0
Stoma site hypergranulation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	0
Stoma site pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Sunburn
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	1	0	0	0	0	0	0
Thermal burn
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0	0	0	0
Tongue injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Upper limb fracture
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0
Venomous sting
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Wrist fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	0	0	0	0
Congenital, familial and genetic disorders
Phimosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Atrioventricular block first degree
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Bradycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Cardiac disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Mitral valve disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	2 / 12 (16.67%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	1	0	0	0	0
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0
Sinus bradycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	2	0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	5 / 19 (26.32%)	1 / 12 (8.33%)	2 / 16 (12.50%)	2 / 11 (18.18%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 6 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	8	1	2	4	2	0	1	0	6	0	2	1
Systolic dysfunction
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	3	0	1	1
Tricuspid valve disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0	0	0	0	0	0
Nervous system disorders
Allodynia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Aphasia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	0	0
Ataxia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Aura
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Depressed level of consciousness
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 6 (0.00%)	4 / 20 (20.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	1	0	0	1	2	0	6	0	6	2
Dysarthria
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Dyskinesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Facial paralysis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Headache
subjects affected / exposed	1 / 3 (33.33%)	11 / 19 (57.89%)	3 / 12 (25.00%)	5 / 16 (31.25%)	1 / 11 (9.09%)	4 / 10 (40.00%)	4 / 10 (40.00%)	3 / 10 (30.00%)	1 / 3 (33.33%)	4 / 9 (44.44%)	1 / 6 (16.67%)	9 / 20 (45.00%)	2 / 10 (20.00%)
occurrences all number	1	15	5	7	1	6	7	9	7	6	1	13	3
Horner's syndrome
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Hydrocephalus
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0	0	0
Lethargy
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	1 / 16 (6.25%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	1	2	0	0	2	0	1	0	1	1
Memory impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	0
Movement disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Muscle spasticity
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Nystagmus
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	6	0	1	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Seizure
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	2	0	2	0	1	2	1	0
Somnolence
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Visual field defect
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	9 / 19 (47.37%)	6 / 12 (50.00%)	7 / 16 (43.75%)	6 / 11 (54.55%)	3 / 10 (30.00%)	4 / 10 (40.00%)	5 / 10 (50.00%)	0 / 3 (0.00%)	4 / 9 (44.44%)	1 / 6 (16.67%)	4 / 20 (20.00%)	2 / 10 (20.00%)
occurrences all number	0	15	11	12	12	5	4	9	0	7	1	9	2
Bone marrow oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Eosinophilia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Hypochromasia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Leukopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Lymphadenitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Lymphadenopathy
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	1	0	0	0	0	1	0	0	0
Lymphopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1	0	0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	2	1	0	0	3	0	0	0	4	0
Thrombocytopenia
subjects affected / exposed	1 / 3 (33.33%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	1	1	0	0	0	0	0	0	0
Thrombocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Ear and labyrinth disorders
Deafness unilateral
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Ear pain
subjects affected / exposed	1 / 3 (33.33%)	2 / 19 (10.53%)	2 / 12 (16.67%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	2	2	0	6	1	0	0	0	0	0	0	0
External ear inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	0	0	0	0
External ear pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Hypoacusis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Middle ear inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0
Otorrhoea
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Tympanic membrane perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Eye disorders
Amblyopia
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0
Astigmatism
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0
Bell's phenomenon
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Blepharitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	2 / 12 (16.67%)	3 / 16 (18.75%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	3	4	0	1	0	0	0	1	0	0	0
Blindness
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Cataract
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Dry eye
subjects affected / exposed	1 / 3 (33.33%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	1	0	0	1	0	1	0	0	0	0	0
Dyschromatopsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Erythema of eyelid
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Eye discharge
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	3 / 16 (18.75%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	3	0	1	0	0	0	0	0	0	0
Eye haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Eye pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	1	0	0	1
Eye pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Eye swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	2 / 12 (16.67%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	0	3	0	0	0	0	0	0	0	0
Eyelid margin crusting
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Gaze palsy
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Heterophoria
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1	0
Hypermetropia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Iridocyclitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	1
Keratitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Lacrimation increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	1	0	0	0	0	0	0	0	0	0	0
Mydriasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	2
Ocular hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Optic disc disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Optic disc haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Optic nerve disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	0	0	0	0
Periorbital oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	1
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Pupillary reflex impaired
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Retinopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Strabismus
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Trichomegaly
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Uveitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	5	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	1 / 10 (10.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	2	1	1	1	0	1	0
Visual acuity reduced
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	1	0	0
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	1	0	0	0
Vitreous floaters
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	1
Abdominal mass
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	8 / 19 (42.11%)	7 / 12 (58.33%)	5 / 16 (31.25%)	1 / 11 (9.09%)	5 / 10 (50.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	2 / 6 (33.33%)	6 / 20 (30.00%)	4 / 10 (40.00%)
occurrences all number	0	11	10	9	1	9	1	4	0	6	2	9	4
Abdominal pain lower
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	5 / 19 (26.32%)	2 / 12 (16.67%)	2 / 16 (12.50%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	1	5	2	2	1	0	0	0	0	0	0	1	0
Anal fissure
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0
Anal incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	3	1	0	0	0	0	0	0	0	0
Anal inflammation
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Anal rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Angular cheilitis
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	1 / 12 (8.33%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	5	1	2	0	1	0	3	0	2	0	2	1
Aphthous ulcer
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	0	0
Chapped lips
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0
Cheilitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	3 / 12 (25.00%)	6 / 16 (37.50%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	1	3	6	0	0	2	1	0	1	0	2	0
Constipation
subjects affected / exposed	1 / 3 (33.33%)	8 / 19 (42.11%)	6 / 12 (50.00%)	3 / 16 (18.75%)	4 / 11 (36.36%)	5 / 10 (50.00%)	2 / 10 (20.00%)	6 / 10 (60.00%)	1 / 3 (33.33%)	2 / 9 (22.22%)	1 / 6 (16.67%)	5 / 20 (25.00%)	2 / 10 (20.00%)
occurrences all number	1	17	9	4	5	6	2	7	1	4	1	6	2
Dental caries
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	1	0	0	0	0	0	0	1	0	0
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	17 / 19 (89.47%)	10 / 12 (83.33%)	9 / 16 (56.25%)	6 / 11 (54.55%)	6 / 10 (60.00%)	5 / 10 (50.00%)	6 / 10 (60.00%)	2 / 3 (66.67%)	3 / 9 (33.33%)	3 / 6 (50.00%)	7 / 20 (35.00%)	5 / 10 (50.00%)
occurrences all number	1	41	16	23	6	27	13	11	4	7	5	18	7
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	2	0	0	0	0	0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	1	0	0	0	0	0	0	1	0
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	0	0	0	0	1	0	2	0	2	0
Gingival bleeding
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Gingival erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Gingival hypertrophy
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Gingival oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Gingival swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Haematemesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	2 / 12 (16.67%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	3	0	0	0	0	0	0	0	0	0	0
Lip blister
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Lip dry
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	2 / 12 (16.67%)	0 / 16 (0.00%)	0 / 11 (0.00%)	3 / 10 (30.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	3	3	0	0	3	0	2	0	1	0	1	0
Lip haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	0	0	0	0
Lip swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Mouth haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	0	0	1	2	1	0	0	0	0	0
Mucous stools
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	6 / 19 (31.58%)	1 / 12 (8.33%)	4 / 16 (25.00%)	3 / 11 (27.27%)	2 / 10 (20.00%)	3 / 10 (30.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	4 / 9 (44.44%)	1 / 6 (16.67%)	8 / 20 (40.00%)	3 / 10 (30.00%)
occurrences all number	0	11	1	4	4	3	6	4	0	9	1	14	4
Odynophagia
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	3	1	1	0	0	0	0	0	0	0	1	0
Oral disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1	0	0
Oral dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Oral pain
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	1
Proctalgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	3 / 12 (25.00%)	2 / 16 (12.50%)	1 / 11 (9.09%)	4 / 10 (40.00%)	3 / 10 (30.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	3	12	3	1	7	3	4	0	2	0	2	0
Teething
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Tooth discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Toothache
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	1	0
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	13 / 19 (68.42%)	9 / 12 (75.00%)	6 / 16 (37.50%)	3 / 11 (27.27%)	3 / 10 (30.00%)	3 / 10 (30.00%)	6 / 10 (60.00%)	1 / 3 (33.33%)	4 / 9 (44.44%)	4 / 6 (66.67%)	9 / 20 (45.00%)	7 / 10 (70.00%)
occurrences all number	1	23	14	14	3	15	10	16	1	6	5	18	11
Hepatobiliary disorders
Jaundice
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Ocular icterus
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 3 (33.33%)	3 / 19 (15.79%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	1	3	0	0	0	1	0	0	0	0	1	3	0
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	7 / 19 (36.84%)	4 / 12 (33.33%)	6 / 16 (37.50%)	1 / 11 (9.09%)	5 / 10 (50.00%)	4 / 10 (40.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 6 (16.67%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	8	4	6	1	5	4	3	0	2	1	1	1
Blister
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	1	1	0	0	0	0	0	0
Dermatitis
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	2 / 12 (16.67%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	2	0	0	0	1	1	0	1	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	6 / 19 (31.58%)	4 / 12 (33.33%)	10 / 16 (62.50%)	1 / 11 (9.09%)	4 / 10 (40.00%)	3 / 10 (30.00%)	4 / 10 (40.00%)	2 / 3 (66.67%)	4 / 9 (44.44%)	1 / 6 (16.67%)	8 / 20 (40.00%)	1 / 10 (10.00%)
occurrences all number	0	8	5	21	1	6	3	6	2	5	1	12	1
Dermatitis atopic
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Dermatitis contact
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Dermatitis diaper
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	2	0	0	0	2	1	0	0	0	0	0
Dermatosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Dry skin
subjects affected / exposed	1 / 3 (33.33%)	12 / 19 (63.16%)	10 / 12 (83.33%)	6 / 16 (37.50%)	4 / 11 (36.36%)	7 / 10 (70.00%)	5 / 10 (50.00%)	6 / 10 (60.00%)	2 / 3 (66.67%)	5 / 9 (55.56%)	3 / 6 (50.00%)	8 / 20 (40.00%)	5 / 10 (50.00%)
occurrences all number	1	19	14	12	4	7	7	9	3	7	4	10	5
Eczema
subjects affected / exposed	1 / 3 (33.33%)	8 / 19 (42.11%)	5 / 12 (41.67%)	9 / 16 (56.25%)	2 / 11 (18.18%)	5 / 10 (50.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 20 (15.00%)	2 / 10 (20.00%)
occurrences all number	1	8	9	11	3	7	1	1	1	0	0	4	2
Eczema asteatotic
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0	0	0	0
Eczema nummular
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	5 / 19 (26.32%)	1 / 12 (8.33%)	5 / 16 (31.25%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	7	2	5	2	0	0	3	0	1	0	2	2
Erythema multiforme
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	0
Erythema nodosum
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	1
Hair colour changes
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	3 / 12 (25.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	2 / 10 (20.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	3	3	1	1	2	0	2	0	1	0	0	0
Hair texture abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	1	1	1	0
Hand dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0
Hyperkeratosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	1 / 20 (5.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	2	0	1	3
Hypertrichosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	1	0
Ingrowing nail
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	0	0
Intertrigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Keratosis pilaris
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0	0
Livedo reticularis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Macule
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	1	0
Nail discolouration
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Nail disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	0	0
Pain of skin
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	1	0
Palmar erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	2	0
Panniculitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	1 / 9 (11.11%)	1 / 6 (16.67%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	3	2	3	1
Papule
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	0	0	0	0	0	0	0	0	2	0
Perioral dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Petechiae
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0
Photosensitivity reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	1	0
Pigmentation disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0	0
Plantar erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Prurigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	5 / 19 (26.32%)	1 / 12 (8.33%)	4 / 16 (25.00%)	2 / 11 (18.18%)	1 / 10 (10.00%)	1 / 10 (10.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	3 / 20 (15.00%)	3 / 10 (30.00%)
occurrences all number	0	6	1	5	2	1	1	3	0	3	0	3	3
Pseudofolliculitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Rash
subjects affected / exposed	1 / 3 (33.33%)	9 / 19 (47.37%)	5 / 12 (41.67%)	8 / 16 (50.00%)	4 / 11 (36.36%)	5 / 10 (50.00%)	6 / 10 (60.00%)	2 / 10 (20.00%)	3 / 3 (100.00%)	6 / 9 (66.67%)	2 / 6 (33.33%)	3 / 20 (15.00%)	2 / 10 (20.00%)
occurrences all number	2	18	9	12	6	5	6	4	4	10	2	3	3
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	1 / 12 (8.33%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	3	1	2	0	0	1	2	0	0	1	5	0
Rash follicular
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1	0
Rash macular
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	1	1	1	0	0	0	0	1	0	1
Rash maculo-papular
subjects affected / exposed	2 / 3 (66.67%)	3 / 19 (15.79%)	4 / 12 (33.33%)	4 / 16 (25.00%)	2 / 11 (18.18%)	4 / 10 (40.00%)	2 / 10 (20.00%)	3 / 10 (30.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	2 / 6 (33.33%)	6 / 20 (30.00%)	5 / 10 (50.00%)
occurrences all number	3	4	6	5	2	6	4	4	1	0	2	12	7
Rash papular
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	3 / 12 (25.00%)	3 / 16 (18.75%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	4 / 10 (40.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)
occurrences all number	0	6	4	4	0	6	0	5	0	1	0	3	1
Rash pruritic
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Seborrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Seborrhoeic dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	1	2	0	0	1	1	0
Skin burning sensation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Skin depigmentation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	1	0
Skin disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	0	0
Skin exfoliation
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	2	0	0	0	0	0	0	0	1	0
Skin fissures
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	3	0	3	4	3	0	0	0	0	0
Skin fragility
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Skin hyperpigmentation
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	1	0	0	0	1	0	2	0	1	0
Skin hypopigmentation
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	1
Skin lesion
subjects affected / exposed	1 / 3 (33.33%)	2 / 19 (10.53%)	3 / 12 (25.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	2	2	4	2	0	2	4	1	0	1	0	3	0
Skin mass
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	2	0
Skin toxicity
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	4 / 16 (25.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	5	0	0	0	1	0	1	0	0	0
Telangiectasia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Urticaria
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	1	0	0	0	1	1	0	0	5	0
Renal and urinary disorders
Albuminuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Crystalluria
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Cystitis noninfective
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	1	0	0	0	1	0	2	0
Glycosuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	1	0
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	1 / 12 (8.33%)	0 / 16 (0.00%)	2 / 11 (18.18%)	1 / 10 (10.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	4 / 9 (44.44%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	10	1	0	2	2	0	4	0	8	0	1	0
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	3 / 12 (25.00%)	2 / 16 (12.50%)	3 / 11 (27.27%)	2 / 10 (20.00%)	0 / 10 (0.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	2 / 6 (33.33%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	14	7	6	4	7	0	12	0	11	2	1	0
Urethritis noninfective
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Urinary incontinence
subjects affected / exposed	1 / 3 (33.33%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	0	0
Urinary retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Urine abnormality
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	0	0	0	0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Adrenocorticotropic hormone deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Growth hormone deficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Hypogonadism
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Precocious puberty
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	5 / 19 (26.32%)	2 / 12 (16.67%)	3 / 16 (18.75%)	1 / 11 (9.09%)	2 / 10 (20.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 3 (33.33%)	4 / 9 (44.44%)	0 / 6 (0.00%)	4 / 20 (20.00%)	0 / 10 (0.00%)
occurrences all number	0	8	3	6	1	3	0	1	1	4	0	4	0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	2 / 12 (16.67%)	4 / 16 (25.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	4	2	4	1	0	2	1	0	1	0	1	0
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1	0
Costochondritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Foot deformity
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Groin pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Joint range of motion decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Kyphosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Muscle atrophy
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	0	0	3	0	1	0	0	0	1	0
Muscle swelling
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	1	0	2	0	0	0	2	0	0	0
Musculoskeletal deformity
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 3 (33.33%)	2 / 9 (22.22%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	0	0	0	0	1	1	4	0	1	1
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	2 / 12 (16.67%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	4	2	1	0	0	1	0	0	0	0	2	0
Osteoporosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	7 / 19 (36.84%)	3 / 12 (25.00%)	3 / 16 (18.75%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	3 / 20 (15.00%)	4 / 10 (40.00%)
occurrences all number	0	11	3	4	2	0	3	2	0	1	0	3	5
Scoliosis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Spinal deformity
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Spinal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Tendonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Toe walking
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Trismus
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Infections and infestations
Beta haemolytic streptococcal infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
COVID-19
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1	0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1	0	1
Conjunctivitis
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	4 / 16 (25.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	2	1	5	5	2	1	0	0	0	1	1	1
Coronavirus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Coxsackie viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Device related infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	1	0	0
Ear infection
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	2 / 12 (16.67%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	2	1	1	1	1	0	0	1	0	2	0
Enterocolitis infectious
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Enterovirus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Epstein-Barr virus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Escherichia urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Eye infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	1	0	0	0	0	0	0	0	0	0
Folliculitis
subjects affected / exposed	0 / 3 (0.00%)	6 / 19 (31.58%)	3 / 12 (25.00%)	4 / 16 (25.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	10	3	5	0	0	4	5	0	0	0	0	1
Fungal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	1	0
Fungal skin infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0	0	0
Furuncle
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	0 / 12 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	2	0	1	1	1	0	0	0	1	0
Gastroenteritis bacterial
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	2	0	0	0
Gastrointestinal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Gingivitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0
Herpes dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Herpes simplex
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Herpes virus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0	0
Hordeolum
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	3	0	1	0	0	0	1	1	0	0	0	1
Impetigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	0	0	0
Infected bite
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Infected skin ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	1
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	2 / 12 (16.67%)	0 / 16 (0.00%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	3	0	0	2	0	0	0	0	0	0	0
Laryngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Localised infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	2	0	0	1	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Lymph gland infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	1
Mucosal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	1
Nail infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	0	0	0	0
Nasal vestibulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	1	3	0
Onychomycosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0	0	0
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	0	0	0	0	0	1	0	0	0	1
Otitis externa
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	2	0	1	0	0	0	0	0	0
Otitis media
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	3 / 12 (25.00%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	2 / 10 (20.00%)
occurrences all number	0	1	3	1	1	0	0	2	0	0	0	2	2
Otitis media acute
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Paronychia
subjects affected / exposed	0 / 3 (0.00%)	16 / 19 (84.21%)	10 / 12 (83.33%)	12 / 16 (75.00%)	0 / 11 (0.00%)	4 / 10 (40.00%)	7 / 10 (70.00%)	7 / 10 (70.00%)	2 / 3 (66.67%)	1 / 9 (11.11%)	1 / 6 (16.67%)	6 / 20 (30.00%)	1 / 10 (10.00%)
occurrences all number	0	46	27	33	0	6	14	14	6	1	1	11	1
Parotitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 3 (33.33%)	0 / 9 (0.00%)	0 / 6 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)
occurrences all number	0	3	1	0	0	1	0	0	1	0	0	4	0
Pharyngitis streptococcal
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	2 / 16 (12.50%)	1 / 11 (9.09%)	2 / 10 (20.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	4	1	3	1	2	0	1	0	0	0	2	0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	2 / 12 (16.67%)	1 / 16 (6.25%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	1	1	0	0	0	0	0	0	0	0
Post procedural infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Pustule
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1	0
Rash pustular
subjects affected / exposed	1 / 3 (33.33%)	5 / 19 (26.32%)	0 / 12 (0.00%)	3 / 16 (18.75%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 6 (16.67%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	1	5	0	5	0	1	0	0	0	1	1	1	1
Respiratory syncytial virus infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	0	0	0	0
Respiratory tract infection bacterial
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Rhinitis
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	0 / 12 (0.00%)	2 / 16 (12.50%)	0 / 11 (0.00%)	2 / 10 (20.00%)	3 / 10 (30.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	12	0	3	0	2	8	1	0	2	0	2	0
Rhinovirus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	1
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0	1	0	1	0	1	0
Skin bacterial infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Skin candida
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Skin infection
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	2 / 12 (16.67%)	3 / 16 (18.75%)	2 / 11 (18.18%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	4	2	3	5	2	0	1	0	0	2	1	0
Staphylococcal infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	1	1	0	0	0	0	0	0
Staphylococcal skin infection
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	3	0	1	0	0	0	0	0
Stoma site infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	0	0
Tinea capitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Tinea faciei
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Tinea infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	0	0	0
Tinea pedis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Tonsillitis
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	1	0	0	0	0	0	0	0	1	0
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Tracheitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	6 / 19 (31.58%)	3 / 12 (25.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	3 / 10 (30.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	1 / 6 (16.67%)	6 / 20 (30.00%)	4 / 10 (40.00%)
occurrences all number	0	9	5	1	0	0	3	5	0	3	1	8	5
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	3	1	1	7	2	3	0	0	0	0	0	0
Varicella
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0	0	0	0	0
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	1 / 12 (8.33%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 6 (16.67%)	1 / 20 (5.00%)	1 / 10 (10.00%)
occurrences all number	0	6	2	1	0	0	2	0	0	1	1	1	1
Viral pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0	0	0	0
Viral rhinitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Wound sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Metabolism and nutrition disorders
Alkalosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Decreased appetite
subjects affected / exposed	2 / 3 (66.67%)	11 / 19 (57.89%)	4 / 12 (33.33%)	5 / 16 (31.25%)	1 / 11 (9.09%)	3 / 10 (30.00%)	2 / 10 (20.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	4 / 20 (20.00%)	0 / 10 (0.00%)
occurrences all number	2	16	4	6	1	3	3	5	0	1	0	4	0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	2 / 12 (16.67%)	1 / 16 (6.25%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	2	1	0	1	0	0	0	0	0	1	0
Hyperchloraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	6	0	0	1	0	0	0	1	0	0	0
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	3 / 12 (25.00%)	4 / 16 (25.00%)	3 / 11 (27.27%)	2 / 10 (20.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	0 / 6 (0.00%)	4 / 20 (20.00%)	1 / 10 (10.00%)
occurrences all number	0	14	4	7	4	12	1	11	0	11	0	12	1
Hyperkalaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	1 / 12 (8.33%)	2 / 16 (12.50%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	5	4	0	0	1	0	0	0	2	0
Hypermagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0	1	0	5	0	1	0
Hypernatraemia
subjects affected / exposed	0 / 3 (0.00%)	5 / 19 (26.32%)	1 / 12 (8.33%)	2 / 16 (12.50%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 10 (0.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	1 / 6 (16.67%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	6	1	2	1	1	0	4	0	6	1	2	0
Hyperphosphataemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	1 / 3 (33.33%)	5 / 19 (26.32%)	6 / 12 (50.00%)	4 / 16 (25.00%)	4 / 11 (36.36%)	3 / 10 (30.00%)	1 / 10 (10.00%)	3 / 10 (30.00%)	0 / 3 (0.00%)	4 / 9 (44.44%)	2 / 6 (33.33%)	3 / 20 (15.00%)	2 / 10 (20.00%)
occurrences all number	1	16	15	4	6	5	1	9	0	12	4	6	2
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	3 / 19 (15.79%)	5 / 12 (41.67%)	3 / 16 (18.75%)	2 / 11 (18.18%)	1 / 10 (10.00%)	1 / 10 (10.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	4 / 9 (44.44%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)
occurrences all number	0	9	9	6	2	2	1	8	0	15	0	2	0
Hypochloraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	0 / 3 (0.00%)	4 / 19 (21.05%)	2 / 12 (16.67%)	4 / 16 (25.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 10 (10.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	3 / 9 (33.33%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	4	5	4	1	0	1	2	0	7	1	0	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	2 / 11 (18.18%)	1 / 10 (10.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	1	3	1	0	3	0	2	0	1	0
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	1 / 12 (8.33%)	0 / 16 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	2 / 9 (22.22%)	1 / 6 (16.67%)	4 / 20 (20.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	0	2	0	0	1	0	3	3	6	1
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	3 / 11 (27.27%)	1 / 10 (10.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	3	1	1	4	1	0	3	0	0	0	0	1
Hypophagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	1	0
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 19 (10.53%)	1 / 12 (8.33%)	1 / 16 (6.25%)	3 / 11 (27.27%)	1 / 10 (10.00%)	0 / 10 (0.00%)	2 / 10 (20.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	1 / 6 (16.67%)	3 / 20 (15.00%)	2 / 10 (20.00%)
occurrences all number	0	3	3	1	10	1	0	3	0	2	1	5	3
Hypoproteinaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	1 / 10 (10.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	0	0	1	0
Obesity
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Salt craving
subjects affected / exposed	0 / 3 (0.00%)	0 / 19 (0.00%)	0 / 12 (0.00%)	1 / 16 (6.25%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	0 / 9 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 3 (0.00%)	1 / 19 (5.26%)	0 / 12 (0.00%)	0 / 16 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 10 (0.00%)	0 / 3 (0.00%)	1 / 9 (11.11%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0

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Were there any global substantial amendments to the protocol? Yes

05 Mar 2014

Subjects must have been less than 18 years of age to enroll. Part B Leukemia cohort was removed. Part B cohort B1 was restricted to subjects with relapsed or refractory neuroblastoma and Part B cohort B4 was added to allow subjects with BRAF V600 mutant solid tumors to be treated with trametinib monotherapy. Guidelines and dose modifications for trametinib events of special interest were updated and RANO criteria were added for disease response assessment for CNS tumors.

14 Apr 2015

Eligibility criteria was revised to clarify that subjects with NF-1 associated PNs and subjects with LCH were eligible. At the request of regulatory, the timeframe for pregnancy testing prior to enrollment was shortened from 14 to 7 days in applicable subjects. Exclusion criteria were changed to exclude only optic pathway tumors that were being actively treated. Cardiovascular exclusion criteria were updated to be consistent with requirements in other dabrafenib and trametinib studies; Removal of RPED (retinal pigment epithelium detachment) as an exclusion criterion, based on current safety data that only requires history of RVO (retinal vein occlusion) as an exclusion; Removal of heparin-sensitivity as an exclusion as there are no known drug-drug interactions between heparin and trametinib or dabrafenib. MRIs were required in Part B for PN subjects. Updated to clarify that there were no prohibited medications in Parts A and B.

05 Jan 2016

This amendment was made to expand the description of Part C to include the dabrafenib RP2D levels and rationale along with the observed safety in pediatric subjects on dabrafenib monotherapy. Updated safety information from adult combination studies was included.

20 Sep 2016

Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GSK1120212 and GSK2118436 by Novartis, the purpose of this protocol Amendment 4 was to delete or replace references to GSK or its staff with that of Novartis and its authorized agents to align with the change of sponsorship and to make administrative changes to align with Novartis processes and procedures.

08 Mar 2017

The purpose of this amendment was to add 2 new specific BRAF V600 mutant disease cohorts (LGG and LCH) for study combination therapy of dabrafenib and trametinib to obtain preliminary efficacy information in these diseases, as well as additional safety, tolerability and PK data for the combination. The 2 dose escalation portions of the protocol (Part A and Part C) were extended to allow additional dose exploration of trametinib in subjects under 6 years of age in an effort to obtain target exposure comparable to adults in this age group.

17 Sep 2018

The purpose of this amendment was the addition of a new pediatric formulation dosage form of dabrafenib 10 mg as dispersible tablets and to update the withdrawal of consent language to align with the new Global Data Protection Requirements.

04 Apr 2019

The purpose of this amendment was to add additional interim analyses of data to support health authority requests/publication requests.

23 Jan 2020

The main purpose of this amendment was to add dose modification requirements for cases of severe cutaneous adverse reactions (SCARs) which had been reported during treatment with dabrafenib in combination with trametinib outside this clinical study. The definition of ‘Study Completion’ was also amended, reducing the minimum treatment duration from 12 months to 6 months. Dabrafenib powder for oral suspension (150 mg stickpack, 10 mg/mL in oral suspension), and trametinib 0.125 mg tablets were removed, as the manufacturing of these formulations was discontinued. Subjects were changed to dabrafenib 10 mg dispersible tablets and trametinib 0.5 mg and 2 mg tablets.

21 Aug 2020

The purpose of this amendment was to add updated RANO criteria specifically for low grade glioma as the basis for independent review. These more recent RANO-LGG criteria allowed for the identification of measurable target lesions in subjects with LGG that may not be gadolinium enhancing and are best seen by T2/FLAIR imaging sequences. These updated RANO - LGG criteria were utilized in supplemental independent RANO response determination for those subjects with LGG. this study. In addition, the contraception information was updated following results from a trametinib PK study which showed that no loss of efficacy of combined hormonal contraceptives (norethindrone and ethinyl estradiol) was expected when co-administered with trametinib monotherapy.

Were there any global interruptions to the trial? No

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

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

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Incidence of treatment emergent adverse events in subjects treated with trametinib monotherapy

Primary: Incidence of treatment emergent adverse events in subjects treated with trametinib monotherapy

Primary: Average steady state plasma concentration (Cavg) of trametinib when administered alone (monotherapy)

Primary: Average steady state plasma concentration (Cavg) of trametinib when administered alone (monotherapy)

Secondary: Trough concentration (Ctrough) of trametinib when administered alone and in combination with dabrafenib

Secondary: Trough concentration (Ctrough) of trametinib when administered alone and in combination with dabrafenib

Secondary: Maximum observed plasma concentration (Cmax) of trametinib when administered alone and in combination with dabrafenib

Secondary: Maximum observed plasma concentration (Cmax) of trametinib when administered alone and in combination with dabrafenib

Secondary: Time to reach maximum plasma concentration (Tmax) of trametinib when administered alone and in combination with dabrafenib

Secondary: Time to reach maximum plasma concentration (Tmax) of trametinib when administered alone and in combination with dabrafenib

Secondary: Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of trametinib when administered alone and in combination with dabrafenib

Secondary: Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of trametinib when administered alone and in combination with dabrafenib

Secondary: Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state (AUCtau) of trametinib when administered alone and in combination with dabrafenib

Secondary: Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state (AUCtau) of trametinib when administered alone and in combination with dabrafenib

Secondary: Apparent plasma clearance (CL/F) of trametinib when administered alone and in combination with dabrafenib

Secondary: Apparent plasma clearance (CL/F) of trametinib when administered alone and in combination with dabrafenib

Secondary: Average steady state plasma concentration (Cavg) of trametinib when administered in combination with dabrafenib

Secondary: Average steady state plasma concentration (Cavg) of trametinib when administered in combination with dabrafenib

Secondary: Incidence of treatment emergent adverse events in subjects treated with trametinib in combination with dabrafenib

Secondary: Incidence of treatment emergent adverse events in subjects treated with trametinib in combination with dabrafenib

Secondary: Best Overall Response (BOR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

Secondary: Best Overall Response (BOR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

Secondary: Objective response rate (ORR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

Secondary: Objective response rate (ORR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

Secondary: Clinical Benefit Rate (CBR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

Secondary: Clinical Benefit Rate (CBR) based on RECIST v1.1, RANO and Dombi criteria and as per investigator assessment

Secondary: Apparent clearance (CL/F) of trametinib estimated with a PopPK model

Secondary: Apparent clearance (CL/F) of trametinib estimated with a PopPK model

Secondary: Apparent central volume (Vc/F) of trametinib estimated with a PopPK model

Secondary: Apparent central volume (Vc/F) of trametinib estimated with a PopPK model

Secondary: Absorption rate constants (Ka1 and Ka2) of trametinib estimated with a PopPK model

Secondary: Absorption rate constants (Ka1 and Ka2) of trametinib estimated with a PopPK model

Secondary: Significant covariates estimated with a PopPK model

Secondary: Significant covariates estimated with a PopPK model

Secondary: Trough concentration (Ctrough) of dabrafenib when administered in combination with trametinib

Secondary: Trough concentration (Ctrough) of dabrafenib when administered in combination with trametinib

Secondary: Maximum observed plasma concentration (Cmax) of dabrafenib when administered in combination with trametinib

Secondary: Maximum observed plasma concentration (Cmax) of dabrafenib when administered in combination with trametinib

Secondary: Time to reach maximum plasma concentration (Tmax) of dabrafenib when administered in combination with trametinib

Secondary: Time to reach maximum plasma concentration (Tmax) of dabrafenib when administered in combination with trametinib

Secondary: Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of dabrafenib when administered in combination with trametinib

Secondary: Area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of dabrafenib when administered in combination with trametinib

Secondary: Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state (AUCtau) of dabrafenib when administered in combination with trametinib

Secondary: Area under the plasma concentration-time curve from time zero to the end of the dosing interval tau at steady-state (AUCtau) of dabrafenib when administered in combination with trametinib

Secondary: Apparent plasma clearance (CL/F) of dabrafenib when administered in combination with trametinib

Secondary: Apparent plasma clearance (CL/F) of dabrafenib when administered in combination with trametinib

Secondary: Average steady state plasma concentration (Cavg) of dabrafenib when administered in combination with trametinib

Secondary: Average steady state plasma concentration (Cavg) of dabrafenib when administered in combination with trametinib

Secondary: Palatability of trametinib oral solution in pediatric subjects assessed by palatability questionnaire

Secondary: Palatability of trametinib oral solution in pediatric subjects assessed by palatability questionnaire

Secondary: Palatability of dabrafenib oral suspension in pediatric subjects assessed by palatability questionnaire

Secondary: Palatability of dabrafenib oral suspension in pediatric subjects assessed by palatability questionnaire

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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