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Clinical Trial Results:
A Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Cobimetinib In Pediatric and Young Adult Patients with Previously Treated Solid Tumors

Summary
EudraCT number	2014-004685-25
Trial protocol	NL IE DK GB DE ES IT FR
Global end of trial date	21 Jul 2021

Results information
Results version number	v2(current)
This version publication date	24 Mar 2022
First version publication date	05 Feb 2022
Other versions	v1
Version creation reason

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

GO29665

ISRCTN number

US NCT number

NCT02639546

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-001425-PIP01-13

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

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

Analysis stage

Final

Date of interim/final analysis

21 Jul 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

To evaluate the Safety and Pharmacokinetics of Cobimetinib

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

20 May 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 3

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

France: 15

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

Israel: 7

Country: Number of subjects enrolled

Italy: 1

Country: Number of subjects enrolled

United States: 14

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 17 centers in 7 countries.

Screening details

A total of 63 participants were screened, of which a total of 56 participants were enrolled. Tumor type was not a determinant of cohort assignment for the phase I portion of the study. The phase II portion of the study was restricted to participants with Low-Grade Glioma.

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

Phase I (Tablet) Cobimetinib (0.6 mg/kg)

Arm description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally once daily at a dose of 0.6 mg/kg.

Phase I (Tablet) Cobimetinib (0.8 mg/kg)

Arm description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally once daily at a dose of 0.8 mg/kg.

Phase I (Tablet) Cobimetinib (1 mg/kg)

Arm description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally once daily at a dose of 1 mg/kg.

Phase I (Suspension) Cobimetinib (0.6 mg/kg)

Arm description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally once daily at a dose of 0.6 mg/kg.

Phase I (Suspension) Cobimetinib (0.8 mg/kg)

Arm description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally once daily at a dose of 0.8 mg/kg.

Phase I (Suspension) Cobimetinib (1 mg/kg)

Arm description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally once daily at a dose of 1 mg/kg.

Phase I (Suspension) Cobimetinib (1.33 mg/kg)

Arm description

Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally once daily at a dose of 1.33 mg/kg.

Phase II (Suspension) Cobimetinib (1 mg/kg)

Arm description

Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Arm type

Experimental

Investigational medicinal product name

Cobimetinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for oral suspension

Routes of administration

Oral use

Dosage and administration details

Cobimetinib was administered orally once daily at a dose of 1 mg/kg.

Number of subjects in period 1	Phase I (Tablet) Cobimetinib (0.6 mg/kg)	Phase I (Tablet) Cobimetinib (0.8 mg/kg)	Phase I (Tablet) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (0.6 mg/kg)	Phase I (Suspension) Cobimetinib (0.8 mg/kg)	Phase I (Suspension) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (1.33 mg/kg)	Phase II (Suspension) Cobimetinib (1 mg/kg)
Started	6	6	6	6	7	8	5	12
Completed	0	0	0	0	0	0	0	0
Not completed	6	6	6	6	7	8	5	12
Withdrawal By Subject	2	2	1	-	-	1	2	1
Study Terminated By Sponsor	-	2	3	4	4	3	3	9
Death	2	2	1	2	2	2	-	-
Lost to follow-up	-	-	1	-	1	1	-	1
PI, physician decision; no response to trt.	2	-	-	-	-	1	-	1

Baseline characteristics

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Reporting group title

Phase I (Tablet) Cobimetinib (0.6 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Tablet) Cobimetinib (0.8 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Tablet) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (0.6 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (0.8 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (1.33 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase II (Suspension) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group values	Phase I (Tablet) Cobimetinib (0.6 mg/kg)	Phase I (Tablet) Cobimetinib (0.8 mg/kg)	Phase I (Tablet) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (0.6 mg/kg)	Phase I (Suspension) Cobimetinib (0.8 mg/kg)	Phase I (Suspension) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (1.33 mg/kg)	Phase II (Suspension) Cobimetinib (1 mg/kg)	Total
Number of subjects	6	6	6	6	7	8	5	12	56
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0
Children (2-11 years)	3	4	5	6	5	6	3	9	41
Adolescents (12-17 years)	3	2	1	0	2	2	2	2	14
Adults (18-64 years)	0	0	0	0	0	0	0	1	1
From 65-84 years	0	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	11.8 ± 3.5	9.5 ± 3.3	9.5 ± 3.4	8.5 ± 1.4	9.7 ± 5.3	8.9 ± 3.1	10.2 ± 3.3	8.7 ± 7.5	-
Sex: Female, Male
Units:
Female	1	2	4	2	0	2	5	7	23
Male	5	4	2	4	7	6	0	5	33
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	1	1	0	1	2	1	1	4	11
Not Hispanic or Latino	5	3	4	1	2	4	3	7	29
Not Stated	0	2	2	4	3	3	1	1	16
Race/Ethnicity, Customized
Units: Subjects
Asian	0	0	0	0	1	0	0	0	1
Black or African American	0	1	1	1	0	0	0	0	3
Unknown	1	1	2	5	4	3	1	1	18
White	5	4	3	0	2	5	4	11	34
Tumor Type
Units: Subjects
Neuroblastoma	0	0	1	0	0	0	0	0	1
High-Grade Glioma	3	1	0	0	1	0	0	0	5
Low-Grade Glioma	1	2	4	5	3	2	3	12	32
Dnet In Noonan's Syndrome	0	0	0	0	0	0	1	0	1
Malignant Peripheral Nerve Sheath Tumor	0	0	0	0	1	1	0	0	2
Metastatic Mediastinal Yolksac Tumor	1	0	0	0	0	0	0	0	1
Non-Rhabdomyosarcoma Soft Tissue Sarcoma	0	1	0	0	0	0	0	0	1
Plexiform Neurofibroma	1	2	1	1	2	4	1	0	12
Rhabdoid Tumor/ATRT	0	0	0	0	0	1	0	0	1

End points

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Reporting group title

Phase I (Tablet) Cobimetinib (0.6 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Tablet) Cobimetinib (0.8 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Tablet) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (0.6 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (0.8 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (1.33 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase II (Suspension) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Subject analysis set title

Cobimetinib (Tablet) Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received Cobimetinib (Tablet) Formulation.

Subject analysis set title

Cobimetinib (Suspension) Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received Cobimetinib (Suspension) Formulation.

Subject analysis set title

Neuroblastoma

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Neuroblastoma.

Subject analysis set title

High Grade Glioma

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with High Grade Glioma.

Subject analysis set title

Low Grade Glioma (Phase I and II)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Low Grade Glioma.

Subject analysis set title

Dnet In Noonan's Syn Tumr (RAS/RAF/MEK/ERK Pathway Activation)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Dnet In Noonan's Syndrome Tumor With RAS/RAF/MEK/ERK Pathway Activation.

Subject analysis set title

Malignant Peripheral Nerve Sheath Tumor

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Malignant Peripheral Nerve Sheath Tumor.

Subject analysis set title

Metstic Mdstnl Ylksc Tumr (RAS/RAF/MEK/ERK Pathway Activation)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Metastatic Mediastinal Yolksac Tumor With RAS/RAF/MEK/ERK Pathway Activation.

Subject analysis set title

Non-Rhabdomyosarcoma Soft Tissue Sarcoma

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Non-Rhabdomyosarcoma Soft Tissue Sarcoma.

Subject analysis set title

Plexiform Neurofibroma

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Plexiform Neurofibroma.

Subject analysis set title

Rhabdoid Tumor/ATRT

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Rhabdoid Tumor/ATRT.

Subject analysis set title

Low Grade Glioma (Phase II)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with Low Grade Glioma.

Subject analysis set title

Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Subject analysis set title

Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Subject analysis set title

Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Subject analysis set title

Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Subject analysis set title

Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Subject analysis set title

Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Subject analysis set title

Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Subject analysis set title

Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Primary: Percentage of Participants with Dose-Limiting Toxicities (DLTs)

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End point title

Percentage of Participants with Dose-Limiting Toxicities (DLTs) ^[1]

End point description

Dose-Limiting Toxicities (DLTs) were defined as cobimetinib-related adverse events occurring within the first 28 days of each administration of cobimetinib.

End point type

Primary

End point timeframe

Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 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 Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Phase I (Tablet) Cobimetinib (0.6 mg/kg)	Phase I (Tablet) Cobimetinib (0.8 mg/kg)	Phase I (Tablet) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (0.6 mg/kg)	Phase I (Suspension) Cobimetinib (0.8 mg/kg)	Phase I (Suspension) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (1.33 mg/kg)	Phase II (Suspension) Cobimetinib (1 mg/kg)
Number of subjects analysed	6	6	6	6	7	8	5	12
Units: Percentage of Participants
number (not applicable)	0	0	33.3	16.7	0	0	60.0	0

No statistical analyses for this end point

Primary: Percentage of Participants with Adverse Events (AEs), including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

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End point title

Percentage of Participants with Adverse Events (AEs), including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) ^[2]

End point description

An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as AEs.

End point type

Primary

End point timeframe

Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Phase I (Tablet) Cobimetinib (0.6 mg/kg)	Phase I (Tablet) Cobimetinib (0.8 mg/kg)	Phase I (Tablet) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (0.6 mg/kg)	Phase I (Suspension) Cobimetinib (0.8 mg/kg)	Phase I (Suspension) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (1.33 mg/kg)	Phase II (Suspension) Cobimetinib (1 mg/kg)
Number of subjects analysed	6	6	6	6	7	8	5	12
Units: Percentage of Participants
number (not applicable)
AEs	100.0	100.0	100.0	100.0	100.0	100.0	100.0	100.0
SAEs	33.3	33.3	33.3	33.3	14.3	25.0	40.0	41.7
AESIs	33.3	33.3	33.3	50.0	42.9	25.0	100.0	58.3

No statistical analyses for this end point

Primary: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib

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End point title

Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib ^[3]

End point description

A prior dose level was defined as an MTD/MAD if at a certain dose level, there were greater than or equal to (>=) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).

End point type

Primary

End point timeframe

Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=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 Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Cobimetinib (Tablet) Population	Cobimetinib (Suspension) Population
Number of subjects analysed	18	38
Units: mg/kg
number (not applicable)	0.8	1

No statistical analyses for this end point

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants with Low-Grade Glioma (LGG) (Phase I and II)

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End point title

Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants with Low-Grade Glioma (LGG) (Phase I and II) ^[4]

End point description

Tumor assessment was performed using Response Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here. The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.

End point type

Primary

End point timeframe

Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	High Grade Glioma	Low Grade Glioma (Phase I and II)
Number of subjects analysed	5	32
Units: Percentage of Participants
number (not applicable)	0	9.4

No statistical analyses for this end point

Primary: Percentage of Participants with Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator using modified International Neuroblastoma Response Criteria (mINRC) for Participants with Neuroblastoma (Phase I)

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End point title

Percentage of Participants with Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator using modified International Neuroblastoma Response Criteria (mINRC) for Participants with Neuroblastoma (Phase I) ^[5]

End point description

Tumor assessment was performed using mINRC for Participants with Neuroblastoma. The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.

End point type

Primary

End point timeframe

Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Neuroblastoma
Number of subjects analysed	1
Units: Percentage of Participants	0

No statistical analyses for this end point

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I)

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End point title

Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I) ^[6]

End point description

Tumor assessment was performed using RECIST v1.1 for Participants with All Other Tumours. The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type.

End point type

Primary

End point timeframe

Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

Notes
[6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Dnet In Noonan's Syn Tumr (RAS/RAF/MEK/ERK Pathway Activation)	Malignant Peripheral Nerve Sheath Tumor	Metstic Mdstnl Ylksc Tumr (RAS/RAF/MEK/ERK Pathway Activation)	Non-Rhabdomyosarcoma Soft Tissue Sarcoma	Plexiform Neurofibroma	Rhabdoid Tumor/ATRT
Number of subjects analysed	1	2	1	1	12	1
Units: Percentage of Participants	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II)

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End point title

Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II) ^[7]

End point description

Tumor assessment was performed using RANO criteria for LGG. The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG).

End point type

Primary

End point timeframe

Baseline up to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Low Grade Glioma (Phase II)
Number of subjects analysed	12
Units: Percentage of Participants
number (not applicable)	8.3

No statistical analyses for this end point

Primary: Progression-Free Survival (PFS) as Determined by the Investigator using mINRC for Participants with Neuroblastoma (Phase I)

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End point title

Progression-Free Survival (PFS) as Determined by the Investigator using mINRC for Participants with Neuroblastoma (Phase I) ^[8]

End point description

End point type

Primary

End point timeframe

From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)

Notes
[8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Neuroblastoma
Number of subjects analysed	1
Units: Months
median (confidence interval 95%)	1.3 (0.0 to 9999999)

No statistical analyses for this end point

Primary: PFS as Determined by the Investigator using RANO criteria for participants with HGG (Phase I) and RECIST v1.1 for partcipants with LGG (Phase I and II)

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End point title

PFS as Determined by the Investigator using RANO criteria for participants with HGG (Phase I) and RECIST v1.1 for partcipants with LGG (Phase I and II) ^[9]

End point description

Tumor assessment was performed using RANO for participants with HGG and RECIST v1.1 for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here. The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type. 9999999 = The upper limit could not be calculated from the data due to insufficient number of participants with events.

End point type

Primary

End point timeframe

From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to approximately 6.75 years)

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	High Grade Glioma	Low Grade Glioma (Phase I and II)
Number of subjects analysed	5	32
Units: Months
median (confidence interval 95%)	1.0 (0.6 to 9999999)	22.0 (9.3 to 9999999)

No statistical analyses for this end point

Primary: PFS as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I)

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End point title

PFS as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I) ^[10]

End point description

End point type

Primary

End point timeframe

From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)

Notes
[10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Dnet In Noonan's Syn Tumr (RAS/RAF/MEK/ERK Pathway Activation)	Malignant Peripheral Nerve Sheath Tumor	Metstic Mdstnl Ylksc Tumr (RAS/RAF/MEK/ERK Pathway Activation)	Non-Rhabdomyosarcoma Soft Tissue Sarcoma	Plexiform Neurofibroma	Rhabdoid Tumor/ATRT
Number of subjects analysed	1	2	1	1	12	1
Units: Months
median (confidence interval 95%)	9999999 (0.0 to 9999999)	4.1 (0.7 to 9999999)	1.1 (0.0 to 9999999)	3.4 (0.0 to 9999999)	9999999 (18.4 to 9999999)	0.5 (0.0 to 9999999)

No statistical analyses for this end point

Primary: PFS as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II)

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End point title

PFS as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II) ^[11]

End point description

Tumor assessment was performed using RANO criteria for Participants with LGG. The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG). 9999999 = The upper limit could not be calculated from the data due to insufficient number of participants with events.

End point type

Primary

End point timeframe

From the time of cobimetinib study drug initiation to the first documented disease progression, or death due to any cause, whichever occurs first (up to 5 years, 2 months)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No Statistical Analyses provided as no formal hypothesis testing was planned for this study.

End point values	Low Grade Glioma (Phase II)
Number of subjects analysed	12
Units: Months
median (confidence interval 95%)	18.4 (3.6 to 9999999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as Determined by the Investigator using RECIST v1.1 for participants with LGG (Phase I and II)

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End point title

Duration of Response (DOR) as Determined by the Investigator using RECIST v1.1 for participants with LGG (Phase I and II)

End point description

Tumor assessment was performed using RECIST v1.1 criteria for participants with LGG. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here. The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type. 9999999, 0.0 to 9999999 = no participants experienced an event and DOR wasn't reached.

End point type

Secondary

End point timeframe

From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

End point values	Low Grade Glioma (Phase I and II)
Number of subjects analysed	3
Units: Months
median (confidence interval 95%)	9999999 (0.0 to 9999999)

No statistical analyses for this end point

Secondary: Recommended Phase II Dose (RP2D) of Cobimetinib

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End point title

Recommended Phase II Dose (RP2D) of Cobimetinib

End point description

A prior dose level was defined as an RP2D if at a certain dose level, there were greater than or equal to (≥) 2 out of 6 participants who had Dose Limiting Toxicities (DLTs).

End point type

Secondary

End point timeframe

Cycle 1 Day 1 up to Cycle 1 Day 28 (cycle length=28 days)

End point values	Cobimetinib (Suspension) Population
Number of subjects analysed	38
Units: mg/kg	1

No statistical analyses for this end point

Secondary: DOR as Determined by the Investigator RANO criteria for Participants with LGG (Phase II)

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End point title

DOR as Determined by the Investigator RANO criteria for Participants with LGG (Phase II)

End point description

Tumor assessment was performed using RANO criteria for Participants with LGG. The safety evaluable population was defined as all participants who received at least one dose of study drug. For phase II, only one tumor type cohort was opened (LGG). 9999999, 0.0 to 9999999 = no participants experienced an event and DOR wasn't reached.

End point type

Secondary

End point timeframe

From first occurrence of objective response to disease progression or death due to any cause, whichever occurs first (up to 5 years, 2 months)

End point values	Low Grade Glioma (Phase II)
Number of subjects analysed	1
Units: Months
median (confidence interval 95%)	9999999 (0.0 to 9999999)

No statistical analyses for this end point

Secondary: Overall Survival (OS) for Participants with Neuroblastoma (Phase I)

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End point title

Overall Survival (OS) for Participants with Neuroblastoma (Phase I)

End point description

OS was defined as the time from initiation of study drug to death from any cause. The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type. 0.0 to 9999999 = The 95% confidence interval could not be calculated from the data of one participant.

End point type

Secondary

End point timeframe

Baseline until death due to any cause (up to 5 years, 2 months)

End point values	Neuroblastoma
Number of subjects analysed	1
Units: Months
median (confidence interval 95%)	4.6 (0.0 to 9999999)

No statistical analyses for this end point

Secondary: OS for Participants with High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II)

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End point title

OS for Participants with High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II)

End point description

OS was defined as the time from initiation of study drug to death from any cause. While the data for LGG in the phase II cohort is presented separately in other parts of the record, it was also considered useful to combine the data for LGG from phase I and phase II, which was done here. The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. For phase II, only one tumor type cohort was opened (LGG). As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type. 9999999 = The upper limit cannot be calculated due to insufficient number of events. (HGG) 9999999, 0.0 to 9999999 = No participants experienced an event and DOR was not reached (LGG)

End point type

Secondary

End point timeframe

Baseline until death due to any cause (up to 5 years, 2 months)

End point values	High Grade Glioma	Low Grade Glioma (Phase I and II)
Number of subjects analysed	5	32
Units: Months
median (confidence interval 95%)	1.4 (0.6 to 9999999)	9999999 (0.0 to 9999999)

No statistical analyses for this end point

Secondary: OS for Participants with All Other Tumours (Phase I)

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End point title

OS for Participants with All Other Tumours (Phase I)

End point description

OS was defined as the time from initiation of study drug to death from any cause. The safety evaluable population was defined as all participants who received at least one dose of study drug. Participants enrolled into phase I (Dose-Escalation) cohorts independent of their tumor type. As the same criteria were not used to assess response in all tumor types, the efficacy analyses were broken down by tumor type. 9999999 = The median and 95% confidence interval could not be calculated from the data due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

Baseline until death due to any cause (up to 5 years, 2 months)

End point values	Dnet In Noonan's Syn Tumr (RAS/RAF/MEK/ERK Pathway Activation)	Malignant Peripheral Nerve Sheath Tumor	Metstic Mdstnl Ylksc Tumr (RAS/RAF/MEK/ERK Pathway Activation)	Non-Rhabdomyosarcoma Soft Tissue Sarcoma	Plexiform Neurofibroma	Rhabdoid Tumor/ATRT
Number of subjects analysed	1	2	1	1	12	1
Units: Months
median (confidence interval 95%)	9999999 (0.0 to 9999999)	5.5 (0.8 to 9999999)	1.1 (0.0 to 9999999)	6.3 (0.0 to 9999999)	9999999 (0.0 to 9999999)	5.1 (0.0 to 9999999)

No statistical analyses for this end point

Secondary: Maximum Plasma Concentration Observed (Cmax) of Cobimetinib

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End point title

Maximum Plasma Concentration Observed (Cmax) of Cobimetinib

End point description

Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Cmax.

End point type

Secondary

End point timeframe

Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (predose=within 4 hours prior to dose; cycle length=28 days)

End point values	Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population)	Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population)	Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population)	Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
Number of subjects analysed	6	6	6	6	7	8	5	12
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n= 6,5,6,6,7,8,4,9)	62.0 ± 82.3	88.3 ± 102	144 ± 58.6	51.5 ± 73.4	67.4 ± 165	136 ± 80.3	111 ± 37.0	44.0 ± 69.8
Cycle 1 Day 21 (n= 5,5,6,6,7,8,4,9)	51.1 ± 74.0	181 ± 134	193 ± 35.0	105 ± 84.5	156 ± 91.2	179 ± 113	172 ± 60.3	116 ± 42

No statistical analyses for this end point

Secondary: Time to Cmax (Tmax) of Cobimetinib

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End point title

Time to Cmax (Tmax) of Cobimetinib

End point description

Plasma samples for determination of Cobimetinib concentration will be collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1. The sampling will allow determination of Tmax.

End point type

Secondary

End point timeframe

Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days)

End point values	Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population)	Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population)	Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population)	Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
Number of subjects analysed	6	6	6	6	7	8	5	12
Units: hr
median (full range (min-max))
Cycle 1 Day 1 (n= 6,5,6,6,7,8,4,9)	4 (2 to 6)	2 (2 to 6)	3 (2 to 4)	4 (2 to 6)	4 (2 to 6)	2 (2 to 4)	5 (2 to 6)	4 (2 to 6)
Cycle 1 Day 21 (n= 5,5,5,6,6,8,2,9)	4 (2 to 6)	4 (2 to 6)	2 (2 to 4)	4 (2 to 6)	2 (2 to 4)	3 (2 to 6)	4 (4 to 4)	2 (2 to 6)

No statistical analyses for this end point

Secondary: Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib

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End point title

Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib

End point description

End point type

Secondary

End point timeframe

Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21 (pre-dose=within 4 hours prior to dose; cycle length=28 days)

End point values	Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population)	Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population)	Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population)	Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
Number of subjects analysed	6	6	6	6	7	8	5	12
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (n= 6,5,6,6,6,8,3,9)	865 ± 83.0	1006 ± 100	1432 ± 50.0	743 ± 67.4	1111 ± 144	1627 ± 74.0	1567 ± 33.1	589 ± 79.5
Cycle 1 Day 21 (n= 5,5,5,6,6,8,2,9)	836 ± 83.5	2802 ± 111	2382 ± 38.4	1624 ± 80.4	1805 ± 109	2562 ± 104	2511 ± 104	1402 ± 59

No statistical analyses for this end point

Secondary: Apparent Clearance (CL/F) of Cobimetinib

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End point title

Apparent Clearance (CL/F) of Cobimetinib

End point description

Plasma samples for determination of Cobimetinib concentration were collected prior to dosing and at 2, 4, 6 and 24 hours after dosing on Days 1 and 21 of Cycle 1, and within 4 hours prior to dosing on Day 1 of Cycle 2. Please note that for this Outcome Measure, the Apparent Clearance of Cobimetinib could not be calculated/estimated as PK samples were collected only up to 24hr post dosing. 9999999 = The Apparent Clearance of Cobimetinib could not be calculated/estimated as PK samples were collected only up to 24hr post dosing which resulted in insufficient data to calculate CL/F.

End point type

Secondary

End point timeframe

Pre-dose, 2, 4, 6, and 24 hours post-dose on Cycle 1 Days 1 and 21; pre-dose on Cycle 2 Day 1 (pre-dose=within 4 hours prior to dose; cycle length=28 days)

End point values	Phase I (Tablet) Cobimetinib (0.6 mg/kg) (PK Population)	Phase I (Tablet) Cobimetinib (0.8 mg/kg) (PK Population)	Phase I (Tablet) Cobimetinib (1 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (0.6 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (0.8 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (1 mg/kg) (PK Population)	Phase I (Suspension) Cobimetinib (1.33 mg/kg) (PK Population)	Phase II (Suspension) Cobimetinib (1 mg/kg) (PK Population)
Number of subjects analysed	6	6	6	6	7	8	5	12
Units: L/hr
geometric mean (geometric coefficient of variation)	9999999 ± 9999999	9999999 ± 9999999	9999999 ± 9999999	9999999 ± 9999999	9999999 ± 9999999	9999999 ± 9999999	9999999 ± 9999999	9999999 ± 9999999

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up until 30 days after the last dose of study drug (up to 5 years, 2 months)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Phase I (Tablet) Cobimetinib (0.6 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Tablet) Cobimetinib (0.8 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Tablet) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (0.6 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.6 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (0.8 mg/kg)

Reporting group description

Dose-Escalation: Participants received 0.8 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase I (Suspension) Cobimetinib (1.33 mg/kg)

Reporting group description

Dose-Escalation: Participants received 1.33 milligrams per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Reporting group title

Phase II (Suspension) Cobimetinib (1 mg/kg)

Reporting group description

Dose-Expansion: Participants received 1 milligram per kilogram (mg/kg) cobimetinib orally once daily on Days 1 to 21 of each 28-day treatment cycle.

Serious adverse events	Phase I (Tablet) Cobimetinib (0.6 mg/kg)	Phase I (Tablet) Cobimetinib (0.8 mg/kg)	Phase I (Tablet) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (0.6 mg/kg)	Phase I (Suspension) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (0.8 mg/kg)	Phase I (Suspension) Cobimetinib (1.33 mg/kg)	Phase II (Suspension) Cobimetinib (1 mg/kg)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 6 (33.33%)	2 / 8 (25.00%)	1 / 7 (14.29%)	2 / 5 (40.00%)	5 / 12 (41.67%)
number of deaths (all causes)	2	2	1	2	2	2	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Femoral neck fracture
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac ventricular thrombosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Headache
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Chorioretinopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pneumothorax
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paronychia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Catheter site infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Phase I (Tablet) Cobimetinib (0.6 mg/kg)	Phase I (Tablet) Cobimetinib (0.8 mg/kg)	Phase I (Tablet) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (0.6 mg/kg)	Phase I (Suspension) Cobimetinib (1 mg/kg)	Phase I (Suspension) Cobimetinib (0.8 mg/kg)	Phase I (Suspension) Cobimetinib (1.33 mg/kg)	Phase II (Suspension) Cobimetinib (1 mg/kg)
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 6 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	8 / 8 (100.00%)	7 / 7 (100.00%)	5 / 5 (100.00%)	12 / 12 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	0	0	0	1
Hair follicle tumour benign
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	0	1
General disorders and administration site conditions
Gait disturbance
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Chest pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	2	0	0	0
Fatigue
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	3 / 6 (50.00%)	2 / 6 (33.33%)	3 / 8 (37.50%)	2 / 7 (28.57%)	1 / 5 (20.00%)	2 / 12 (16.67%)
occurrences all number	2	2	5	2	3	3	1	2
Inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Localised oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Xerosis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Nodule
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Asthenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	2
Mucosal inflammation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Extravasation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Malaise
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Pyrexia
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 8 (25.00%)	1 / 7 (14.29%)	2 / 5 (40.00%)	3 / 12 (25.00%)
occurrences all number	2	2	3	1	2	1	3	5
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Reproductive system and breast disorders
Balanoposthitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Scrotal ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Vulvovaginal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	4 / 12 (33.33%)
occurrences all number	3	1	2	1	0	1	1	5
Dyspnoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	3	0	0	0	2	0	0	0
Nasal congestion
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	2	0	2	0	0	0	1
Pleural effusion
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	1	1	2	0	0	0	1	1
Rhinorrhoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Pneumonia aspiration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Cough
subjects affected / exposed	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 6 (16.67%)	2 / 6 (33.33%)	1 / 8 (12.50%)	1 / 7 (14.29%)	0 / 5 (0.00%)	3 / 12 (25.00%)
occurrences all number	3	4	1	2	1	1	0	5
Sputum decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	1	0	1	0
Behaviour disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Anxiety
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	1	0
Inappropriate affect
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	2
Bradyphrenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Investigations
Blood bicarbonate decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	0	0	0	2
Ejection fraction decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	3	1	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	2
Blood chloride increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	3
Aspartate aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1	0	0	2	1
White blood cell count decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 7 (28.57%)	0 / 5 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	9	0	0	0	3	0	8
Blood creatinine decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Anion gap increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	3
Lymphocyte count decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 7 (14.29%)	0 / 5 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	0	4	1	1	0	4
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Body temperature decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Platelet count increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	2
Cortisol decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Intraocular pressure increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	1	0	0
Neutrophil count decreased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 7 (28.57%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	7	0	0	0	3	0	5
Transaminases increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Protein total decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	3
Blood creatinine increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	1	1	0	0
Mean cell volume increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Lymphocyte count increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 7 (28.57%)	0 / 5 (0.00%)	4 / 12 (33.33%)
occurrences all number	0	0	3	1	1	3	0	8
White blood cell count increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Body temperature increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Oxygen saturation decreased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Weight increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	0	0	0	0	0	2
Blood cholesterol increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Platelet count decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Alanine aminotransferase increased
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	2 / 5 (40.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	3	0
Neutrophil count increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	1
Injury, poisoning and procedural complications
Skin abrasion
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 7 (14.29%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	2	0	1	1	0	1
Face injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Thermal burn
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Wrist fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	1
Foreign body in ear
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Hand fracture
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Contusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	3	0	1	0	0	0
Limb injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0
Arthropod bite
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Ligament sprain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Foot fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Head injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	5	0	0	0	0	0
Skin laceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Tooth fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Fall
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	0	0	4	0	1	0	1	1
Abdominal injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Skin wound
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Congenital, familial and genetic disorders
Iris hamartoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Nervous system disorders
Headache
subjects affected / exposed	3 / 6 (50.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	2 / 6 (33.33%)	4 / 8 (50.00%)	3 / 7 (42.86%)	3 / 5 (60.00%)	7 / 12 (58.33%)
occurrences all number	5	4	2	4	4	8	5	11
Dizziness
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	1	0	2	0	0	0	1	0
Paraesthesia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	4	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Lethargy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Neuralgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Leukopenia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	3 / 12 (25.00%)
occurrences all number	0	7	0	3	0	0	0	6
Lymphadenopathy
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 8 (25.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	1	1	1	3	0	0	2
Eye disorders
Retinal detachment
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Conjunctivitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Ocular hyperaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0
Punctate keratitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	0	0	1
Ocular hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Miosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Detachment of retinal pigment epithelium
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Optic disc disorder
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Visual acuity reduced transiently
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Serous retinal detachment
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	2	0
Retinal disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Corneal neovascularisation
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Optic atrophy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Dry eye
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0
Visual impairment
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Eye pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0
Eye disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Visual field defect
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Eyelid skin dryness
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Eyelid ptosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Chorioretinopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0
Gastrointestinal disorders
Toothache
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Dyspepsia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Tongue ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	0	1	1	0	0	1	4	2
Lip haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Vomiting
subjects affected / exposed	1 / 6 (16.67%)	2 / 6 (33.33%)	4 / 6 (66.67%)	2 / 6 (33.33%)	4 / 8 (50.00%)	2 / 7 (28.57%)	2 / 5 (40.00%)	7 / 12 (58.33%)
occurrences all number	1	4	9	2	7	9	2	14
Anal haemorrhage
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Constipation
subjects affected / exposed	3 / 6 (50.00%)	2 / 6 (33.33%)	3 / 6 (50.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	3 / 12 (25.00%)
occurrences all number	3	3	5	0	3	0	1	3
Lip ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Glossodynia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Oesophagitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Haematochezia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Proctalgia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Dry mouth
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	3 / 6 (50.00%)	0 / 6 (0.00%)	3 / 8 (37.50%)	2 / 7 (28.57%)	0 / 5 (0.00%)	2 / 12 (16.67%)
occurrences all number	2	1	3	0	5	7	0	2
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Gastritis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Dental caries
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Abdominal distension
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Stomatitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	1	1	0
Faeces hard
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Tooth impacted
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Abdominal pain
subjects affected / exposed	2 / 6 (33.33%)	3 / 6 (50.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 7 (28.57%)	2 / 5 (40.00%)	3 / 12 (25.00%)
occurrences all number	2	3	2	1	1	2	2	7
Diarrhoea
subjects affected / exposed	3 / 6 (50.00%)	4 / 6 (66.67%)	5 / 6 (83.33%)	4 / 6 (66.67%)	4 / 8 (50.00%)	2 / 7 (28.57%)	4 / 5 (80.00%)	4 / 12 (33.33%)
occurrences all number	5	17	8	6	6	3	10	11
Mouth ulceration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0
Aphthous ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Anorectal discomfort
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Skin and subcutaneous tissue disorders
Papule
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Rash
subjects affected / exposed	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 7 (28.57%)	1 / 5 (20.00%)	2 / 12 (16.67%)
occurrences all number	0	5	2	1	1	2	1	2
Skin fissures
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Hyperkeratosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Pruritus
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	1	0	1	0
Rash papular
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	1	0	0	2
Dermatitis atopic
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	0	0	1
Telangiectasia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Rash erythematous
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	0	0	0	1
Skin lesion
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Eczema
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 7 (14.29%)	0 / 5 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	1	1	1	1	1	0	2
Rash maculo-papular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	1	5	0	0	1
Dermatitis contact
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Acne
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	1	1	0
Eczema asteatotic
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Photosensitivity reaction
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Hirsutism
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Xeroderma
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Skin ulcer
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Onychomadesis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0
Ingrowing nail
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0
Hand dermatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Rash macular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Miliaria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Dandruff
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	2
Skin mass
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Alopecia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0
Hyperhidrosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Seborrhoea
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Purpura
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	2
Dermatitis acneiform
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 7 (14.29%)	3 / 5 (60.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	1	1	1	3	1
Dry skin
subjects affected / exposed	2 / 6 (33.33%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	2 / 8 (25.00%)	3 / 7 (42.86%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	6	2	2	0	2	3	2	1
Erythema
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	1	0	1	0	1	0	0
Pityriasis alba
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Renal and urinary disorders
Urinary incontinence
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0
Urinary hesitation
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Acute kidney injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	2
Urinary tract pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Micturition urgency
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0
Pollakiuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	2	0	0	0	0	1
Urinary retention
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0
Polyuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Dysuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	0	0	0	1
Endocrine disorders
Precocious puberty
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	1	2	0	0
Pain in extremity
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 8 (0.00%)	2 / 7 (28.57%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	1	6	0	0	3	1	0
Back pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	2 / 8 (25.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	6	0	2	1	0	0
Arthralgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 8 (25.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	4	1	2	0	0	0
Groin pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Joint swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	1	0	0	0
Spinal deformity
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Pain in jaw
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Flank pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Infections and infestations
Scarlet fever
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	2 / 12 (16.67%)
occurrences all number	0	1	1	0	0	0	1	2
Rhinitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Catheter site infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	1
Anorectal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Hand-foot-and-mouth disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0
Viral tonsillitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Viral infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	1	0	0	0
COVID-19
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Tonsillitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Fungal skin infection
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0
Paronychia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	1 / 8 (12.50%)	1 / 7 (14.29%)	1 / 5 (20.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	2	1	1	1	2
Rash pustular
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	0	0	1
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	5	0	0	0	2	0
Varicella
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 7 (14.29%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	1	1	0	1
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	1	0	0	0	0	2
Localised infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Rhinovirus infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Skin infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	1	0	2	0
Ear infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Oral herpes
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0
H1N1 influenza
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Folliculitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	1	0	1	0	0
Oral candidiasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	1	0	0	1	0	2
Suspected COVID-19
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	1
Hordeolum
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Influenza
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	1	0	1	0	0	0	1	1
Impetigo
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0
Nail infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Otitis media
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Pharyngitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	1	0	0	2	0	0	1
Staphylococcal infection
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0
Metabolism and nutrition disorders
Glucose tolerance impaired
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	3	0	1	0	1	0	0
Hyperkalaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Dehydration
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Hypophosphataemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Hypoalbuminaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0
Hypomagnesaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	2 / 7 (28.57%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	1	0	5	0	2	0	0
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 7 (0.00%)	1 / 5 (20.00%)	0 / 12 (0.00%)
occurrences all number	0	4	0	6	0	0	1	0
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	5	0	0	0	0
Hypernatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 7 (14.29%)	0 / 5 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hyperuricaemia
subjects affected / exposed	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 7 (0.00%)	0 / 5 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	0	0	2
Decreased appetite
subjects affected / exposed	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 6 (33.33%)	0 / 6 (0.00%)	2 / 8 (25.00%)	2 / 7 (28.57%)	1 / 5 (20.00%)	1 / 12 (8.33%)
occurrences all number	1	1	2	0	2	2	1	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

18 May 2015

Following updates were made: [1] Addition of complete rationale for using both tablet and liquid formulations; [2] Modification of guidance regarding frequency and nature of ophthalmology examinations; [3] Clarification of PK Outcome Measure; [4] Updates to Inclusion/Exclusion Criteria and [5] Addition of Safety Analysis.

05 Aug 2015

Following updates were made: [1] Removal of Liquid Formulation from study, so only Tablet Formulation to be kept; [2] Addition of Enrolment restrictions; [3] Modification of Dose Escalation rules; [4] Change in Starting Dose of Dose Escalation from 0.8 mg/kg/day to 0.6 mg/kg/day and [5] Dose-Limiting Toxicity (DLT) updates.

02 Feb 2016

Following updates were made: [1] Removal of references to perception of clinical benefit; [2] Updating of cardiac function DLT rules; [3] Updating of Intrapatient dose escalation guidance and [4] Clarification of Dose reduction guidance.

15 Jun 2016

Following updates were made: [1] Addition of new Suspension Formulation; [2] Updates to Safety Information regarding Cobimetinib and [3] Additional Study Changes.

03 Nov 2016

Following updates were made: [1] Updated to align with most current available data with regards to the risks associated to Cobimetinib; [2] Updates to list of defined DLTs during the Dose Escalation phase; [3] Addition of new Eligibility Criteria; [4] Modification to International Neuroblastoma Response Criteria (INRC) used in this study; [5] Clarification of de-escalation rules and [6] Clarifications to Appendix 1.

07 Feb 2017

Following updates were made: [1] Restoration of dose modification guidance; [2] Clarification to Inclusion criteria and [3] Additional information relating to intracerebral hemorrhage.

10 May 2017

Following updates were made: [1] Revisions made to determination of the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of each Cobimetinib formulation (tablet and suspension); [2] Clarification that enrolment of expansion cohorts may begin only after the IMC has reviewed pharmacokinetic (PK) and safety data and [3] Updates to include rationale for requiring a separate suspension dose escalation beginning at one level below that of the tablet MTD/MAD.

09 May 2018

Following updates were made: [1] Incorporation of Response Assessment in Neuro-Oncology (RANO) criteria for LGG; [2] Update to Inclusion Criteria; [3] Number of Study Subjects increased to approximately 70; [4] Updates to the interim efficacy analyses; [5] Updates to study stopping rules; [6] Clarification to Exclusion Criteria and [7] Updates to Appendix 5 and 10.

06 Jul 2018

Following update was made: [1] The objective response rate (ORR) for low-grade glioma (LGG) incorporating minor response, has been made an exploratory endpoint.

11 Apr 2019

Following updates were made: [1] Reduction in the frequency of tumor assessments for subjects who have completed at least 12 cycles of Cobimetinib therapy; [2] Plasma samples collection updated to align with the new tumor assessments schedule; [3] Reduction in the frequency of ophthalmologic examinations for subjects who have completed 6 cycles of Cobimetinib therapy and [4] Updates to Appendix 1 and 10.

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.

None reported

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Clinical trials

Clinical Trial Results: A Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Cobimetinib In Pediatric and Young Adult Patients with Previously Treated Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with Dose-Limiting Toxicities (DLTs)

Primary: Percentage of Participants with Dose-Limiting Toxicities (DLTs)

Primary: Percentage of Participants with Adverse Events (AEs), including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

Primary: Percentage of Participants with Adverse Events (AEs), including Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

Primary: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib

Primary: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of Cobimetinib

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants with Low-Grade Glioma (LGG) (Phase I and II)

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with High-Grade Glioma (HGG) (Phase I) and RECIST v1.1 for Participants with Low-Grade Glioma (LGG) (Phase I and II)

Primary: Percentage of Participants with Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator using modified International Neuroblastoma Response Criteria (mINRC) for Participants with Neuroblastoma (Phase I)

Primary: Percentage of Participants with Objective Response (Complete Response (CR) or Partial Response (PR)) as Determined by the Investigator using modified International Neuroblastoma Response Criteria (mINRC) for Participants with Neuroblastoma (Phase I)

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I)

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I)

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II)

Primary: Percentage of Participants with Objective Response (CR or PR) as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II)

Primary: Progression-Free Survival (PFS) as Determined by the Investigator using mINRC for Participants with Neuroblastoma (Phase I)

Primary: Progression-Free Survival (PFS) as Determined by the Investigator using mINRC for Participants with Neuroblastoma (Phase I)

Primary: PFS as Determined by the Investigator using RANO criteria for participants with HGG (Phase I) and RECIST v1.1 for partcipants with LGG (Phase I and II)

Primary: PFS as Determined by the Investigator using RANO criteria for participants with HGG (Phase I) and RECIST v1.1 for partcipants with LGG (Phase I and II)

Primary: PFS as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I)

Primary: PFS as Determined by the Investigator using RECIST v1.1 criteria for Participants with All Other Tumours (Phase I)

Primary: PFS as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II)

Primary: PFS as Determined by the Investigator using RANO criteria for Participants with LGG (Phase II)

Secondary: Duration of Response (DOR) as Determined by the Investigator using RECIST v1.1 for participants with LGG (Phase I and II)

Secondary: Duration of Response (DOR) as Determined by the Investigator using RECIST v1.1 for participants with LGG (Phase I and II)

Secondary: Recommended Phase II Dose (RP2D) of Cobimetinib

Secondary: Recommended Phase II Dose (RP2D) of Cobimetinib

Secondary: DOR as Determined by the Investigator RANO criteria for Participants with LGG (Phase II)

Secondary: DOR as Determined by the Investigator RANO criteria for Participants with LGG (Phase II)

Secondary: Overall Survival (OS) for Participants with Neuroblastoma (Phase I)

Secondary: Overall Survival (OS) for Participants with Neuroblastoma (Phase I)

Secondary: OS for Participants with High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II)

Secondary: OS for Participants with High-Grade Glioma (HGG) (Phase I) and Low-Grade Glioma (LGG) (Phase I and II)

Secondary: OS for Participants with All Other Tumours (Phase I)

Secondary: OS for Participants with All Other Tumours (Phase I)

Secondary: Maximum Plasma Concentration Observed (Cmax) of Cobimetinib

Secondary: Maximum Plasma Concentration Observed (Cmax) of Cobimetinib

Secondary: Time to Cmax (Tmax) of Cobimetinib

Secondary: Time to Cmax (Tmax) of Cobimetinib

Secondary: Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib

Secondary: Area Under the Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of Cobimetinib

Secondary: Apparent Clearance (CL/F) of Cobimetinib

Secondary: Apparent Clearance (CL/F) of Cobimetinib

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase I/II, Multicenter, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Cobimetinib In Pediatric and Young Adult Patients with Previously Treated Solid Tumors